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  • 1
    Publication Date: 2018-02-21
    Description: by Tomoko Fujii, Hiroyuki Oka, Junji Katsuhira, Juichi Tonosu, Satoshi Kasahara, Sakae Tanaka, Ko Matsudaira Depression is a relevant risk factor for low back pain and is associated with the outcomes of low back pain. Depression also often overlaps with somatisation. As previous studies have suggested that somatisation or a higher somatic symptom burden has a role in the outcomes of low back pain, the aim of the present cross-sectional study was to examine whether somatic symptom burden was associated with health-related quality of life in individuals with chronic low back pain independent of depression. We analyzed internet survey data on physical and mental health in Japanese adults aged 20–64 years with chronic low back pain (n = 3,100). Health-related quality of life was assessed using the EuroQol five dimensions (EQ-5D) questionnaire. Somatic symptom burden and depression were assessed using the Somatic Symptom Scale-8 (SSS-8) and the Patient Health Questionnaire-2 (PHQ-2), respectively. SSS-8 score was categorized as no to minimal (0–3), low (4–7), medium (8–11), high (12–15), and very high (16–32). The association between SSS-8 and EQ-5D was examined using linear regression models, adjusting for depression and other covariates, including age, sex, BMI, smoking, marital status, education, exercise, employment, and the number of comorbid diseases. A higher somatic symptom burden was significantly associated with a lower health-related quality of life independent of depression and the number of comorbid diseases (regression coefficient = 0.040 for SSS-8 high vs. very high and 0.218 for non to minimal vs. very high, p trend
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2018-02-21
    Description: by Shiyun Xiao, Wen Zhang, Nancy R. Manley The postnatal thymus is an efficient microenvironment for T cell specification and differentiation. B cells are also present in the thymus and have been recently shown to impact T cell selection, however, the mechanisms controlling B cell development in the thymus are largely unknown. In Foxn1 lacZ mutant mice, down-regulation of Foxn1 expression in thymic epithelial cells beginning 1 week after birth caused a dramatic reduction of T progenitors and an increase of B cell progenitors. This time point is coincident with the switch from fetal to adult-type hematopoietic stem cells (HSCs), which is regulated by the Lin28-Let7 system. We hypothesize that the thymic environment might regulate this process to suppress fetal-type B cell development in the thymus. In this study we show that in the Foxn1 lacZ thymus, although the down-regulation of Lin28 in thymocytes was normal, up-regulation of Let-7 was impaired. The failure to up-regulate Let-7 caused a transient increase of Arid3a in B precursors, which is known to promote fetal-type B cell fate. Over-expression of Lin28a in HSCs also reduced Let-7 and promoted Arid3a expression in BM and thymic B progenitors, increasing B cell production in the thymus. The level of Let-7 in thymic B progenitors was up regulated by in vitro co-culture with IL15, Vitamin-D3, and retinoic acid, thus down-regulating Arid3a to promote B cell differentiation. All of these signals were produced in thymic epithelial cells (TECs) related to Let-7 expression in thymic B progenitors, and down-regulated in Foxn1 lacZ mutants. Our data show that signals provided by TEC control thymic B cell development by up-regulating Let-7 , suppressing Arid3a expression in intrathymic progenitor B cells to limit their proliferation during the neonatal to adult transition.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2018-02-21
    Description: by Shiyun Xiao, Wen Zhang, Nancy R. Manley Background Hematopoietic stem cells (HSCs) derived from birth through adult possess differing differentiation potential for T or B cell fate in the thymus; neonatal bone marrow (BM) cells also have a higher potential for B cell production in BM compared to adult HSCs. We hypothesized that this hematopoietic-intrinsic B potential might also regulate B cell development in the thymus during ontogeny. Methods Foxn1 lacZ mutant mice are a model in which down regulation of a thymic epithelial cell (TEC) specific transcription factor beginning one week postnatal causes a dramatic reduction of thymocytes production. In this study, we found that while T cells were decreased, the frequency of thymic B cells was greatly increased in these mutants in the perinatal period. We used this model to characterize the mechanisms in the thymus controlling B cell development. Results Foxn1 lacZ mutants, T cell committed intrathymic progenitors (DN1a,b) were progressively reduced beginning one week after birth, while thymic B cells peaked at 3–4 weeks with pre-B-II progenitor phenotype, and originated in the thymus. Heterochronic chimeras showed that the capacity for thymic B cell production was due to a combination of higher B potential of neonatal HSCs, combined with a thymic microenvironment deficiency including reduction of DL4 and increase of IL-7 that promoted B cell fate. Conclusion Our findings indicate that the capacity and time course for thymic B-cell production are primarily controlled by the hematopoietic-intrinsic potential for B cells themselves during ontogeny, but that signals from TECs microenvironment also influence the frequency and differentiation potential of B cell development in the thymus.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2018-02-21
    Description: by Takayoshi Matsuda, Takuhiro Ito, Chie Takemoto, Kazushige Katsura, Mariko Ikeda, Motoaki Wakiyama, Mutsuko Kukimoto-Niino, Shigeyuki Yokoyama, Yoshikazu Kurosawa, Mikako Shirouzu Growing numbers of therapeutic antibodies offer excellent treatment strategies for many diseases. Elucidation of the interaction between a potential therapeutic antibody and its target protein by structural analysis reveals the mechanism of action and offers useful information for developing rational antibody designs for improved affinity. Here, we developed a rapid, high-yield cell-free system using dialysis mode to synthesize antibody fragments for the structural analysis of antibody–antigen complexes. Optimal synthesis conditions of fragments (Fv and Fab) of the anti-EGFR antibody 059–152 were rapidly determined in a day by using a 30-μl-scale unit. The concentration of supplemented disulfide isomerase, DsbC, was critical to obtaining soluble antibody fragments. The optimal conditions were directly applicable to a 9-ml-scale reaction, with linear scalable yields of more than 1 mg/ml. Analyses of purified 059-152-Fv and Fab showed that the cell-free synthesized antibody fragments were disulfide-bridged, with antigen binding activity comparable to that of clinical antibodies. Examination of the crystal structure of cell-free synthesized 059-152-Fv in complex with the extracellular domain of human EGFR revealed that the epitope of 059-152-Fv broadly covers the EGF binding surface on domain III, including residues that formed critical hydrogen bonds with EGF (Asp355 EGFR , Gln384 EGFR , H409 EGFR , and Lys465 EGFR ), so that the antibody inhibited EGFR activation. We further demonstrated the application of the cell-free system to site-specific integration of non-natural amino acids for antibody engineering, which would expand the availability of therapeutic antibodies based on structural information and rational design. This cell-free system could be an ideal antibody-fragment production platform for functional and structural analysis of potential therapeutic antibodies and for engineered antibody development.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
    Publication Date: 2018-02-21
    Description: by Erick González-Medina, José Alfredo Castillo-Guerrero, Sharon Zinah Herzka, Guillermo Fernández Understanding the role of diet in the physiological condition of adults during reproduction and hence its effect on reproductive performance is fundamental to understand reproductive strategies in long-lived animals. In birds, little is known about the influence of the quality of food consumed at the beginning of the reproductive period and its short-term effects on reproductive performance. To assess the role of diet in the physiological condition of female blue-footed booby, Sula nebouxii (BFBO), during reproduction we evaluated whether individual differences in diet (assessed by using δ 13 C and δ 15 N values of whole blood from female birds and muscle tissue of the principal prey species) prior to egg laying and during incubation influenced their lipid metabolic profile (measured as triglyceride levels and C:N ratio) and their reproductive performance (defined by laying date, clutch size and hatching success). Females with higher δ 15 N values in their blood during the courtship and incubation periods had a higher lipid metabolic profile, earlier laying date, greater clutch size (2–3 eggs) and higher hatching success. Females that laid earlier and more eggs (2–3 eggs) consumed more Pacific anchoveta ( Cetengraulis mysticetus ) and Pacific thread herring ( Opisthonema libertate ) than did other females. These two prey species also had high amounts of lipids (C:N ratio) and caloric content (Kcal/g fresh weight). The quality of food consumed by females at the beginning of reproduction affected their physiological condition, as well as their short-term reproductive performance. Our work emphasizes the importance of determining the influence of food quality during reproduction to understand the reproductive decisions and consequences in long-lived animals.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
    Publication Date: 2018-02-21
    Description: by Romain Irague, Christopher M. Topham, Nelly Martineau, Audrey Baylac, Clément Auriol, Thomas Walther, Jean-Marie François, Isabelle André, Magali Remaud-Siméon An end-point ADP/NAD + acid/alkali assay procedure, directly applicable to library screening of any type of ATP-utilising/ADP producing enzyme activity, was implemented. Typically, ADP production is coupled to NAD + co-enzyme formation by the conventional addition of pyruvate kinase and lactate dehydrogenase. Transformation of enzymatically generated NAD + into a photometrically active alkali derivative product is then achieved through the successive application of acidic/alkali treatment steps. The assay was successfully miniaturized to search for malate kinase activity in a structurally-guided library of LysC aspartate kinase variants comprising 6,700 clones. The screening procedure enabled the isolation of nine positive variants showing novel kinase activity on (L)-malate, the best mutant, LysC V115A:E119S:E434V exhibited strong substrate selectivity for (L)-malate compared to (L)-aspartate with a ( k cat / K m ) malate /( k cat / K m ) aspartate ratio of 86. Double mutants V115A:E119S, V115A:E119C and E119S:E434V were constructed to further probe the origins of stabilising substrate binding energy gains for (L)-malate due to mutation. The introduction of less sterically hindering side-chains in engineered enzymes carrying E119S and V115A mutations increases the effective volume available for substrate binding in the catalytic pocket. Improved binding of the (L)-malate substrate may be assisted by less hindered movement of the Phe184 aromatic side-chain. Additional favourable long-range electostatic effects on binding arising from the E434V surface mutation are conditionally dependent upon the presence of the V115A mutation close to Phe184 in the active-site.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
    Publication Date: 2018-02-21
    Description: by Chenlong He, Zuren Feng, Zhigang Ren In this paper, we propose a connectivity-preserving flocking algorithm for multi-agent systems in which the neighbor set of each agent is determined by the hybrid metric-topological distance so that the interaction topology can be represented as the range-limited Delaunay graph, which combines the properties of the commonly used disk graph and Delaunay graph. As a result, the proposed flocking algorithm has the following advantages over the existing ones. First, range-limited Delaunay graph is sparser than the disk graph so that the information exchange among agents is reduced significantly. Second, some links irrelevant to the connectivity can be dynamically deleted during the evolution of the system. Thus, the proposed flocking algorithm is more flexible than existing algorithms, where links are not allowed to be disconnected once they are created. Finally, the multi-agent system spontaneously generates a regular quasi-lattice formation without imposing the constraint on the ratio of the sensing range of the agent to the desired distance between two adjacent agents. With the interaction topology induced by the hybrid distance, the proposed flocking algorithm can still be implemented in a distributed manner. We prove that the proposed flocking algorithm can steer the multi-agent system to a stable flocking motion, provided the initial interaction topology of multi-agent systems is connected and the hysteresis in link addition is smaller than a derived upper bound. The correctness and effectiveness of the proposed algorithm are verified by extensive numerical simulations, where the flocking algorithms based on the disk and Delaunay graph are compared.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2018-02-21
    Description: by Tomaz Crochemore, Thiago Domingos Corrêa, Marcus D. Lance, Cristina Solomon, Ary Serpa Neto, João Carlos de Campos Guerra, Priscila Scolmeister Lellis, Livia Muller Bernz, Natalia Nunes, Cassio Massashi Mancio, Ana Paula Hitomi Yokoyama, Eliézer Silva Background Transfusion therapy is associated with increased morbidity, mortality and costs. Conventional coagulation tests (CCT) are weak bleeding predictors, poorly reflecting coagulation in vivo. Thromboelastometry (ROTEM) provides early identification of coagulation disorders and can guide transfusion therapy by goals, reducing blood components transfusion. Objective The aim of this study is to describe coagulation profile of critically ill patients using ROTEM and evaluate the association between CCT and thromboelastometry. Methods This is a retrospective, observational study conducted in medical-surgical intensive care unit (ICU). Adult patients (≥18 years) admitted to ICU between November 2012 and December 2014, in whom ROTEM analyses were performed for bleeding management were included in this study. The first ROTEM and CCT after ICU admission were recorded simultaneously. Additionally, we collected data on blood components transfusion and hemostatic agents immediately after laboratory tests results. Results The study included 531 patients. Most ROTEM tests showed normal coagulation profile [INTEM (54.8%), EXTEM (54.1%) and FIBTEM (53.3%)] with divergent results in relation to CCT: low platelet count (51.8% in INTEM and 55.9% in EXTEM); prolonged aPTT (69.9% in INTEM and 63.7% in EXTEM) and higher INR (23.8% in INTEM and 27.4% in EXTEM). However 16,7% of patients with normocoagulability in ROTEM received platelet concentrates and 10% fresh frozen plasma. Conclusion The predominant ROTEM profile observed in this sample of critically ill patients was normal. In contrast, CCT suggested coagulopathy leading to a possibly unnecessary allogenic blood component transfusion. ROTEM test may avoid inappropriate allogeneic blood products transfusion in these patients.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-21
    Description: by Min-Ju Kim, Gyeyoon Yim, Hyun-Young Park Background Sleep disturbance is one of the common complaints in menopause. This study investigated the relationship between menopausal symptoms and sleep quality in middle-aged women. Method This cross-sectional observational study involved 634 women aged 44–56 years attending a healthcare center at Kangbuk Samsung Hospitals. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI).Multiple linear regression analysis was performed to assess the associations between Menopause-specific Quality of Life (MENQOL) scores and PSQI scores and Menopause-specific Quality of Life (MENQOL)scores. Results The mean PSQI score was 3.6±2.3, and the rates of poor sleep quality(PSQI score 〉 5) in premenopausal, perimenopausal, and postmenopausal women were 14.4%, 18.2%, and 30.2%, respectively. Total PSQI score, specifically the sleep latency, habitual sleep efficiency and sleep disturbances scores, were significantly increased in postmenopausal women. Multiple linear regression analysis adjusted for age, BMI, hypertension, diabetes, smoking, marital status, family income, education, employment status, parity, physical activity, depression symptoms, perceived stress and menopausal status showed that higher PSQI score was positively correlated with higher vasomotor(ß = 0.240, P = 0.020)and physical(ß = 0.572, P
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2018-02-21
    Description: by Masaharu Iwasaki, Petra Minder, Yíngyún Caì, Jens H. Kuhn, John R. Yates III, Bruce E. Torbett, Juan C. de la Torre Several mammalian arenaviruses (mammarenaviruses) cause hemorrhagic fevers in humans and pose serious public health concerns in their endemic regions. Additionally, mounting evidence indicates that the worldwide-distributed, prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. Concerns about human-pathogenic mammarenaviruses are exacerbated by of the lack of licensed vaccines, and current anti-mammarenavirus therapy is limited to off-label use of ribavirin that is only partially effective. Detailed understanding of virus/host-cell interactions may facilitate the development of novel anti-mammarenavirus strategies by targeting components of the host-cell machinery that are required for efficient virus multiplication. Here we document the generation of a recombinant LCMV encoding a nucleoprotein (NP) containing an affinity tag (rLCMV/Strep-NP) and its use to capture the NP-interactome in infected cells. Our proteomic approach combined with genetics and pharmacological validation assays identified ATPase Na + /K + transporting subunit alpha 1 (ATP1A1) and prohibitin (PHB) as pro-viral factors. Cell-based assays revealed that ATP1A1 and PHB are involved in different steps of the virus life cycle. Accordingly, we observed a synergistic inhibitory effect on LCMV multiplication with a combination of ATP1A1 and PHB inhibitors. We show that ATP1A1 inhibitors suppress multiplication of Lassa virus and Candid#1, a live-attenuated vaccine strain of Junín virus, suggesting that the requirement of ATP1A1 in virus multiplication is conserved among genetically distantly related mammarenaviruses. Our findings suggest that clinically approved inhibitors of ATP1A1, like digoxin, could be repurposed to treat infections by mammarenaviruses pathogenic for humans.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 11
    Publication Date: 2018-02-22
    Description: by Óscar Herrero, Mónica Aquilino, Paloma Sánchez-Argüello, Rosario Planelló Bisphenol S (BPS) is an industrial alternative to the endocrine disruptor bisphenol A (BPA), and can be found in many products labeled “BPA-free”. Its use has grown in recent years, and presently it is considered a ubiquitous emerging pollutant. To date there is a lack of information on the effects of BPS on invertebrates, although they represent more than 95% of known species in the animal kingdom and are crucial for the structure and proper function of ecosystems. In this study, real-time RT-PCR was used to determine the early detrimental effects of BPS on the transcriptional rate of genes in the model species Chironomus riparius , specifically those related to the ecdysone pathway ( EcR , ERR , E74 , Vtg , cyp18a1 ) crucial for insect development and metamorphosis, stress and biotransformation mechanisms ( hsp70 , hsp40 , cyp4g , GPx , GSTd3 ) that regulate adaptive responses and determine survival, and ribosome biogenesis ( its2 , rpL4 , rpL13 ) which is essential for protein synthesis and homeostasis. While 24-hour exposure to 0.5, 5, 50, and 500 μg/L BPS had no effect on larval survival, almost all the studied genes were upregulated following a non-monotonic dose-response curve. Genes with the greatest increases in transcriptional activity (fold change relative to control) were EcR (3.8), ERR (2), E74 (2.4), cyp18a1 (2.5), hsp70 (1.7), hsp40 (2.5), cyp4g (6.4), GPx (1.8), and GST (2.1), while others including Vtg , GAPDH , and selected ribosomal genes remained stable. We also measured the transcriptional activity of these genes 24 hours after BPS withdrawal and a general downregulation compared to controls was observed, though not significant in most cases. Our findings showed that BPS exposure altered the transcriptional profile of these genes, which may have consequences for the hormone system and several metabolic pathways. Although further research is needed to elucidate its mode of action, these results raise new concerns about the safety of BPA alternatives.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
    Publication Date: 2018-02-22
    Description: by Linnéa Lagerstedt, Juan José Egea-Guerrero, Ana Rodríguez-Rodríguez, Alejandro Bustamante, Joan Montaner, Amir El Rahal, Elisabeth Andereggen, Lara Rinaldi, Asita Sarrafzadeh, Karl Schaller, Jean-Charles Sanchez Traumatic brain injury is a common event where 70%–90% will be classified as mild TBI (mTBI). Among these, only 10% will have a brain lesion visible via CT scan. A triage biomarker would help clinicians to identify patients with mTBI who are at risk of developing a brain lesion and require a CT scan. The brain cells damaged by the shearing, tearing and stretching of a TBI event set off inflammation cascades. These cause altered concentrations of a high number of both pro-inflammatory and anti-inflammatory proteins. This study aimed to discover a novel diagnostic biomarker of mTBI by investigating a broad panel of inflammation biomarkers and their capacity to correctly identify CT-positive and CT-negative patients. Patients enrolled in this study had been diagnosed with mTBI, had a GCS score of 15 and suffered from at least one clinical symptom. There were nine patients in the discovery group, 45 for verification, and 133 mTBI patients from two different European sites in the validation cohort. All patients gave blood samples, underwent a CT scan and were dichotomised into CT-positive and CT-negative groups for statistical analyses. The ability of each protein to classify patients was evaluated with sensitivity set at 100%. Three of the 92 inflammation proteins screened—MCP-1, MIP-1alpha and IL-10 –were further investigated in the verification group, and at 100% sensitivity their specificities reached 7%, 0% and 31%, respectively. IL-10 was validated on a larger cohort in comparison to the most studied mTBI diagnostic triage protein to date, S100B. Levels of both proteins were significantly higher in CT-positive than in CT-negative patients (p 〈 0.001). S100B’s specificity at 100% sensitivity was 18% (95% CI 10.8–25.2), whereas IL-10 reached a specificity of 27% (95% CI 18.9–35.1). These results showed that IL-10 might be an interesting and clinically useful diagnostic tool, capable of differentiating between CT-positive and CT-negative mTBI patients.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
    Publication Date: 2018-02-22
    Description: by Gabriel Velez, Daniel A. Machlab, Peter H. Tang, Yang Sun, Stephen H. Tsang, Alexander G. Bassuk, Vinit B. Mahajan Differences in regional protein expression within the human retina may explain molecular predisposition of specific regions to ophthalmic diseases like age-related macular degeneration, cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy. To quantify protein levels in the human retina and identify patterns of differentially-expressed proteins, we collected foveomacular, juxta-macular, and peripheral retina punch biopsies from healthy donor eyes and analyzed protein content by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression was analyzed with 1-way ANOVA, gene ontology, pathway representation, and network analysis. We identified a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina. Six hundred ninety-seven differentially-expressed proteins included those unique to and abundant in each anatomic region. Proteins with higher expression in each region include: heat-shock protein 90-alpha (HSP90AA1), and pyruvate kinase (PKM) in the foveomacular retina; vimentin (VIM) and fructose-bisphosphate aldolase C (ALDOC); and guanine nucleotide-binding protein subunit beta-1 (GNB1) and guanine nucleotide-binding protein subunit alpha-1 (GNAT1) in the peripheral retina. Pathway analysis identified downstream mediators of the integrin signaling pathway to be highly represented in the foveomacular region (P = 6.48 e–06). Metabolic pathways were differentially expressed among all retinal regions. Gene ontology analysis showed that proteins related to antioxidant activity were higher in the juxta-macular and the peripheral retina, but present in lower amounts in the foveomacular retina. Our proteomic analysis suggests that certain retinal regions are susceptible to different forms of metabolic and oxidative stress. The findings give mechanistic insight into retina function, reveal important molecular processes, and prioritize new pathways for therapeutic targeting.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
    Publication Date: 2018-02-22
    Description: by Rachel Ravago-Gotanco, Talna Lorena de la Cruz, Ma. Josefa Pante, Philippe Borsa The taxonomy of the mottled rabbitfish Siganus fuscescens species complex has long been challenging. In this study, we analyzed microsatellite genotypes, mitochondrial lineages, and morphometric data from 373 S . fuscescens individuals sampled from the northern Philippines and Hong Kong (South China Sea, Philippine Sea and Sulu Sea basins), to examine putative species boundaries in samples comprising three co-occurring mitochondrial lineages previously reported to characterize S . fuscescens (Clade A and Clade B) or S . canaliculatus (Clade C). We report the existence of two cryptic species within S . fuscescens in the northeast region of the South China Sea and northern Philippine Sea, supported by genetic and morphological differences. Individual-based assignment methods recovered concordant groupings of individuals into two nuclear genotype clusters (Cluster 1, Cluster 2) with (1) limited gene flow, if any, between them ( F ST = 0.241; P 〈 0.001); (2) low frequency of later-generation hybrids; (3) significant association with mitochondrial Clade A and Clade B, respectively; and (4) subtle yet significant body shape differences as inferred from geometric morphometric analysis. The divergence between mitochondrial Clade C and the two other clades was not matched by genetic differences at microsatellite marker loci. The occurrence of discordant mitonuclear combinations (20.5% of the total number of individuals) is thought to result from mitochondrial introgression, consistent with a scenario of demographic, and presumably spatial, post-Pleistocene expansion of populations from northern regions into a secondary contact zone in the South China Sea. Mitonuclear discordance due to introgression obscures phylogenetic relationships for recently-diverged lineages, and cautions against the use of mitochondrial markers alone for species identification within the mottled rabbitfish species complex in the South China Sea region.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 15
    Publication Date: 2018-02-22
    Description: by Hatice Gulcin Gumus, Miriam Illa, Laura Pla, Monica Zamora, Fatima Crispi, Eduard Gratacos Objective To evaluate the perinatal effects of a prenatal therapy based on intra-amniotic nutritional supplementation in a rabbit model of intrauterine growth restriction (IUGR). Methods IUGR was surgically induced in pregnant rabbits at gestational day 25 by ligating 40–50% of uteroplacental vessels of each gestational sac. At the same time, modified-parenteral nutrition solution (containing glucose, amino acids and electrolytes) was injected into the amniotic sac of nearly half of the IUGR fetuses (IUGR-T group n = 106), whereas sham injections were performed in the rest of fetuses (IUGR group n = 118). A control group without IUGR induction but sham injection was also included (n = 115). Five days after the ligation procedure, a cesarean section was performed to evaluate fetal cardiac function, survival and birth weight. Results Survival was significantly improved in the IUGR fetuses that were treated with intra-amniotic nutritional supplementation as compared to non-treated IUGR animals (survival rate: controls 71% vs. IUGR 44% p = 0.003 and IUGR-T 63% vs. IUGR 44% p = 0.02), whereas, birth weight (controls mean 43g ± SD 9 vs. IUGR 36g ± SD 9 vs. IUGR-T 35g ± SD 8, p = 0.001) and fetal cardiac function were similar among the IUGR groups. Conclusion Intra-amniotic injection of a modified-parenteral nutrient solution appears to be a promising therapy for reducing mortality among IUGR. These results provide an opportunity to develop new intra-amniotic nutritional strategies to reach the fetus by bypassing the placental insufficiency.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
    Publication Date: 2018-02-22
    Description: by Lyvianne Decourtye, Maud Clemessy, Erik Mire, Tatiana Ledent, Laurence Périn, Iain C. Robinson, Yves Le Bouc, Laurent Kappeler Nutrition plays a critical role in programming and shaping linear growth during early postnatal life through direct action on the development of the neuroendocrine somatotropic (GH/IGF-1) axis. IGF-1 is a key factor in modulating the programming of linear growth during this period. Notably, IGF-1 preferentially stimulates axonal growth of GHRH neurons in the arcuate nucleus of the hypothalamus (Arc), which is crucial for the proliferation of somatotroph progenitors in the pituitary, thus influencing later GH secretory capacity. However, other nutrition-related hormones may also be involved. Among them, insulin shares several structural and functional similarities with IGF-1, as well as downstream signaling effectors. We investigated the role of insulin in the control of Arc axonal growth using an in vitro model of arcuate explants culture and a cell-type specific approach (GHRH-eGFP mice) under both physiological conditions (normally fed pups) and those of dietary restriction (underfed pups). Our data suggest that insulin failed to directly control axonal growth of Arc neurons or influence specific IGF-1-mediated effects on GHRH neurons. Insulin may act on neuronal welfare, which appears to be dependent on neuronal sub-populations and is influenced by the nutritional status of pups in which Arc neurons develop.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
    Publication Date: 2018-02-22
    Description: by Marco Franceschini, Michela Goffredo, Sanaz Pournajaf, Stefano Paravati, Maurizio Agosti, Francesco De Pisi, Daniele Galafate, Federico Posteraro Background Upper limb recovery is one of the main goals of post-stroke rehabilitation due to its importance for autonomy in Activities of Daily Living (ADL). Although the efficacy of upper limb Robot-assisted Therapy (RT) is well established in literature, the impact of the initial status of the patient on the effects of RT is still understudied. This paper aims to identify whether demographic, clinical and motor characteristics of stroke patients may influence the ability to independently perform ADL after RT. Methods A retrospective study was conducted on sixty stroke patients who conducted planar upper limb goal-directed tasks with the InMotion 2.0 robot. The RT was administered 5 days/week for 4 weeks and each session lasted 45 minutes. The primary outcome measure was the Modified Barthel Index (BI), dichotomized into favourable (BI ≥75) and unfavourable (BI
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-22
    Description: by Eman Hassan Beshr, Hazem Abdelghany, Mahmoud Eteiba This paper presents a novel optimization technique for energy management studies of an isolated microgrid. The system is supplied by various Distributed Energy Resources (DERs), Diesel Generator (DG), a Wind Turbine Generator (WTG), Photovoltaic (PV) arrays and supported by fuel cell/electrolyzer Hydrogen storage system for short term storage. Multi-objective optimization is used through non-dominated sorting genetic algorithm to suit the load requirements under the given constraints. A novel multi-objective flower pollination algorithm is utilized to check the results. The Pros and cons of the two optimization techniques are compared and evaluated. An isolated microgrid is modelled using MATLAB software package, dispatch of active/reactive power, optimal load flow analysis with slack bus selection are carried out to be able to minimize fuel cost and line losses under realistic constraints. The performance of the system is studied and analyzed during both summer and winter conditions and three case studies are presented for each condition. The modified IEEE 15 bus system is used to validate the proposed algorithm.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 19
    Publication Date: 2018-02-22
    Description: by Bridget S. Fisher, Richard R. Green, Rachel R. Brown, Matthew P. Wood, Tiffany Hensley-McBain, Cole Fisher, Jean Chang, Andrew D. Miller, William J. Bosche, Jeffrey D. Lifson, Maud Mavigner, Charlene J. Miller, Michael Gale Jr., Guido Silvestri, Ann Chahroudi, Nichole R. Klatt, Donald L. Sodora Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 20
    Publication Date: 2018-02-22
    Description: by Yufeng Yang, Yannan Wang, Licong Jia, Guohong Yang, Xinzhi Xu, Hong Zhai, Shaozhen He, Junxia Li, Xiaodong Dai, Na Qin, Cancan Zhu, Qingchang Liu Previously, we obtained the sweetpotato somatic hybrid KT1 from a cross between sweetpotato ( Ipomoea batatas (L.) Lam.) cv. Kokei No. 14 and its drought-tolerant wild relative I . triloba L. KT1 not only inherited the thick storage root characteristic of Kokei No. 14 but also the drought-tolerance trait of I . triloba L. The aim of this study was to explore the molecular mechanism of the drought tolerance of KT1. Four-week-old in vitro -grown plants of KT1, Kokei No. 14, and I . triloba L. were subjected to a simulated drought stress treatment (30% PEG6000) for 0, 6, 12 and 24 h. Total RNA was extracted from samples at each time point, and then used for transcriptome sequencing. The gene transcript profiles of KT1 and its parents were compared to identify differentially expressed genes, and drought-related modules were screened by a weighted gene co-expression network analysis. The functions of ABI-like protein and Ca 2+ -ATPase, two proteins screened from the cyan and light yellow modules, were analyzed in terms of their potential roles in drought tolerance in KT1 and its parents. These analyses of the drought responses of KT1 and its somatic donors at the transcriptional level provide new annotations for the molecular mechanism of drought tolerance in the somatic hybrid KT1 and its parents.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 21
    Publication Date: 2018-02-23
    Description: by Rachel O. Coats, Raymond J. Holt, Geoffrey P. Bingham, Mark A. Mon-Williams The duration of reach-to-grasp movements is influenced by the size of the contact surfaces, such that grasping objects with smaller contact surface areas takes longer. But what is the influence of asymmetric contact surfaces? In Experiment 1a, participants reached-to-lift wooden blocks off a table top, with the contact locations for the thumb and index finger varying in surface size. The time taken to lift the block was driven primarily by the thumb contact surface, which showed a larger effect size for the dependent variable of movement duration than the index finger’s contact surface. In Experiment 1b participants reached-to-grasp (but not lift) the blocks. The same effect was found with duration being largely driven by contact surface size for the thumb. Experiment 2 tested whether this finding generalised to movements towards conical frusta grasped in a different plane mounted off the table top. Experiment 2 showed that movement duration again was dictated primarily by the size of the thumb’s contact surface. The thumb contact surface was the visible surface in experiments 1 and 2 so Experiment 3 explored grasping when the index finger’s contact surface was visible (participants grasped the frusta with the index finger at the top). An interaction between thumb and finger surface size was now found to determine movement duration. These findings provide the first empirical report of the impact of asymmetric contact surfaces on prehension, and may have implications for scientists who wish to model reach-to-grasp behaviours.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 22
    Publication Date: 2018-02-23
    Description: by Chonticha Saisawang, Atichat Kuadkitkan, Prasert Auewarakul, Duncan R. Smith, Albert J. Ketterman It has been estimated for dengue infection that the global population at risk is 3.5 billion people, which makes dengue an important public health problem. The causative agents of dengue are dengue viruses. For dengue virus replication, the dengue virus NS5 protein is of special importance as it has several enzyme activities important for viral replication. Previous reports of phosphorylation and SUMOylation of dengue NS5 have shown these protein modifications have important consequences for NS5 functions. In this report we identify glutathionylation, another reversible post translation modification that impacts on NS5 enzyme activity. Using dengue virus infected cells we employed specific antibodies and mass spectrometry to identify 3 cysteine residues of NS5 protein as being glutathionylated. Glutathionylation is a post translational protein modification where glutathione is covalently attached to a cysteine residue. We showed glutathionylation occurs on 3 conserved cysteine residues of dengue NS5. Then we generated two flavivirus recombinant full length proteins, dengue NS5 and Zika NS5, to characterize two of the NS5 enzyme activities, namely, guanylyltransferase and RNA-dependent RNA polymerase activities. We show glutathionylation of dengue and Zika NS5 affects enzyme activities of the two flavivirus proteins. The data suggests that glutathionylation is a general feature of the flavivirus NS5 protein and the modification has the potential to modulate several of the NS5 enzyme functions.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
    Publication Date: 2018-02-23
    Description: by Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-Johan Jakobsson, Jon Lampa The cholinergic anti-inflammatory pathway (CAP) is an innate neural reflex where parasympathetic and sympathetic nerves work jointly to control inflammation. Activation of CAP by vagus nerve stimulation (VNS) has paved way for novel therapeutic strategies in treating inflammatory diseases. Recently, we discovered that VNS mediated splenic acetylcholine (ACh) release and subsequent immunosuppression in response to LPS associated inflammation is impaired in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1) expression, a key enzyme responsible for prostaglandin E2 synthesis. Here, we have further investigated the consequences of mPGES-1 deficiency on various molecular/cellular events in the spleen which is critical for the optimal functioning of VNS in endotoxaemic mice. First, VNS induced splenic norepinephrine (NE) release in both mPGES-1 (+/+) and (-/-) mice. Compared to mPGES-1 (+/+), immunomodulatory effects of NE on cytokines were strongly compromised in mPGES-1 (-/-) splenocytes. Interestingly, while LPS increased choline acetyltransferase (ChAT) protein level in mPGES-1 (+/+) splenocytes, it failed to exert similar effects in mPGES-1 (-/-) splenocytes despite unaltered β 2 AR protein expression. In addition, nicotine inhibited TNFα release by LPS activated mPGES-1 (+/+) splenocytes in vitro . However, such immunosuppressive effects of nicotine were reversed both in mPGES-1 (-/-) mouse splenocytes and human PBMC treated with mPGES-1 inhibitor. In summary, our data implicate PGE2 as an important mediator of ACh synthesis and noradrenergic/cholinergic molecular events in the spleen that constitute a crucial part of the CAP immune regulation. Our results suggest a possible link between cholinergic and PG system of CAP that may be of clinical significance in VNS treatment.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 24
    Publication Date: 2018-02-23
    Description: by Abraham Lwidiko, Stephen Matthew Kibusi, Azan Nyundo, Bonaventura C. T. Mpondo Background Children and adolescents continue to have HIV/AIDS in southern Saharan Africa. Scaling up of HIV services has significantly improved access to ARV and consequently improved on morbidity and mortality related to HIV/AIDS including opportunistic infection. Despite the above efforts, non-communicable conditions including mental disorders such as depression have been observed to contribute to the burden of disabilities about which little is documented. This study, therefore, aimed to determine the magnitude of depressive symptoms and the associated factors among HIV-infected children and adolescents. Methods The study was a matched case-control design involving 300 cases of HIV-infected children matched by age and sex against 600 uninfected controls. Systematic sampling technique was used to select the cases while multistage sampling technique was employed to identify villages/ streets purposive and sampling technique was employed to obtain participants from households. Results The overall prevalence of depressive symptoms among the cohort of 900 participants was found to be 12.9%, with 27% of HIV-infected and 5.8% of HIV-uninfected children and adolescents screened positive for depressive symptoms. Multiple logistic regression revealed that being HIV-infected (AOR 1.96(1.11–3.45)), residing in a rural setting (AOR 0.61(0.39–0.96)) and history of childhood deprivation (AOR 4.76 (2.79–8.13)) were significantly associated with depressive symptoms. Conclusion HIV infected adolescents are more affected by depression compared to non-infected counterparts. Childhood deprivation was significantly associated with presence of depressive symptoms. Integration of mental health evaluation and treatment into the HIV care provided for adolescents can be beneficial. More studies to delineate factors associated with depressed adolescents with HIV may add value to the body of knowledge and overall improvement of care.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 25
    Publication Date: 2018-02-23
    Description: by Miguel J. Divo, Bartolome R. Celli, Beatriz Poblador-Plou, Amaia Calderón-Larrañaga, Juan Pablo de-Torres, Luis A. Gimeno-Feliu, Juan Bertó, Javier J. Zulueta, Ciro Casanova, Victor M. Pinto-Plata, Carlos Cabrera-Lopez, Francesca Polverino, Jonás Carmona Píréz, Alexandra Prados-Torres, Jose M. Marin, on behalf of the EpiChron—BODE Collaborative Group Background Aging is an important risk factor for most chronic diseases. Patients with COPD develop more comorbidities than non-COPD subjects. We hypothesized that the development of comorbidities characteristically affecting the elderly occur at an earlier age in subjects with the diagnosis of COPD. Methods and findings We included all subjects carrying the diagnosis of COPD (n = 27,617), and a similar number of age and sex matched individuals without the diagnosis, extracted from the 727,241 records of individuals 40 years and older included in the EpiChron Cohort (Aragon, Spain). We compared the cumulative number of comorbidities, their prevalence and the mortality risk between both groups. Using network analysis, we explored the connectivity between comorbidities and the most influential comorbidities in both groups. We divided the groups into 5 incremental age categories and compared their comorbidity networks. We then selected those comorbidities known to affect primarily the elderly and compared their prevalence across the 5 age groups. In addition, we replicated the analysis in the smokers’ subgroup to correct for the confounding effect of cigarette smoking. Subjects with COPD had more comorbidities and died at a younger age compared to controls. Comparison of both cohorts across 5 incremental age groups showed that the number of comorbidities, the prevalence of diseases characteristic of aging and network’s density for the COPD group aged 56–65 were similar to those of non-COPD 15 to 20 years older. The findings persisted after adjusting for smoking. Conclusion Multimorbidity increases with age but in patients carrying the diagnosis of COPD, these comorbidities are seen at an earlier age.
    Electronic ISSN: 1932-6203
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  • 26
    Publication Date: 2018-02-23
    Description: by Sílvia Abril, Mireia Diaz, Alain Lenoir, Carolina Ivon Paris, Raphaël Boulay, Crisanto Gómez In insect societies, chemical communication plays an important role in colony reproduction and individual social status. Many studies have indicated that cuticular hydrocarbons (CHCs) are the main chemical compounds encoding reproductive status. However, these studies have largely focused on queenless or monogynous species whose workers are capable of egg laying and have mainly explored the mechanisms underlying queen-worker or worker-worker reproductive conflicts. Less is known about what occurs in highly polygynous ant species with permanently sterile workers. Here, we used the Argentine ant as a model to examine the role of CHCs in communicating reproductive information in such insect societies. The Argentine ant is unicolonial, highly polygynous, and polydomous. We identified several CHCs whose presence and levels were correlated with queen age, reproductive status, and fertility. Our results also provide new insights into queen executions in the Argentine ant, a distinctive feature displayed by this species in its introduced range. Each spring, just before new sexuals appear, workers eliminate up to 90% of the mated queens in their colonies. We discovered that queens that survived execution had different CHC profiles from queens present before and during execution. More specifically, levels of some CHCs were higher in the survivors, suggesting that workers could eliminate queens based on their chemical profiles. In addition, queen CHC profiles differed based on season and species range (native vs. introduced). Overall, the results of this study provide new evidence that CHCs serve as queen signals and do more than just regulate worker reproduction.
    Electronic ISSN: 1932-6203
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  • 27
    Publication Date: 2018-02-23
    Description: by Taina Conrad, Robert J. Paxton, Günter Assum, Manfred Ayasse In some insect species, females may base their choice for a suitable mate on male odor. In the red mason bee, Osmia bicornis , female choice is based on a male’s odor bouquet as well as its thorax vibrations, and its relatedness to the female, a putative form of optimal outbreeding. Interestingly, O . bicornis can be found as two distinct color morphs in Europe, which are thought to represent subspecies and between which we hypothesize that female discrimination may be particularly marked. Here we investigated (i) if these two colors morphs do indeed represent distinct, reproductively differentiated populations, (ii) how odor bouquets of male O . bicornis vary within and between populations, and (iii) whether variation in male odor correlates with genetic distance, which might represent a cue by which females could optimally outbreed. Using GC and GC-MS analysis of male odors and microsatellite analysis of males and females from 9 populations, we show that, in Denmark, an area of subspecies sympatry, the two color morphs at any one site do not differ, either in odor bouquet or in population genetic differentiation. Yet populations across Europe are distinct in their odor profile as well as being genetically differentiated. Odor differences do not, however, mirror genetic differentiation between populations. We hypothesize that populations from Germany, England and Denmark may be under sexual selection through female choice for local odor profiles, which are not related to color morph though which could ultimately lead to population divergence and speciation.
    Electronic ISSN: 1932-6203
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  • 28
    Publication Date: 2018-02-23
    Description: by Alexandra A. Portnova, Gaurav Mukherjee, Keshia M. Peters, Ann Yamane, Katherine M. Steele Assistive technology, such as wrist-driven orthoses (WDOs), can be used by individuals with spinal cord injury to improve hand function. A lack of innovation and challenges in obtaining WDOs have limited their use. These orthoses can be heavy and uncomfortable for users and also time-consuming for orthotists to fabricate. The goal of this research was to design a WDO with user (N = 3) and orthotist (N = 6) feedback to improve the accessibility, customizability, and function of WDOs by harnessing advancements in 3D-printing. The 3D-printed WDO reduced hands-on assembly time to approximately 1.5 hours and the material costs to $15 compared to current fabrication methods. Varying improvements in users' hand function were observed during functional tests, such as the Jebsen Taylor Hand Function Test. For example, one participant's ability on the small object task improved by 29 seconds with the WDO, while another participant took 25 seconds longer to complete this task with the WDO. Two users had a significant increase in grasp strength with the WDO (13–122% increase), while the other participant was able to perform a pinching grasp for the first time. The WDO designs are available open-source to increase accessibility and encourage future innovation.
    Electronic ISSN: 1932-6203
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  • 29
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-23
    Description: by Tom Brown, Nick Brown, Elliott J. Stollar A need exists to develop bioinformatics for predicting differences in protein function, especially for members of a domain family who share a common fold, yet are found in a diverse array of proteins. Many domain families have been conserved over large evolutionary spans and representative genomic data during these periods are now available. This allows a simple method for grouping domain sequences to reveal common and unique/specific binding residues. As such, we hypothesize that sequence alignment analysis of the yeast SH3 domain family across ancestral species in the fungal kingdom can determine whether each member encodes specific information to bind unique peptide targets. With this approach, we identify important specific residues for a given domain as those that show little conservation within an alignment of yeast domain family members (paralogs) but are conserved in an alignment of its direct relatives (orthologs). We find most of the yeast SH3 domain family members have maintained unique amino acid conservation patterns that suggest they bind peptide targets with high intrinsic specificity through varying degrees of non-canonical recognition. For a minority of domains, we predict a less diverse binding surface, likely requiring additional factors to bind targets specifically. We observe that our predictions are consistent with high throughput binding data, which suggests our approach can probe intrinsic binding specificity in any other interaction domain family that is maintained during evolution.
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  • 30
    Publication Date: 2018-02-23
    Description: by Meha Bhatt, Stefan Perera, Laura Zielinski, Rebecca B. Eisen, Sharon Yeung, Wala El-Sheikh, Jane DeJesus, Sumathy Rangarajan, Heather Sholer, Elizabeth Iordan, Pam Mackie, Shofiqul Islam, Mahshid Dehghan, Lehana Thabane, Zainab Samaan Background Suicidal behaviour remains challenging for clinicians to predict, with few established risk factors and warning signs among psychiatric patients. Aim We aimed to describe characteristics and identify risk factors for suicide attempts among patients with psychiatric disorders. Methods Multivariable logistic regression analysis, adjusted for clinically important confounders, was employed to determine risk factors for suicide attempts within a psychiatric patient population. Results The case (n = 146) and control groups (n = 104) did not differ significantly with regards to sociodemographic characteristics. The majority of the participants who had attempted suicide did so with high intent to die, and expected to die without medical intervention. The primary method of attempt was pharmaceutical overdose among the case participants (73.3%). Results showed impulsivity (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.03–1.30) and borderline personality symptoms (OR = 1.07, 95% CI = 1.01–1.13) were significantly associated with attempted suicide. Conclusions Our findings indicate that known sociodemographic risk factors for suicide may not apply within psychiatric populations. Prevention strategies for suicidal behaviour in psychiatric patients may be effective, including limited access to means for suicide attempts (i.e. excess pharmaceutical drugs) and target screening for high-risk personality and impulsivity traits.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 31
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-23
    Description: by Ksenia S. Onufrieva, Alexey V. Onufriev An accurate quantitative relationship between key characteristics of an insect population, such as season-long and peak abundances, can be very useful in pest management programs. To the best of our knowledge, no such relationship has yet been established. Here we establish a predictive linear relationship between insect catch M pw during the week of peak abundance, the length of seasonal flight period, F (number of weeks) and season-long cumulative catch (abundance) A = 0.41 M pw F . The derivation of the equation is based on several general assumptions and does not involve fitting to experimental data, which implies generality of the result. A quantitative criterion for the validity of the model is presented. The equation was tested using extensive data collected on captures of male gypsy moths Lymantria dispar (L.) (Lepidoptera: Erebidae) in pheromone-baited traps during 15 years. The model was also tested using trap catch data for two species of mosquitoes, Culex pipiens (L.) (Diptera: Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae), in Gravid and BG-sentinel mosquito traps, respectively. The simple, parameter-free equation approximates experimental data points with relative error of 13% and R 2 = 0.997, across all of the species tested. For gypsy moth, we also related season-long and weekly trap catches to the daily trap catches during peak flight. We describe several usage scenarios, in which the derived relationships are employed to help link results of small-scale field studies to the operational pest management programs.
    Electronic ISSN: 1932-6203
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  • 32
    Publication Date: 2018-02-23
    Description: by Thamir Alandijany, Ashley P. E. Roberts, Kristen L. Conn, Colin Loney, Steven McFarlane, Anne Orr, Chris Boutell
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  • 33
    Publication Date: 2018-02-23
    Description: by Dayse Távora-Vieira, Andre Wedekind, Roberta Marino, Suzanne C. Purdy, Gunesh P. Rajan Objectives To assess the use of cortical auditory evoked potentials (CAEPs) to verify, and if necessary, optimize the cochlear implant (CI) fitting of adult CI users with postlingual single-sided deafness (SSD). Methods Sound field cortical responses to the speech tokens /m/, /g/, /t/, and /s/ were recorded from input to the CI while the normal hearing ear was masked. Responses were evaluated by visual inspection and classified as presence or absence of the CAEPs components P1, N1, P2. In case of an absence fitting was adjusted accordingly. After fitting, subjects were asked to use their new setting for 2–3 weeks for acclimatization purposes and then return for retesting. At retesting, new CAEP recordings were performed to objectively ensure that the new fitting maps effectively activated the auditory cortex. Results In 14/19 subjects, as per visual inspection, clear CAEPs were recorded by each speech token and were, therefore, not refit. In the other 5 subjects, CAEPs could not be evoked for at least one speech token. The fitting maps in these subjects were adjusted until clear CAEPs were evoked for all 4 speech tokens. Conclusions CAEP can be used to quickly and objectively verify the suitability of CI fitting in experienced adult CI users with SSD. If used in the early post-implantation stage, this method could help CI users derive greater benefit for CI use and, therefore, be more committed to auditory training.
    Electronic ISSN: 1932-6203
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  • 34
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-23
    Description: by Jennifer Claire Hoving
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  • 35
    Publication Date: 2018-02-23
    Description: by Louise E. Hogan, Joshua Vasquez, Kristen S. Hobbs, Emily Hanhauser, Brandon Aguilar-Rodriguez, Rajaa Hussien, Cassandra Thanh, Erica A. Gibson, Alexander B. Carvidi, Louis C. B. Smith, Shahzada Khan, Martin Trapecar, Shomyseh Sanjabi, Ma Somsouk, Cheryl A. Stoddart, Daniel R. Kuritzkes, Steven G. Deeks, Timothy J. Henrich HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ART are urgently needed. Here, we demonstrate that CD4 + T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4 + lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.
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  • 36
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-23
    Description: by Jarrod J. Mousa, Elad Binshtein, Stacey Human, Rachel H. Fong, Gabriela Alvarado, Benjamin J. Doranz, Martin L. Moore, Melanie D. Ohi, James E. Crowe Jr. Respiratory syncytial virus (RSV) is a major human pathogen that infects the majority of children by two years of age. The RSV fusion (F) protein is a primary target of human antibodies, and it has several antigenic regions capable of inducing neutralizing antibodies. Antigenic site IV is preserved in both the pre-fusion and post-fusion conformations of RSV F. Antibodies to antigenic site IV have been described that bind and neutralize both RSV and human metapneumovirus (hMPV). To explore the diversity of binding modes at antigenic site IV, we generated a panel of four new human monoclonal antibodies (mAbs) and competition-binding suggested the mAbs bind at antigenic site IV. Mutagenesis experiments revealed that binding and neutralization of two mAbs (3M3 and 6F18) depended on arginine (R) residue R429. We discovered two R429-independent mAbs (17E10 and 2N6) at this site that neutralized an RSV R429A mutant strain, and one of these mAbs (17E10) neutralized both RSV and hMPV. To determine the mechanism of cross-reactivity, we performed competition-binding, recombinant protein mutagenesis, peptide binding, and electron microscopy experiments. It was determined that the human cross-reactive mAb 17E10 binds to RSV F with a binding pose similar to 101F, which may be indicative of cross-reactivity with hMPV F. The data presented provide new concepts in RSV immune recognition and vaccine design, as we describe the novel idea that binding pose may influence mAb cross-reactivity between RSV and hMPV. Characterization of the site IV epitope bound by human antibodies may inform the design of a pan-Pneumovirus vaccine.
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  • 37
    Publication Date: 2018-02-23
    Description: by Marco Biddau, Anne Bouchut, Jack Major, Tracy Saveria, Julie Tottey, Ojore Oka, Marcel van-Lith, Katherine Elizabeth Jennings, Jana Ovciarikova, Amy DeRocher, Boris Striepen, Ross Frederick Waller, Marilyn Parsons, Lilach Sheiner Apicomplexan parasites are global killers, being the causative agents of diseases like toxoplasmosis and malaria. These parasites are known to be hypersensitive to redox imbalance, yet little is understood about the cellular roles of their various redox regulators. The apicoplast, an essential plastid organelle, is a verified apicomplexan drug target. Nuclear-encoded apicoplast proteins traffic through the ER and multiple apicoplast sub-compartments to their place of function. We propose that thioredoxins contribute to the control of protein trafficking and of protein function within these apicoplast compartments. We studied the role of two Toxoplasma gondii apicoplast thioredoxins ( Tg ATrx), both essential for parasite survival. By describing the cellular phenotypes of the conditional depletion of either of these redox regulated enzymes we show that each of them contributes to a different apicoplast biogenesis pathway. We provide evidence for Tg ATrx1’s involvement in ER to apicoplast trafficking and Tg ATrx2 in the control of apicoplast gene expression components. Substrate pull-down further recognizes gene expression factors that interact with Tg ATrx2. We use genetic complementation to demonstrate that the function of both Tg ATrxs is dependent on their disulphide exchange activity. Finally, Tg ATrx2 is divergent from human thioredoxins. We demonstrate its activity in vitro thus providing scope for drug screening. Our study represents the first functional characterization of thioredoxins in Toxoplasma , highlights the importance of redox regulation of apicoplast functions and provides new tools to study redox biology in these parasites.
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  • 38
    Publication Date: 2018-02-23
    Description: by Ying Wang, Craig L. Zirbel, Neocles B. Leontis, Biao Ding
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  • 39
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-23
    Description: by Lei Sun, Helen K. Alexander, Balazs Bogos, Daniel J. Kiviet, Martin Ackermann, Sebastian Bonhoeffer Whether mutations in bacteria exhibit a noticeable delay before expressing their corresponding mutant phenotype was discussed intensively in the 1940s to 1950s, but the discussion eventually waned for lack of supportive evidence and perceived incompatibility with observed mutant distributions in fluctuation tests. Phenotypic delay in bacteria is widely assumed to be negligible, despite the lack of direct evidence. Here, we revisited the question using recombineering to introduce antibiotic resistance mutations into E . coli at defined time points and then tracking expression of the corresponding mutant phenotype over time. Contrary to previous assumptions, we found a substantial median phenotypic delay of three to four generations. We provided evidence that the primary source of this delay is multifork replication causing cells to be effectively polyploid, whereby wild-type gene copies transiently mask the phenotype of recessive mutant gene copies in the same cell. Using modeling and simulation methods, we explored the consequences of effective polyploidy for mutation rate estimation by fluctuation tests and sequencing-based methods. For recessive mutations, despite the substantial phenotypic delay, the per-copy or per-genome mutation rate is accurately estimated. However, the per-cell rate cannot be estimated by existing methods. Finally, with a mathematical model, we showed that effective polyploidy increases the frequency of costly recessive mutations in the standing genetic variation (SGV), and thus their potential contribution to evolutionary adaptation, while drastically reducing the chance that de novo recessive mutations can rescue populations facing a harsh environmental change such as antibiotic treatment. Overall, we have identified phenotypic delay and effective polyploidy as previously overlooked but essential components in bacterial evolvability, including antibiotic resistance evolution.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 40
    Publication Date: 2018-02-23
    Description: by Edgar Herrera-Delgado, Ruben Perez-Carrasco, James Briscoe, Peter Sollich Gene regulatory networks (GRNs) control cellular function and decision making during tissue development and homeostasis. Mathematical tools based on dynamical systems theory are often used to model these networks, but the size and complexity of these models mean that their behaviour is not always intuitive and the underlying mechanisms can be difficult to decipher. For this reason, methods that simplify and aid exploration of complex networks are necessary. To this end we develop a broadly applicable form of the Zwanzig-Mori projection. By first converting a thermodynamic state ensemble model of gene regulation into mass action reactions we derive a general method that produces a set of time evolution equations for a subset of components of a network. The influence of the rest of the network, the bulk, is captured by memory functions that describe how the subnetwork reacts to its own past state via components in the bulk. These memory functions provide probes of near-steady state dynamics, revealing information not easily accessible otherwise. We illustrate the method on a simple cross-repressive transcriptional motif to show that memory functions not only simplify the analysis of the subnetwork but also have a natural interpretation. We then apply the approach to a GRN from the vertebrate neural tube, a well characterised developmental transcriptional network composed of four interacting transcription factors. The memory functions reveal the function of specific links within the neural tube network and identify features of the regulatory structure that specifically increase the robustness of the network to initial conditions. Taken together, the study provides evidence that Zwanzig-Mori projections offer powerful and effective tools for simplifying and exploring the behaviour of GRNs.
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  • 41
    Publication Date: 2018-02-23
    Description: by Pin-Nan Cheng, Yen-Cheng Chiu, Hung-Chih Chiu, Shih-Chieh Chien Background Control of hepatitis C virus infection (HCV) is an increasingly important issue. Enhancing screening coverage is necessary to discover more HCV infected subjects in community. However, a substantial population is unaware of HCV infection that needs more attention. Aim The aims of this study were to evaluate the status of HCV infected residents in remote villages, to compare characteristics between already known and unaware HCV infection subjects, and to analyze the disease insights. Patients and methods Screening intervention for liver diseases was conducted in remote villages of Tainan City of southern Taiwan from August 2014 to July 2016. Items of screening examinations included questionnaire, blood sampling for liver tests and viral hepatitis markers (hepatitis B surface antigen and anti-HCV antibody), abdominal sonography survey, and liver stiffness measurement by transient elastography. Quantitation of HCV RNA was measured for residents with positive anti-HCV antibody. Results A total of 194 (13.5%) out of 1439 participants showed positive for anti-HCV antibody. HCV viremia was detected in 119 (61.3%) residents. Previously unaware HCV infection by questionnaire record was present in 68 (35.1%) of ant-HCV positive residents. By multivariate logistic analysis, unaware HCV infected residents exhibited significantly mild liver fibrosis (OR 0.876, 95% CI 0.782~0.981, p = 0.022), more prevalent of heart diseases (OR 6.082, 95% CI 1.963~18.839, p = 0.002), and less cluster of family history of liver diseases (OR 0.291, 95% CI 0.113~0.750, p = 0.011) when comparing with already known HCV infected residents. Among the 126 already know HCV infected residents, only 59 (46.8%) received antiviral treatment or regular follow-up. No concept or no willing to receive medical care was observed in 44 (34.9%) residents. Conclusion In HCV endemic villages of Taiwan, residents with unaware HCV infection comprised about one third of HCV infected residents and exhibited obscure characteristics to identify. Less than half of already known HCV infected residents received adequate medical care. To eliminate HCV infection, vigorous efforts on enhancing screening coverage, educating update knowledge of liver diseases, and linking to medical care are urgently needed.
    Electronic ISSN: 1932-6203
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  • 42
    Publication Date: 2018-02-24
    Description: by Emma Karlsson, Jae Ho Shin, Gunnar Westman, Leif A. Eriksson, Lisbeth Olsson, Valeria Mapelli The biobased production of adipic acid, a precursor in the production of nylon, is of great interest in order to replace the current petrochemical production route. Glucose-rich lignocellulosic raw materials have high potential to replace the petrochemical raw material. A number of metabolic pathways have been proposed for the microbial conversion of glucose to adipic acid, but achieved yields and titers remain to be improved before industrial applications are feasible. One proposed pathway starts with lysine, an essential metabolite industrially produced from glucose by microorganisms. However, the drawback of this pathway is that several reactions are involved where there is no known efficient enzyme. By changing the order of the enzymatic reactions, we were able to identify an alternative pathway with one unknown enzyme less compared to the original pathway. One of the reactions lacking known enzymes is the reduction of the unsaturated α,β bond of 6-amino- trans -2-hexenoic acid and trans -2-hexenedioic acid. To identify the necessary enzymes, we selected N -ethylmaleimide reductase from Escherichia coli and Old Yellow Enzyme 1 from Saccharomyces pastorianus . Despite successful in silico docking studies, where both target substrates could fit in the enzyme pockets, and hydrogen bonds with catalytic residues of both enzymes were predicted, no in vitro activity was observed. We hypothesize that the lack of activity is due to a difference in electron withdrawing potential between the naturally reduced aldehyde and the carboxylate groups of our target substrates. Suggestions for protein engineering to induce the reactions are discussed, as well as the advantages and disadvantages of the two metabolic pathways from lysine. We have highlighted bottlenecks associated with the lysine pathways, and proposed ways of addressing them.
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  • 43
    Publication Date: 2018-02-24
    Description: by Dionysios C. Watson, Eirini Moysi, Antonio Valentin, Cristina Bergamaschi, Santhi Devasundaram, Sotirios P. Fortis, Jenifer Bear, Elena Chertova, Julian Bess Jr., Ray Sowder, David J. Venzon, Claire Deleage, Jacob D. Estes, Jeffrey D. Lifson, Constantinos Petrovas, Barbara K. Felber, George N. Pavlakis B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8 + T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (T FH ) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8 + T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8 + cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry) of LN revealed increased numbers of granzyme B + T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals. Trial registration: ClinicalTrials.gov NCT02452268
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  • 44
    Publication Date: 2018-02-24
    Description: by P. J. Klasse, Thomas J. Ketas, Christopher A. Cottrell, Gabriel Ozorowski, Gargi Debnath, Diawoye Camara, Erik Francomano, Pavel Pugach, Rajesh P. Ringe, Celia C. LaBranche, Marit J. van Gils, Christine A. Bricault, Dan H. Barouch, Shane Crotty, Guido Silvestri, Sudhir Kasturi, Bali Pulendran, Ian A. Wilson, David C. Montefiori, Rogier W. Sanders, Andrew B. Ward, John P. Moore The native-like, soluble SOSIP.664 trimer based on the BG505 clade A env gene of HIV-1 is immunogenic in various animal species, of which the most studied are rabbits and rhesus macaques. The trimer induces autologous neutralizing antibodies (NAbs) consistently but at a wide range of titers and with incompletely determined specificities. A precise delineation of immunogenic neutralization epitopes on native-like trimers could help strategies to extend the NAb response to heterologous HIV-1 strains. One autologous NAb epitope on the BG505 Env trimer is known to involve residues lining a hole in the glycan shield that is blocked by adding a glycan at either residue 241 or 289. This glycan-hole epitope accounts for the NAb response of most trimer-immunized rabbits but not for that of a substantial subset. Here, we have used a large panel of mutant BG505 Env-pseudotyped viruses to define additional sites. A frequently immunogenic epitope in rabbits is blocked by adding a glycan at residue 465 near the junction of the gp120 V5 loop and β24 strand and is influenced by amino-acid changes in the structurally nearby C3 region. We name this new site the “C3/465 epitope”. Of note is that the C3 region was under selection pressure in the infected infant from whom the BG505 virus was isolated. A third NAb epitope is located in the V1 region of gp120, although it is rarely immunogenic. In macaques, NAb responses induced by BG505 SOSIP trimers are more often directed at the C3/465 epitope than the 241/289-glycan hole.
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  • 45
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-24
    Description: by Yan Huo, Yuanling Yu, Liying Chen, Qiong Li, Mengting Zhang, Zhiyu Song, Xiaoying Chen, Rongxiang Fang, Lili Zhang Insect vitellogenin (Vg) has been considered to be synthesized in the fat body. Here, we found that abundant Vg protein is synthesized in Laodelphax striatellus hemocytes as well. We also determined that only the hemocyte-produced Vg binds to Rice stripe virus (RSV) in vivo . Examination of the subunit composition of L . striatellus Vg (LsVg) revealed that LsVg was processed differently after its expression in different tissues. The LsVg subunit able to bind to RSV exist stably only in hemocytes, while fat body-produced LsVg lacks the RSV-interacting subunit. Nymph and male L . striatellus individuals also synthesize Vg but only in hemocytes, and the proteins co-localize with RSV. We observed that knockdown of LsVg transcripts by RNA interference decreased the RSV titer in the hemolymph, and thus interfered with systemic virus infection. Our results reveal the sex-independent expression and tissue-specific processing of LsVg and also unprecedentedly connect the function of this protein in mediating virus transmission to its particular molecular forms existing in tissues previously known as non-Vg producing.
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  • 46
    Publication Date: 2018-02-24
    Description: by Romesh G. Abeysuriya, Jonathan Hadida, Stamatios N. Sotiropoulos, Saad Jbabdi, Robert Becker, Benjamin A. E. Hunt, Matthew J. Brookes, Mark W. Woolrich Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP.
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  • 47
    Publication Date: 2018-02-27
    Description: by Chloe Spalding, Emma Keen, David J Smith, Anne-Marie Krachler, Sara Jabbari Here we formulate a mechanistic mathematical model to describe the growth dynamics of P. aeruginosa in the presence of the β -lactam antibiotic meropenem. The model is mechanistic in the sense that carrying capacity is taken into account through the dynamics of nutrient availability rather than via logistic growth. In accordance with our experimental results we incorporate a sub-population of cells, differing in morphology from the normal bacillary shape of P. aeruginosa bacteria, which we assume have immunity from direct antibiotic action. By fitting this model to experimental data we obtain parameter values that give insight into the growth of a bacterial population that includes different cell morphologies. The analysis of two parameters sets, that produce different long term behaviour, allows us to manipulate the system theoretically in order to explore the advantages of a shape transition that may potentially be a mechanism that allows P. aeruginosa to withstand antibiotic effects. Our results suggest that inhibition of this shape transition may be detrimental to bacterial growth and thus suggest that the transition may be a defensive mechanism implemented by bacterial machinery. In addition to this we provide strong theoretical evidence for the potential therapeutic strategy of using antimicrobial peptides (AMPs) in combination with meropenem. This proposed combination therapy exploits the shape transition as AMPs induce cell lysis by forming pores in the cytoplasmic membrane, which becomes exposed in the spherical cells.
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  • 48
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    Public Library of Science (PLoS)
    Publication Date: 2018-02-27
    Description: by Huijing Du, Yangyang Wang, Daniel Haensel, Briana Lee, Xing Dai, Qing Nie The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.
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  • 49
    Publication Date: 2018-02-27
    Description: by Tauqeer Hussain Mallhi, Amer Hayat Khan, Azreen Syazril Adnan, Azmi Sarriff, Yusra Habib Khan, Siew Hua Gan Background Despite myriad improvements in the care of dengue patients, acute kidney injury (AKI) remained least appreciated intricacy of dengue infection. Exiting literature does not provide any information on renal outcomes among dengue patients surviving an episode of AKI. Methods Dengue patients who developed AKI were followed up for post-discharge period of three months and renal recovery was assessed by using recovery criteria based on different thresholds of serum creatinine (SCr) and estimated glomerular filtration rates (eGFR). Results Out of the 526 dengue participants, AKI was developed in 72 (13.7%) patients. Renal recovery was assessed among AKI survivors (n = 71). The use of less (±50% recovery to baseline) to more (±5% recovery to baseline) stringent definitions of renal recovery yielded recovery rates from 88.9% to 2.8% by SCr and 94.4% to 5.6% by eGFR, as renal function biomarkers. At the end of study, eight patients had AKI with AKIN-II (n = 7) and AKIN-III (n = 1). Approximately 50% patients (n = 36/71) with AKI had eGFR primitive to CKD stage 2, while 18.3% (n = 13/71) and 4.2% (n = 3/71) patients had eGFR corresponding to advanced stages of CKD (stage 3 & 4). Factors such as renal insufficiencies at hospital discharge, multiple organ involvements, advance age, female gender and diabetes mellitus were associated with poor renal outcomes. Conclusions We conclude that dengue patients with AKI portend unsatisfactory short-term renal outcomes and deserve a careful and longer follow-up, especially under nephrology care.
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  • 50
    Publication Date: 2018-03-06
    Description: by Ryuta Uraki, Andrew K. Hastings, Andrea Gloria-Soria, Jeffrey R. Powell, Erol Fikrig Few animal models of Zika virus (ZIKV) infection have incorporated arthropod-borne transmission. Here, we establish an Aedes aegypti mosquito model of ZIKV infection of mice, and demonstrate altered vector competency among three strains, (Orlando, ORL, Ho Chi Minh, HCM, and Patilas, PAT). All strains acquired ZIKV in their midguts after a blood meal from infected mice, but ZIKV transmission only occurred in mice fed upon by HCM, and to a lesser extent PAT, but not ORL, mosquitoes. This defect in transmission from ORL or PAT mosquitoes was overcome by intrathoracic injection of ZIKV into mosquito. Genetic analysis revealed significant diversity among these strains, suggesting a genetic basis for differences in ability for mosquito strains to transmit ZIKV. The intrathoracic injection mosquito-mouse transmission model is critical to understanding the influence of mosquitoes on ZIKV transmission, infectivity and pathogenesis in the vertebrate host, and represents a natural transmission route for testing vaccines and therapeutics. (152 words)
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  • 51
    Publication Date: 2018-03-06
    Description: by Chia-Hao Chang, Yu-Ting Liu, Shih-Che Weng, I-Yi Chen, Po-Nien Tsao, Shin-Hong Shiao The Notch signaling pathway is a highly evolutionarily-conserved cell-cell signaling pathway that regulates many events during development. It plays a pivotal role in the regulation of fundamental cellular processes, such as cell proliferation, stem cell maintenance, and differentiation during embryonic and adult development. However, functions of Notch signaling in Aedes aegypti , the major mosquito vector for dengue, are largely unknown. In this study, we identified a unique feature of A . aegypti Notch (AaNotch) in the control of the sterile-like phenotype in female mosquitoes. Silencing AaNotch with a reverse genetic approach significantly reduced the fecundity and fertility of the mosquito. Silencing AaNotch also resulted in the prevention of micropyle formation, which led to impaired fertilization. In addition, JNK phosphorylation (a signaling molecule in the non-canonical Notch signaling pathway) was inhibited in the absence of AaNotch. Furthermore, treatment with a JNK inhibitor in the mosquito resulted in impaired fecundity and fertility. Taken together, our results demonstrate that non-canonical Notch signaling is essential for controlling fertility in the A . aegypti mosquito.
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  • 52
    Publication Date: 2018-03-06
    Description: by The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration , Amy L. Slogrove, Michael Schomaker, Mary-Ann Davies, Paige Williams, Suna Balkan, Jihane Ben-Farhat, Nancy Calles, Kulkanya Chokephaibulkit, Charlotte Duff, Tanoh François Eboua, Adeodata Kekitiinwa-Rukyalekere, Nicola Maxwell, Jorge Pinto, George Seage III, Chloe A. Teasdale, Sebastian Wanless, Josiane Warszawski, Kara Wools-Kaloustian, Marcel Yotebieng, Venessa Timmerman, Intira J. Collins, Ruth Goodall, Colette Smith, Kunjal Patel, Mary Paul, Diana Gibb, Rachel Vreeman, Elaine J. Abrams, Rohan Hazra, Russell Van Dyke, Linda-Gail Bekker, Lynne Mofenson, Marissa Vicari, Shaffiq Essajee, Martina Penazzato, Gabriel Anabwani, Edith Q. Mohapi, Peter N. Kazembe, Makhosazana Hlatshwayo, Mwita Lumumba, Tessa Goetghebuer, Claire Thorne, Luisa Galli, Annemarie van Rossum, Carlo Giaquinto, Magdalena Marczynska, Laura Marques, Filipa Prata, Luminita Ene, Liubov Okhonskaia, Pablo Rojo, Claudia Fortuny, Lars Naver, Christoph Rudin, Sophie Le Coeur, Alla Volokha, Vanessa Rouzier, Regina Succi, Annette Sohn, Azar Kariminia, Andrew Edmonds, Patricia Lelo, Samuel Ayaya, Patricia Ongwen, Laura F. Jefferys, Sam Phiri, Mwangelwa Mubiana-Mbewe, Shobna Sawry, Lorna Renner, Mariam Sylla, Mark J. Abzug, Myron Levin, James Oleske, Miriam Chernoff, Shirley Traite, Murli Purswani, Ellen G. Chadwick, Ali Judd, Valériane Leroy Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5–5.2) years for the total cohort and 6.4 (3.6–8.0) years in Europe, 3.7 (2.0–5.4) years in North America, 2.5 (1.2–4.4) years in South and Southeast Asia, 5.0 (2.7–7.5) years in South America and the Caribbean, and 2.1 (0.9–3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3–2.1) years in North America to 7.1 (5.3–8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4–2.6) years in North America to 7.9 (6.0–9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%–2.8%), 15.6% (15.1%–16.0%), and 11.3% (10.9%–11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%–1.1%]) and highest in South America and the Caribbean (4.4% [3.1%–6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%–6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%–13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
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  • 53
    Publication Date: 2018-03-06
    Description: by Lu Zhao, Mengchen Shi, Lina Zhou, Hengchang Sun, Xiaona Zhang, Lei He, Zeli Tang, Caiqin Wang, Yinjuan Wu, Tingjin Chen, Mei Shang, Xinyi Zhou, Zhipeng Lin, Xuerong Li, Xinbing Yu, Yan Huang Background Clonorchis sinensis ( C . sinensis ) is the most widespread human liver fluke in East Asia including China and Korea. Clonorchiasis as a neglected tropical zoonosis, leads to serious economic and public health burden in China. There are considerable evidences for an etiological relation between chronic clonorchiasis and liver fibrosis in human beings. Liver fibrosis is a highly conserved and over-protected response to hepatic tissue injury. Immune cells including CD4 + T cell as well as dendritic cell (DC), and pro-fibrogenic cytokines like interleukin 4 (IL-4), IL-13 have been identified as vital manipulators in liver fibrogenesis. Our previous studies had a mere glimpse of T helper type 2 (Th2) dominant immune responses as key players in liver fibrosis induced by C . sinensis infection, but little is known about the involved mechanisms in this pathological process. Methodology/Principal findings By flow cytometry (FACS), adult-derived total proteins of C . sinensis ( Cs TPs) down-regulated the expression of surface markers CD80, CD86 and major histocompatibility complex class II (MHC-II) on lipopolysaccharide (LPS) induced DC. ELISA results demonstrated that Cs TPs inhibited IL-12p70 release from LPS-treated bone marrow-derived dendritic cells (BMDC). IL-10 level increased in a time-dependent manner in LPS-treated BMDCs after incubation with Cs TPs. CD4 + T cells incubated with LPS-treated BMDCs plus Cs TPs could significantly elevate IL-4 level by ELISA. Meanwhile, elevated expression of pro-fibrogenic mediators including IL-13 and IL-4 were detected in a co-culture system of LPS-activated BMDCs and naive T cells containing Cs TPs. In vivo , Cs TPs-immunized mice enhanced expression of type 2 cytokines IL-13, IL-10 and IL-4 in both splenocytes and hepatic tissue. Exposure of BMDCs to Cs TPs activated expression of mannose receptor (MR) but not toll like receptor 2 (TLR2), TLR4, C-type lectin receptor DC-SIGN and Dectin-2 on the cell surface by RT-PCR and FACS. Blockade of MR almost completely reversed the capacity of Cs TPs to suppress LPS-induced BMDCs surface markers CD80, CD86 and MHC-II expression, and further made these BMDCs fail to induce a Th2-skewed response as well as Th2 cell-associated cytokines IL-13 and IL-4 release in vitro . Conclusions/Significance Collectively, we validated that Cs TPs could suppress the maturation of BMDCs in the presence of LPS via binding MR, and showed that the Cs TPs-pulsed BMDCs actively polarized naive T helper cells to Th2 cells though the production of IL-10 instead of IL-12. Cs TPs endowed host with the capacity to facilitate Th2 cytokines production including IL-13 and IL-4 in vitro and vivo . The study might provide useful information for developing potential therapeutic targets against the disease.
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  • 54
    Publication Date: 2018-03-06
    Description: by Nathália F. Lima, Raquel M. Gonçalves-Lopes, Yvonne C. M. Kruize, Maria Yazdanbakhsh, Marcelo U. Ferreira Background Chronic helminth infections typically induce an immunoregulatory environment, with markedly reduced immune responses to both parasite-specific and unrelated bystander antigens. Here we tested whether these changes are also observed in human infections with Mansonella ozzardi , a neglected filarial nematode widely distributed across Latin America. Methods CD4 + T cell populations from microfilaremic (Fil+) and uninfected (Fil-) inhabitants in M . ozzardi -endemic riverine communities in Brazil were characterized by flow cytometry analysis. Plasma concentrations of a wide range of cytokines and chemokines were measured. We examined whether M . ozzardi infection is associated with suppressed in vitro lymphoproliferative and inflammatory cytokine responses upon stimulation with filarial antigen, unrelated antigens or mitogens. Principal findings/Conclusions Fil+ subjects had lower plasma levels of selected inflammatory cytokines, such as TNF-α, IL-8, and IL-6, than their Fil- counterparts. However, we found no evidence for attenuated T-cell responses to filarial antigens or co-endemic pathogens, such as malaria parasites and Toxoplasma gondii . CD4 + T cells expressing CD39, an ectonucleosidase involved in the generation of the anti-inflammatory molecule adenosine, were increased in frequency in Fil+ subjects, compared to uninfected controls. Significantly, such an expansion was directly proportional to microfilarial loads. Surprisingly, CD39 blocking with a neutralizing antibody suppressed antigen-driven lymphoproliferation in vitro , while decreasing inflammatory cytokine responses, in Fil+ and Fil- individuals. These findings suggest that circulating CD4 + CD39 + T cells comprise subsets with both regulatory and stimulatory roles that contribute to the immune homeostasis in chronic M . ozzardi infection.
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  • 55
    Publication Date: 2018-03-06
    Description: by Annabelle de St. Maurice, Luke Nyakarahuka, Lawrence Purpura, Elizabeth Ervin, Alex Tumusiime, Stephen Balinandi, Jackson Kyondo, Sophia Mulei, Patrick Tusiime, Craig Manning, Pierre E. Rollin, Barbara Knust, Trevor Shoemaker Background Rift Valley Fever virus (RVF) is a zoonotic virus in the Phenuiviridae family. RVF outbreaks can cause significant morbidity and mortality in humans and animals. Following the diagnosis of two RVF cases in March 2016 in southern Kabale district, Uganda, we conducted a knowledge, attitudes and practice (KAP) survey to identify knowledge gaps and at-risk behaviors related to RVF. Methodology/Principal findings A multidisciplinary team interviewed 657 community members, including abattoir workers, in and around Kabale District, Uganda. Most participants (90%) had knowledge of RVF and most (77%) cited radio as their primary information source. Greater proportions of farmers (68%), herdsmen (79%) and butchers (88%) thought they were at risk of contracting RVF compared to persons in other occupations (60%, p
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  • 56
    Publication Date: 2018-03-06
    Description: by Richard Suu-Ire, Lineke Begeman, Ashley C. Banyard, Andrew C. Breed, Christian Drosten, Elisa Eggerbauer, Conrad M. Freuling, Louise Gibson, Hooman Goharriz, Daniel L. Horton, Daisy Jennings, Ivan V. Kuzmin, Denise Marston, Yaa Ntiamoa-Baidu, Silke Riesle Sbarbaro, David Selden, Emma L. Wise, Thijs Kuiken, Anthony R. Fooks, Thomas Müller, James L. N. Wood, Andrew A. Cunningham Rabies is a fatal neurologic disease caused by lyssavirus infection. People are infected through contact with infected animals. The relative increase of human rabies acquired from bats calls for a better understanding of lyssavirus infections in their natural hosts. So far, there is no experimental model that mimics natural lyssavirus infection in the reservoir bat species. Lagos bat virus is a lyssavirus that is endemic in straw-colored fruit bats ( Eidolon helvum ) in Africa. Here we compared the susceptibility of these bats to three strains of Lagos bat virus (from Senegal, Nigeria, and Ghana) by intracranial inoculation. To allow comparison between strains, we ensured the same titer of virus was inoculated in the same location of the brain of each bat. All bats (n = 3 per strain) were infected, and developed neurological signs, and fatal meningoencephalitis with lyssavirus antigen expression in neurons. There were three main differences among the groups. First, time to death was substantially shorter in the Senegal and Ghana groups (4 to 6 days) than in the Nigeria group (8 days). Second, each virus strain produced a distinct clinical syndrome. Third, the spread of virus to peripheral tissues, tested by hemi-nested reverse transcriptase PCR, was frequent (3 of 3 bats) and widespread (8 to 10 tissues positive of 11 tissues examined) in the Ghana group, was frequent and less widespread in the Senegal group (3/3 bats, 3 to 6 tissues positive), and was rare and restricted in the Nigeria group (1/3 bats, 2 tissues positive). Centrifugal spread of virus from brain to tissue of excretion in the oral cavity is required to enable lyssavirus transmission. Therefore, the Senegal and Ghana strains seem most suitable for further pathogenesis, and for transmission, studies in the straw-colored fruit bat.
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  • 57
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    Public Library of Science (PLoS)
    Publication Date: 2018-03-06
    Description: by Edessa Negera, Stephen L. Walker, Tsehainesh Lemma, Abraham Aseffa, Diana N. Lockwood, Hazel M. Dockrell Complement C1q is a soluble protein capable of initiating components of the classical pathway in host defence system. In earlier qualitative studies, C1q has been implicated in the pathogenesis of Erythema Nodosum Leprosum (ENL). However, little is known about the role of this complement in ENL reaction. In the present study we described the protein level of C1q production and its gene expression in the peripheral blood and skin biopsies in patients with ENL reaction and lepromatous leprosy (LL) patient controls before and after treatment. Thirty untreated patients with ENL reaction and 30 non-reactional LL patient controls were recruited at ALERT Hospital, Ethiopia. Peripheral blood and skin biopsies were obtained from each patient before and after treatment. The level of circulating C1q in the plasma was determined by enzyme-linked immunosorbent assay. The mRNA expression of the three C1q components, C1qA, C1qB, and C1qC in the peripheral blood and skin biopsies was determined by qPCR. Circulating C1q in the peripheral blood of untreated ENL patients was significantly decreased compared to LL patient controls. Untreated ENL patients had increased C1q gene expression in the peripheral blood compared to LL controls. Similarly, C1qA and C1qC gene expression were substantially increased in the skin biopsies of untreated ENL patients compared to LL controls. However, after treatment none of these genes show significant difference in both groups. In conclusion, while circulating C1q is inversely correlated with active ENL reactions, its gene expression is directly correlated with ENL. The decreased circulating C1q may suggest the utilization of C1q in immune-complex formation in these patients. Therefore, C1q could be a potential diagnostic marker for active ENL reactions as well as for monitoring ENL treatment.
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  • 58
    Publication Date: 2018-03-06
    Description: by Idris Mhaidi, Sofia El kacem, Mouad Ait Kbaich, Adil El Hamouchi, M’hammed Sarih, Khadija Akarid, Meryem Lemrani Background Cutaneous leishmaniasis (CL) is an infectious disease caused by various species of Leishmania and transmitted by several species of sand flies. CL is among the most neglected tropical diseases, and it has represented a major health threat over the past 20 years in Morocco. The main objectives of this study were to identify relevant sand fly species and detect Leishmania infection in the most prevalent species and patient skin samples in Taza, a focus of CL in North-eastern Morocco. Methodology and finding A total of 3672 sand flies were collected by CDC miniature light traps. Morphological identification permitted the identification of 13 species, namely 10 Phlebotomus species and 3 Sergentomyia species. P . longicuspis was the most abundant species, comprising 64.08% of the total collected sand flies, followed by P . sergenti (20.1%) and P . perniciosus (8.45%). Using nested-kDNA PCR, seven pools of P . sergenti were positive to Leishmania tropica DNA, whereas 23 pools of P . longicuspis and 4 pools of P . perniciosus tested positive for Leishmania infantum DNA. The rates of P . longicuspis and P . perniciosus Leishmania infection were 2.51% (23/915) and 7.27% (4/55), respectively, whereas the infection prevalence of P . sergenti was 3.24%. We also extracted DNA from lesion smears of 12 patients suspected of CL, among them nine patients were positive with enzymatic digestion of ITS1 by Hae III revealing two profiles. The most abundant profile, present in eight patients, was identical to L . infantum , whereas L . tropica was found in one patient. The results of RFLP were confirmed by sequencing of the ITS1 DNA region. Conclusion This is the first molecular detection of L . tropica and L . infantum in P . sergenti and P . longicuspis , respectively, in this CL focus. Infection of P . perniciosus by L . infantum was identified for the first time in Morocco. This study also underlined the predominance of L . infantum and its vector in this region, in which L . tropica has been considered the causative agent of CL for more than 20 years.
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  • 59
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    Public Library of Science (PLoS)
    Publication Date: 2018-03-06
    Description: by Kebede Deribe, Jorge Cano, Mei L. Trueba, Melanie J. Newport, Gail Davey Background Podoconiosis is one of the few diseases that could potentially be eliminated within one generation. Nonetheless, the global distribution of the disease remains largely unknown. The global atlas of podoconiosis was conceived to define the epidemiology and distribution of podoconiosis through dedicated surveys and assembling the available epidemiological data. Methods We have synthesized the published literature on the epidemiology of podoconiosis. Through systematic searches in SCOPUS and MEDLINE from inception to February 14, 2018, we identified observational and population-based studies reporting podoconiosis. To establish existence of podoconiosis, we used case reports and presence data. For a study to be included in the prevalence synthesis, it needed to be a population-based survey that involved all residents within a specific area. Studies that did not report original data were excluded. We undertook descriptive analyses of the extracted data. This study is registered with PROSPERO, number CRD42018084959. Results We identified 3,260 records, of which 27 studies met the inclusion criteria. Podoconiosis was described to exist or be endemic in 32 countries, 18 from the African Region, 3 from Asia and 11 from Latin America. Overall, podoconiosis prevalence ranged from 0·10% to 8.08%, was highest in the African region, and was substantially higher in adults than in children and adolescents. The highest reported prevalence values were in Africa (8.08% in Cameroon, 7.45% in Ethiopia, 4.52% in Uganda, 3.87% in Kenya and 2.51% in Tanzania). In India, a single prevalence of 0.21% was recorded from Manipur, Mizoram and Rajasthan states. None of the Latin American countries reported prevalence data. Conclusion Our data suggest that podoconiosis is more widespread in the African Region than in the rest of the regions, although this could be related to the fact that most podoconiosis epidemiological research has been focused in the African continent. The assembled dataset confirms that comprehensive podoconiosis control strategies such as promotion of footwear and personal hygiene are urgently needed in endemic parts of Africa. Mapping, active surveillance and a systematic approach to the monitoring of disease burden must accompany the implementation of podoconiosis control activities.
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  • 60
    Publication Date: 2018-03-06
    Description: by Mathieu Bangert, María D. Flores-Chávez, Ivonne P. Llanes-Acevedo, Carolina Arcones, Carmen Chicharro, Emilia García, Sheila Ortega, Javier Nieto, Israel Cruz Background Visceral leishmaniasis (VL), the most severe form of leishmaniasis, is endemic in Europe with Mediterranean countries reporting endemic status alongside a worrying northward spread. Serological diagnosis, including immunochromatographic test based on the recombinant antigen rK39 (rK39-ICT) and a direct agglutination test (DAT) based on the whole parasite antigen, have been validated in regions with high VL burden, such as eastern Africa and the Indian subcontinent. To date, no studies using a large set of patients have performed an assessment of both methods within Europe. Methodology/Principal findings We selected a range of clinical serum samples from patients with confirmed VL (including HIV co-infection), Chagas disease, malaria, other parasitic infections and negative samples (n = 743; years 2009–2015) to test the performance of rK39-ICT rapid test (Kalazar Detect Rapid Test; InBios International, Inc., USA) and DAT (ITM-DAT/VLG; Institute of Tropical Medicine Antwerp, Belgium). An in-house immunofluorescence antibody test (IFAT), was included for comparison. Estimated sensitivities for rK39-ICT and DAT in HIV-negative VL patients were 83.1% [75.1–91.2] and 84.2% [76.3–92.1], respectively. Sensitivity was reduced to 67.3% [52.7–82.0] for rK39 and increased to 91.3% [82.1–100.0] for DAT in HIV/VL co-infected patients. The in-house IFAT was more sensitive in HIV-negative VL patients, 84.2% [76.3–92.1] than in HIV/VL patients, 79.4% [73.3–96.2]. DAT gave 32 false positives in sera from HIV-negative VL suspects, compared to 0 and 2 for rK39 and IFAT, respectively, but correctly detected more HIV/VL patients (42/46) than rK39 (31/46) and IFAT (39/46). Conclusions/Significance Though rK39-ICT and DAT exhibited acceptable sensitivity and specificity a combination with other tests is required for highly sensitive diagnosis of VL cases in Spain. Important variation in the performance of the tests were seen in patients co-infected with HIV or with other parasitic infections. This study can help inform the choice of serological test to be used when screening or diagnosing VL in a European Mediterranean setting.
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  • 61
    Publication Date: 2018-03-06
    Description: by Kossi Komlan, Patrick S. Vossberg, Richard G. Gantin, Tchalim Solim, Francois Korbmacher, Méba Banla, Koffi Padjoudoum, Potchoziou Karabou, Carsten Köhler, Peter T. Soboslay Background Mass drug administration (MDA) of ivermectin has become the main intervention to control onchocerciasis or “river blindness”. In Togo, after many years of MDA, Onchocerca volvulus infection has declined dramatically, and elimination appears achievable, but in certain river basins the current situation remains unknown. We have conducted parasitological, serological, ophthalmological, and entomological assessments in northern and central Togo within the river basins of Ôti, Kéran and Mô. Methodology/Principal findings Examinations were completed in 1,455 participants from 11 onchocerciasis sentinel villages, and O . volvulus transmission by Simulium damnosum sensu lato (s.l.) was evaluated. In children (aged 1–10 years), the prevalence of microfilariae (Mf) was 2.3% and in adults it ranged from 5.1 to 13.3%. Positive IgG4 responses to O . volvulus adult (crude) worm antigen (OvAg) and the recombinant Ov16 antigen were in all-ages 48.7% and 34.4%, and 29.1% and 14.9% in children, respectively. In the river basin villages of Kéran, Mô and Ôti, the IgG4 seroprevalences to OvAg in children were 51.7%, 23.5% and 12.7%, respectively, and to the Ov16 antigen 33.3% (Kéran) and 5.2% (Ôti). Onchocerciasis ocular lesions (punctate keratitis, evolving iridocyclitis and chorioretinitis) were observed in children and young adults. O . volvulus -specific DNA (Ov150) was detected by poolscreen in vector samples collected from Tchitchira/Kéran(22.8%), Bouzalo/Mô(11.3%), Baghan/Mô(2.9%) and Pancerys/Ôti(4.9%); prevalences of O . volvulus infection in S . damnosum s.l. were, respectively, 1%, 0.5%, 0.1% and 0.2%. Conclusions/Significance In the northern and central river basins in Togo, interruption of O . volvulus transmission has not yet been attained. Patent O . volvulus infections, positive antibody responses, progressive ocular onchocerciasis were diagnosed, and parasite transmission by S . damnosum s.l. occurred close to the survey locations. Future interventions may require approaches selectively targeted to non-complying endemic populations, to the seasonality of parasite transmission and national onchocerciasis control programs should harmonize cross-border MDA as a coordinated intervention.
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  • 62
    Publication Date: 2018-03-06
    Description: by Moudachirou Ibikounlé, Ablavi Onzo-Aboki, Justin Doritchamou, Jean-Jacques Tougoué, Pélagie Mimonnou Boko, Boris S. Savassi, Edoux Joel Siko, Aboudou Daré, Wilfrid Batcho, Achille Massougbodji, Dorothée Akoko Kindé-Gazard, Achille Kaboré Background National mapping of soil-transmitted helminth infections (STH) was conducted for the first time in all of the 77 districts of Benin (West Africa) from 2013 to 2015. This mapping aimed to provide basic epidemiological data essential for the implementation of the national strategy against the neglected tropical diseases (NTDs) in the context of achieving the WHO target of controlling these infections by 2020. Methods In each district, 5 schools were purposively selected in 5 villages and 50 school-children (25 girls and 25 boys) from ages 8 to 14 years were randomly enrolled in each school. In total, 19,250 stool samples of school children (9,625 girls and 9,625 boys) from 385 schools were examined by Kato-Katz technique. Results The three major species of STH (hookworm, Ascaris lumbricoides and Trichuris trichiura ) were observed with intra- and inter-specific variations in the prevalence and the intensity of these parasites. Hookworm infection was present in all of the surveyed districts with an average prevalence of 17.14% (95% CI 16.6%-17.6%). Among the infected schoolchildren, at national level, 90.82%, 6.73% and 2.45% of infections were of light, moderate and heavy parasite intensities respectively. A. lumbricoides infection, with a national average prevalence of 5.35% (95% CI 5.00%-5.60%),was the second most prevalent STH, and 84.37%, 14.27% and 1.36% of the infections were of light, moderate and heavy parasite intensities, respectively. T . trichiura had a national average prevalence of 1.15% (95% CI 0.90%-1.20%) and 80.45%, 13.18% and 6.36% infections were of light, moderate and heavy parasite intensities, respectively. The national cumulative prevalence of the three STH infections was 22.74% (95% CI 22.15%-23.33%), with58.44% (45/77) of the districts requiring mass treatment according to WHO recommendations. In all of the surveyed districts, multiple infections by STH species were common, and boys seemed more at risk of hookworm and Ascaris infections. Conclusions This first national mapping provided an overview of the epidemiological pattern of STH infections and was essential for the implementation of a control strategy with an effective preventive chemotherapy treatment (PCT). Results show that while preventive chemotherapy is not indicated for children in 32/77 districts, 43 require annual deworming and two require twice yearly deworming. If no environmental change occurs, and no mass treatment is delivered, prevalence is likely to remain stable for many years owing to poor hygiene and sanitation.
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  • 63
    Publication Date: 2018-03-06
    Description: by Mariwan M. M. Al-Bajalan, Sirwan M. A. Al-Jaf, Sherko S. Niranji, Dler R. Abdulkareem, Khudhair K. Al-Kayali, Hirotomo Kato Background Cutaneous leishmaniasis (CL) is a neglected worldwide, zoonotic, vector-borne, tropical disease that is a threat to public health. This threat may spread from endemic to non-endemic areas. Current research has exploited epidemiological, molecular and phylogenetical studies to determine the danger of an outbreak of CL in the borderline area between northern and central Iraq from 2014–2017. Methodology/Principal findings For the first time, using sequence analysis of the cytochrome b gene, the occurrence of CL in the borderline area between northern and central Iraq was confirmed to be due to Leishmania major . The phylogenetic analysis indicated that it was closely related to the L . major MRHO/IR/75/ER strain in Iran. Conclusions and significance In conclusion, the genotype confirmation of the L . major strain will improve our understanding of the epidemiology of the disease. This is important for facilitating control programs to prevent the further spread of CL. Furthermore, this area could be considered as a model for further research on the risk of global CL epidemics in other non-endemic countries where both reservoir hosts and sandfly vectors are present.
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  • 64
    Publication Date: 2018-03-06
    Description: by Florian Douam, Floriane Fusil, Margot Enguehard, Linda Dib, Francesca Nadalin, Loïc Schwaller, Gabriela Hrebikova, Jimmy Mancip, Laurent Mailly, Roland Montserret, Qiang Ding, Carine Maisse, Emilie Carlot, Ke Xu, Els Verhoeyen, Thomas F. Baumert, Alexander Ploss, Alessandra Carbone, François-Loïc Cosset, Dimitri Lavillette Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without altering viral entry mechanisms. The functions and structures of the two envelope glycoproteins of the Hepatitis C Virus (HCV), E1 and E2, are poorly described. Especially, how these two proteins mediate the HCV fusion process between the viral and the cell membrane remains elusive. Here, as a proof of concept, we aimed to take advantage of an original coevolution method recently developed to shed light on the HCV fusion mechanism. When first applied to the well-characterized Dengue Virus (DENV) envelope glycoproteins, coevolution analysis was able to predict important structural features and rearrangements of these viral protein complexes. When applied to HCV E1E2, computational coevolution analysis predicted that E1 and E2 refold interdependently during fusion through rearrangements of the E2 Back Layer (BL). Consistently, a soluble BL-derived polypeptide inhibited HCV infection of hepatoma cell lines, primary human hepatocytes and humanized liver mice. We showed that this polypeptide specifically inhibited HCV fusogenic rearrangements, hence supporting the critical role of this domain during HCV fusion. By combining coevolution analysis and in vitro assays, we also uncovered functionally-significant coevolving signals between E1 and E2 BL/Stem regions that govern HCV fusion, demonstrating the accuracy of our coevolution predictions. Altogether, our work shed light on important structural features of the HCV fusion mechanism and contributes to advance our functional understanding of this process. This study also provides an important proof of concept that coevolution can be employed to explore viral protein mediated-processes, and can guide the development of innovative translational strategies against challenging human-tropic viruses.
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  • 65
    Publication Date: 2018-03-06
    Description: by Avantika S. Chitre, Michael G. Kattah, Yenny Y. Rosli, Montha Pao, Monika Deswal, Steven G. Deeks, Peter W. Hunt, Mohamed Abdel-Mohsen, Luis J. Montaner, Charles C. Kim, Averil Ma, Ma Somsouk, Joseph M. McCune Trial registration ClinicalTrials.gov Clinical Trial NCT00594880
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  • 66
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    Public Library of Science (PLoS)
    Publication Date: 2018-03-06
    Description: by Bo G. Lindberg, Xiongzhuo Tang, Widad Dantoft, Priya Gohel, Shiva Seyedoleslami Esfahani, Jessica M. Lindvall, Ylva Engström Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene nubbin ( nub ) encodes two transcription factor isoforms, Nub-PB and Nub-PD, which antagonistically regulate immune gene expression in Drosophila . Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-κB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co-overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte-specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15 . Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host-microbe interactions mediated by antagonistic transcription factor isoforms.
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  • 67
    Publication Date: 2018-03-06
    Description: by Kendra A. Bussey, Ulrike Lau, Sophie Schumann, Antonio Gallo, Lisa Osbelt, Markus Stempel, Christine Arnold, Josef Wissing, Hans Henrik Gad, Rune Hartmann, Wolfram Brune, Lothar Jänsch, Adrian Whitehouse, Melanie M. Brinkmann Kaposi’s sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function of ORF20 and its role in the viral life cycle is not well understood. ORF20 encodes three largely uncharacterized isoforms, which we found were localized predominantly in the nuclei and nucleoli. Quantitative affinity purification coupled to mass spectrometry (q-AP-MS) identified numerous specific interacting partners of ORF20, including ribosomal proteins and the interferon-stimulated gene product (ISG) oligoadenylate synthetase-like protein (OASL). Both endogenous and transiently transfected OASL co-immunoprecipitated with ORF20, and this interaction was conserved among all ORF20 isoforms and multiple ORF20 homologs of the UL24 family in other herpesviruses. Characterization of OASL interacting partners by q-AP-MS identified a very similar interactome to that of ORF20. Both ORF20 and OASL copurified with 40S and 60S ribosomal subunits, and when they were co-expressed, they associated with polysomes. Although ORF20 did not have a global effect on translation, ORF20 enhanced RIG-I induced expression of endogenous OASL in an IRF3-dependent but IFNAR-independent manner. OASL has been characterized as an ISG with antiviral activity against some viruses, but its role for gammaherpesviruses was unknown. We show that OASL and ORF20 mRNA expression were induced early after reactivation of latently infected HuARLT-rKSHV.219 cells. Intriguingly, we found that OASL enhanced infection of KSHV. During infection with a KSHV ORF20stop mutant, however, OASL-dependent enhancement of infectivity was lost. Our data have characterized the interaction of ORF20 with OASL and suggest ORF20 usurps the function of OASL to benefit KSHV infection.
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  • 68
    Publication Date: 2018-03-06
    Description: by Saijo Thomas, Jiyoti Verma, Megan Woolfit, Scott L. O’Neill Wolbachia is currently being developed as a novel tool to block the transmission of dengue viruses (DENV) by Aedes aegypti . A number of mechanisms have been proposed to explain the DENV-blocking phenotype in mosquitoes, including competition for fatty acids like cholesterol, manipulation of host miRNAs and upregulation of innate immune pathways in the mosquito. We examined the various stages in the DENV infection process to better understand the mechanism of Wolbachia -mediated virus blocking (WMVB). Our results suggest that infection with Wolbachia does not inhibit DENV binding or cell entry, but reduces virus replication. In contrast to a previous report, we also observed a similar reduction in replication of West Nile virus (WNV). This reduced replication is associated with rapid viral RNA degradation in the cytoplasm. We didn’t find a role for host miRNAs in WMVB. Further analysis showed that the 3’ end of the virus subgenomic RNA was protected and accumulated over time suggesting that the degradation is XRN1-mediated. We also found that sub genomic flavivirus RNA accumulation inactivated XRN1 in mosquito cells in the absence of Wolbachia and led to enhancement of RNA degradation in its presence. Depletion of XRN1 decreased WMVB which was associated with a significant increase in DENV RNA. We also observed that WMVB is influenced by virus MOI and rate of virus replication. A comparatively elevated blocking was observed for slowly replicating DENV, compared to WNV. Similar results were obtained while analysing different DENV serotypes.
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  • 69
    Publication Date: 2018-03-06
    Description: by Da-Bing Lu, Yao Deng, Huan Ding, You-Sheng Liang, Joanne P. Webster
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  • 70
    Publication Date: 2018-03-06
    Description: by Diego Fernandez Slezak, Mariano Sigman, Guillermo A. Cecchi We present a theory of decision-making in the presence of multiple choices that departs from traditional approaches by explicitly incorporating entropic barriers in a stochastic search process. We analyze response time data from an on-line repository of 15 million blitz chess games, and show that our model fits not just the mean and variance, but the entire response time distribution (over several response-time orders of magnitude) at every stage of the game. We apply the model to show that (a) higher cognitive expertise corresponds to the exploration of more complex solution spaces, and (b) reaction times of users at an on-line buying website can be similarly explained. Our model can be seen as a synergy between diffusion models used to model simple two-choice decision-making and planning agents in complex problem solving.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 71
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    Publication Date: 2018-03-06
    Description: by Pilar Sellés, Vicenta Ávila, Tomás Martínez, Liz Ysla This paper deals with the skills related to the early reading acquisition in two countries that share language. Traditionally on reading readiness research there is a great interest to find out what factors affect early reading ability, but differ from other academic skills that affect general school learnings. Furthermore, it is also known how the influence of pre-reading variables in two countries with the same language, affect the development of the reading. On the other hand, several studies have examined what skills are related to reading readiness (phonological awareness, alphabetic awareness, naming speed, linguistic skills, metalinguistic knowledge and basic cognitive processes), but there are no studies showing whether countries can also influence the development of these skills.Our main objective in this study was to establish whether there were differences in the degree of acquisition of these skills between Spanish (119 children) and Peruvian (128 children), five years old children assessed in their own countries and after controlling Economic, Social and Cultural Status (ESCS). The results show that there are significant differences in the degree of acquisition of these skills between these two samples. It's especially relevant, in these results, that the main predictor in a regression study was the country of origin, explaining a higher percentage of variance than other variables such as age differences, in months, or gender. These findings corroborate the results obtained in other studies with migrant population.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 72
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    Publication Date: 2018-03-06
    Description: by Mercedes Rubio, Mariona Bustamante, Carles Hernandez-Ferrer, Dietmar Fernandez-Orth, Lorena Pantano, Yaris Sarria, Maria Piqué-Borras, Kilian Vellve, Silvia Agramunt, Ramon Carreras, Xavier Estivill, Juan R. Gonzalez, Alfredo Mayor Circulating small RNAs, including miRNAs but also isomiRs and other RNA species, have the potential to be used as non-invasive biomarkers for communicable and non-communicable diseases. This study aims to characterize and compare small RNA profiles in human biofluids. For this purpose, RNA was extracted from plasma and breast milk samples from 15 healthy postpartum mothers. Small RNA libraries were prepared with the NEBNext® small RNA library preparation kit and sequenced in an Illumina HiSeq2000 platform. miRNAs, isomiRs and clusters of small RNAs were annotated using seqBuster/seqCluster framework in 5 plasma and 10 milk samples that passed the initial quality control. The RNA yield was 81 ng/mL [standard deviation (SD): 41] and 3985 ng/mL (SD: 3767) for plasma and breast milk, respectively. Mean number of good quality reads was 4.04 million (M) (40.01% of the reads) in plasma and 12.5M (89.6%) in breast milk. One thousand one hundred eighty two miRNAs, 12,084 isomiRs and 1,053 small RNA clusters that included piwi-interfering RNAs (piRNAs), tRNAs, small nucleolar RNAs (snoRNA) and small nuclear RNAs (snRNAs) were detected. Samples grouped by biofluid, with 308 miRNAs, 1,790 isomiRs and 778 small RNA clusters differentially detected. In summary, plasma and milk showed a different small RNA profile. In both, miRNAs, piRNAs, tRNAs, snRNAs, and snoRNAs were identified, confirming the presence of non-miRNA species in plasma, and describing them for the first time in milk.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 73
    Publication Date: 2018-03-07
    Description: by Manish Jaiswal, Nele A. Haelterman, Hector Sandoval, Bo Xiong, Taraka Donti, Auinash Kalsotra, Shinya Yamamoto, Thomas A. Cooper, Brett H. Graham, Hugo J. Bellen
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 74
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    Public Library of Science (PLoS)
    Publication Date: 2018-03-07
    Description: by Kelsey E. Hazegh, Travis Nemkov, Angelo D’Alessandro, John D. Diller, Jenifer Monks, James L. McManaman, Kenneth L. Jones, Kirk C. Hansen, Tânia Reis
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 75
    Publication Date: 2018-03-07
    Description: by Timothy Powell-Jackson, Camilla Fabbri, Varun Dutt, Sarah Tougher, Kultar Singh Background To assess the effect of health information on immunisation uptake in rural India, we conducted an individually randomised controlled trial of health information messages targeting the mothers of unvaccinated or incompletely vaccinated children through home visits in rural Uttar Pradesh, India. Methods and findings The study tested a brief intervention that provided mothers face-to-face with information on the benefits of the tetanus vaccine. Participants were 722 mothers of children aged 0–36 months who had not received 3 doses of diphtheria–pertussis–tetanus (DPT) vaccine (DPT3). Mothers were randomly assigned in a ratio of 1:1:1 to 1 of 3 study arms: mothers in the first treatment group received information framed as a gain (e.g., the child is less likely to get tetanus and more likely to be healthy if vaccinated), mothers in the second treatment group received information framed in terms of a loss (e.g., the child is more likely to get tetanus and suffer ill health if not vaccinated), and the third arm acted as a control group, with no information given to the mother. Surveys were conducted at baseline (September 2015) and after the intervention (April 2016). The primary outcome was the proportion of children who had received DPT3 measured after 7 months of follow-up. The analysis was by intention to treat. A total of 16 (2.2%) participants were lost to follow-up. The coverage of DPT3 was 28% in the control group and 43% in the pooled information groups, giving a risk difference of 15 percentage points (95% CI: 7% to 22%, p 〈 0.001) and a relative risk of 1.52 (95% CI: 1.2 to 1.9, p 〈 0.001). The information intervention increased the rate of measles vaccination by 22 percentage points (risk difference: 22%, 95% CI: 14% to 30%, p 〈 0.001; relative risk: 1.53, 95% CI: 1.29 to 1.80) and the rate of full immunisation by 14 percentage points (risk difference: 14%, 95% CI: 8% to 21%, p 〈 0.001; relative risk: 1.72, 95% CI: 1.29 to 2.29). It had a large positive effect on knowledge of the causes, symptoms, and prevention of tetanus but no effect on perceptions of vaccine efficacy. There was no difference in the proportion of children with DPT3 between the group that received information framed as a loss and the group that received information framed as a gain (risk difference: 4%, 95% CI: −5% to 13%; p = 0.352; relative risk: 1.11, 95% CI: 0.90 to 1.36). The cost per disability-adjusted life year averted of providing information was US$186, making the intervention highly cost-effective with respect to the WHO-recommended threshold of once the gross domestic product per capita (US$793 in the case of Uttar Pradesh). Key study limitations include the modest sample size for this trial, limiting power to detect small differences in the framing of information, and the potential for contamination among households. Conclusions Providing mothers of unvaccinated/incompletely vaccinated children with information on tetanus and the benefits of DPT vaccination substantially increased immunisation coverage and was highly cost-effective. The framing of the health information message did not appear to matter. Trial registration The trial is registered with ISRCTN, number ISRCTN84560580.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 76
    Publication Date: 2018-03-07
    Description: by Ghislaine Dehaene-Lambertz, Karla Monzalvo, Stanislas Dehaene How does education affect cortical organization? All literate adults possess a region specialized for letter strings, the visual word form area (VWFA), within the mosaic of ventral regions involved in processing other visual categories such as objects, places, faces, or body parts. Therefore, the acquisition of literacy may induce a reorientation of cortical maps towards letters at the expense of other categories such as faces. To test this cortical recycling hypothesis, we studied how the visual cortex of individual children changes during the first months of reading acquisition. Ten 6-year-old children were scanned longitudinally 6 or 7 times with functional magnetic resonance imaging (fMRI) before and throughout the first year of school. Subjects were exposed to a variety of pictures (words, numbers, tools, houses, faces, and bodies) while performing an unrelated target-detection task. Behavioral assessment indicated a sharp rise in grapheme–phoneme knowledge and reading speed in the first trimester of school. Concurrently, voxels specific to written words and digits emerged at the VWFA location. The responses to other categories remained largely stable, although right-hemispheric face-related activity increased in proportion to reading scores. Retrospective examination of the VWFA voxels prior to reading acquisition showed that reading encroaches on voxels that are initially weakly specialized for tools and close to but distinct from those responsive to faces. Remarkably, those voxels appear to keep their initial category selectivity while acquiring an additional and stronger responsivity to words. We propose a revised model of the neuronal recycling process in which new visual categories invade weakly specified cortex while leaving previously stabilized cortical responses unchanged.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 77
    Publication Date: 2018-03-07
    Description: by Jenny Tran, Robyn Norton, Nathalie Conrad, Fatemeh Rahimian, Dexter Canoy, Milad Nazarzadeh, Kazem Rahimi Background Multimorbidity in people with cardiovascular disease (CVD) is common, but large-scale contemporary reports of patterns and trends in patients with incident CVD are limited. We investigated the burden of comorbidities in patients with incident CVD, how it changed between 2000 and 2014, and how it varied by age, sex, and socioeconomic status (SES). Methods and findings We used the UK Clinical Practice Research Datalink with linkage to Hospital Episode Statistics, a population-based dataset from 674 UK general practices covering approximately 7% of the current UK population. We estimated crude and age/sex-standardised (to the 2013 European Standard Population) prevalence and 95% confidence intervals for 56 major comorbidities in individuals with incident non-fatal CVD. We further assessed temporal trends and patterns by age, sex, and SES groups, between 2000 and 2014. Among a total of 4,198,039 people aged 16 to 113 years, 229,205 incident cases of non-fatal CVD, defined as first diagnosis of ischaemic heart disease, stroke, or transient ischaemic attack, were identified. Although the age/sex-standardised incidence of CVD decreased by 34% between 2000 to 2014, the proportion of CVD patients with higher numbers of comorbidities increased. The prevalence of having 5 or more comorbidities increased 4-fold, rising from 6.3% (95% CI 5.6%–17.0%) in 2000 to 24.3% (22.1%–34.8%) in 2014 in age/sex-standardised models. The most common comorbidities in age/sex-standardised models were hypertension (28.9% [95% CI 27.7%–31.4%]), depression (23.0% [21.3%–26.0%]), arthritis (20.9% [19.5%–23.5%]), asthma (17.7% [15.8%–20.8%]), and anxiety (15.0% [13.7%–17.6%]). Cardiometabolic conditions and arthritis were highly prevalent among patients aged over 40 years, and mental illnesses were highly prevalent in patients aged 30–59 years. The age-standardised prevalence of having 5 or more comorbidities was 19.1% (95% CI 17.2%–22.7%) in women and 12.5% (12.0%–13.9%) in men, and women had twice the age-standardised prevalence of depression (31.1% [28.3%–35.5%] versus 15.0% [14.3%–16.5%]) and anxiety (19.6% [17.6%–23.3%] versus 10.4% [9.8%–11.8%]). The prevalence of depression was 46% higher in the most deprived fifth of SES compared with the least deprived fifth (age/sex-standardised prevalence of 38.4% [31.2%–62.0%] versus 26.3% [23.1%–34.5%], respectively). This is a descriptive study of routine electronic health records in the UK, which might underestimate the true prevalence of diseases. Conclusions The burden of multimorbidity and comorbidity in patients with incident non-fatal CVD increased between 2000 and 2014. On average, older patients, women, and socioeconomically deprived groups had higher numbers of comorbidities, but the type of comorbidities varied by age and sex. Cardiometabolic conditions contributed substantially to the burden, but 4 out of the 10 top comorbidities were non-cardiometabolic. The current single-disease paradigm in CVD management needs to broaden and incorporate the large and increasing burden of comorbidities.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 78
    Publication Date: 2018-03-07
    Description: by Iraci Duarte Lima, Adila L. M. Lima, Carolina de Oliveira Mendes-Aguiar, José F. V. Coutinho, Mary E. Wilson, Richard D. Pearson, José Wilton Queiroz, Selma M. B. Jeronimo Background Visceral leishmaniasis (VL) caused by Leishmania infantum became a disease of urban areas in Brazil in the last 30 years and there has been an increase in asymptomatic L . infantum infection with these areas. Methodology/Principal findings A retrospective study of human VL was performed in the state of Rio Grande do Norte, Brazil, for the period of 1990–2014. The data were divided into five-time periods. For all VL cases, data on sex, age, nutritional status and childhood vaccination were collected. Geographic information system tools and statistical models were used to analyze the dispersion of human VL. The mean annual incidence of VL was 4.6 cases/100,000 inhabitants, with total 3,252 cases reported. The lethality rate was 6.4%. Over time the annual incidence of VL decreased in the 0–4 years ( p
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 79
    Publication Date: 2018-03-07
    Description: by Oliver T. Mytton, Christopher Jackson, Arno Steinacher, Anna Goodman, Claudia Langenberg, Simon Griffin, Nick Wareham, James Woodcock Background The National Health Service (NHS) Health Check programme was introduced in 2009 in England to systematically assess all adults in midlife for cardiovascular disease risk factors. However, its current benefit and impact on health inequalities are unknown. It is also unclear whether feasible changes in how it is delivered could result in increased benefits. It is one of the first such programmes in the world. We sought to estimate the health benefits and effect on inequalities of the current NHS Health Check programme and the impact of making feasible changes to its implementation. Methods and findings We developed a microsimulation model to estimate the health benefits (incident ischaemic heart disease, stroke, dementia, and lung cancer) of the NHS Health Check programme in England. We simulated a population of adults in England aged 40–45 years and followed until age 100 years, using data from the Health Survey of England (2009–2012) and the English Longitudinal Study of Aging (1998–2012), to simulate changes in risk factors for simulated individuals over time. We used recent programme data to describe uptake of NHS Health Checks and of 4 associated interventions (statin medication, antihypertensive medication, smoking cessation, and weight management). Estimates of treatment efficacy and adherence were based on trial data. We estimated the benefits of the current NHS Health Check programme compared to a healthcare system without systematic health checks. This counterfactual scenario models the detection and treatment of risk factors that occur within ‘routine’ primary care. We also explored the impact of making feasible changes to implementation of the programme concerning eligibility, uptake of NHS Health Checks, and uptake of treatments offered through the programme. We estimate that the NHS Health Check programme prevents 390 (95% credible interval 290 to 500) premature deaths before 80 years of age and results in an additional 1,370 (95% credible interval 1,100 to 1,690) people being free of disease (ischaemic heart disease, stroke, dementia, and lung cancer) at age 80 years per million people aged 40–45 years at baseline. Over the life of the cohort (i.e., followed from 40–45 years to 100 years), the changes result in an additional 10,000 (95% credible interval 8,200 to 13,000) quality-adjusted life years (QALYs) and an additional 9,000 (6,900 to 11,300) years of life. This equates to approximately 300 fewer premature deaths and 1,000 more people living free of these diseases each year in England. We estimate that the current programme is increasing QALYs by 3.8 days (95% credible interval 3.0–4.7) per head of population and increasing survival by 3.3 days (2.5–4.1) per head of population over the 60 years of follow-up. The current programme has a greater absolute impact on health for those living in the most deprived areas compared to those living in the least deprived areas (4.4 [2.7–6.5] days of additional quality-adjusted life per head of population versus 2.8 [1.7–4.0] days; 5.1 [3.4–7.1] additional days lived per head of population versus 3.3 [2.1–4.5] days). Making feasible changes to the delivery of the existing programme could result in a sizable increase in the benefit. For example, a strategy that combines extending eligibility to those with preexisting hypertension, extending the upper age of eligibility to 79 years, increasing uptake of health checks by 30%, and increasing treatment rates 2.5-fold amongst eligible patients (i.e., ‘maximum potential’ scenario) results in at least a 3-fold increase in benefits compared to the current programme (1,360 premature deaths versus 390; 5,100 people free of 1 of the 4 diseases versus 1,370; 37,000 additional QALYs versus 10,000; 33,000 additional years of life versus 9,000). Ensuring those who are assessed and eligible for statins receive statins is a particularly important strategy to increase benefits. Estimates of overall benefit are based on current incidence and management, and future declines in disease incidence or improvements in treatment could alter the actual benefits observed in the long run. We have focused on the cardiovascular element of the NHS Health Check programme. Some important noncardiovascular health outcomes (e.g., chronic obstructive pulmonary disease [COPD] prevention from smoking cessation and cancer prevention from weight loss) and other parts of the programme (e.g., brief interventions to reduce harmful alcohol consumption) have not been modelled. Conclusions Our model indicates that the current NHS Health Check programme is contributing to improvements in health and reducing health inequalities. Feasible changes in the organisation of the programme could result in more than a 3-fold increase in health benefits.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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