CaRLO

Description: Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

Description: Pallidal deep brain stimulation (DBS) is an increasingly used therapy for Parkinson’s disease (PD). Here, we study the effect of DBS on pallidal oscillatory activity as well as on symptom severity in an individual with PD implanted with a new pulse generator (Medtronic Percept system) which facilitates chronic recording of local field potentials (LFP) through implanted DBS lead. Pallidal LFPs were recorded while delivering stimulation in a monopolar configuration using stepwise increments (0.5 mA, every 20 s). At each stimulation amplitude, the power spectral density (PSD) was computed, and beta power (13–30 Hz) was calculated and correlated with the degree of bradykinesia. Pallidal beta power was reduced when therapeutic stimulation was delivered. Beta power correlated to the severity of bradykinesia. Worsening of parkinsonism when excessive stimulation was applied was associated with a rebound in the beta band power. These preliminary results suggest that pallidal beta power might be used as an objective marker of the disease state in PD. The use of brain sensing from implanted neural interfaces may in the future facilitate clinical programming. Detection of rebound could help to optimize benefits and minimize worsening from overstimulation.

Description: Lower respiratory tract infections are associated with high morbidity and mortality and significant clinical harm. Due to the limited ability of traditional pathogen detection methods, anti-infective therapy is mostly empirical. Therefore, it is difficult to adopt targeted drug therapy. In recent years, metagenomic next-generation sequencing (mNGS) technology has provided a promising means for pathogen-specific diagnosis and updated the diagnostic strategy for lower respiratory tract infections. This article reviews the diagnostic value of mNGS for lower respiratory tract infections, the impact of different sampling methods on the detection efficiency of mNGS, and current technical difficulties in the clinical application of mNGS.

Description: Extrachromosomal circular DNA (eccDNA), existing as double-stranded circular DNA, is derived and free from chromosomes. It is common in eukaryotes but has a strong heterogeneity in count, length, and origin. It has been demonstrated that eccDNA could function in telomere and rDNA maintenance, aging, drug resistance, tumorigenesis, and phenotypic variations of plants and animals. Here we review the current knowledge about eccDNA in category, biogenesis, recognition, and functions. We also provide perspectives on the potential implications of eccDNA in life science.

Description: As a pivotal regulator of 5’ splice site recognition, U1 small nuclear ribonucleoprotein (U1 snRNP)-specific protein C (U1C) regulates pre-mRNA splicing by interacting with other components of the U1 snRNP complex. Previous studies have shown that U1 snRNP and its components are linked to a variety of diseases, including cancer. However, the phylogenetic relationships and expression profiles of U1C have not been studied systematically. To this end, we identified a total of 110 animal U1C genes and compared them to homologues from yeast and plants. Bioinformatics analysis shows that the structure and function of U1C proteins is relatively conserved and is found in multiple copies in a few members of the U1C gene family. Furthermore, the expression patterns reveal that U1Cs have potential roles in cancer progression and human development. In summary, our study presents a comprehensive overview of the animal U1C gene family, which can provide fundamental data and potential cues for further research in deciphering the molecular function of this splicing regulator.

Description: BackgroundApparent diffusion coefficients (ADCs) obtained with diffusion-weighted imaging (DWI) are highly valuable for the detection and staging of prostate cancer and for assessing the response to treatment. However, DWI suffers from significant anatomic distortions and susceptibility artifacts, resulting in reduced accuracy and reproducibility of the ADC calculations. The current methods for improving the DWI quality are heavily dependent on software, hardware, and additional scan time. Therefore, their clinical application is limited. An accelerated ADC generation method that maintains calculation accuracy and repeatability without heavy dependence on magnetic resonance imaging scanners is of great clinical value.ObjectivesWe aimed to establish and evaluate a supervised learning framework for synthesizing ADC images using generative adversarial networks.MethodsThis prospective study included 200 patients with suspected prostate cancer (training set: 150 patients; test set #1: 50 patients) and 10 healthy volunteers (test set #2) who underwent both full field-of-view (FOV) diffusion-weighted imaging (f-DWI) and zoomed-FOV DWI (z-DWI) with b-values of 50, 1,000, and 1,500 s/mm2. ADC values based on f-DWI and z-DWI (f-ADC and z-ADC) were calculated. Herein we propose an ADC synthesis method based on generative adversarial networks that uses f-DWI with a single b-value to generate synthesized ADC (s-ADC) values using z-ADC as a reference. The image quality of the s-ADC sets was evaluated using the peak signal-to-noise ratio (PSNR), root mean squared error (RMSE), structural similarity (SSIM), and feature similarity (FSIM). The distortions of each ADC set were evaluated using the T2-weighted image reference. The calculation reproducibility of the different ADC sets was compared using the intraclass correlation coefficient. The tumor detection and classification abilities of each ADC set were evaluated using a receiver operating characteristic curve analysis and a Spearman correlation coefficient.ResultsThe s-ADCb1000 had a significantly lower RMSE score and higher PSNR, SSIM, and FSIM scores than the s-ADCb50 and s-ADCb1500 (all P 〈 0.001). Both z-ADC and s-ADCb1000 had less distortion and better quantitative ADC value reproducibility for all the evaluated tissues, and they demonstrated better tumor detection and classification performance than f-ADC.ConclusionThe deep learning algorithm might be a feasible method for generating ADC maps, as an alternative to z-ADC maps, without depending on hardware systems and additional scan time requirements.

Description: Purpose: In this study, a novel surgical technique was developed for umbilical hernias, in which a laparoscopic cephalic approach plus a posterior sheath and an extraperitoneal approach was employed. The aim of this study was to determine the results of this new technique.Methods: From 2019 to 2020, 21 patients (81.8% men) with an umbilical hernia underwent a laparoscopic cephalic approach plus a posterior sheath and extraperitoneal approach, performed by two surgeons specializing in abdominal wall surgery, in two academic hospitals. Intraoperative and postoperative complications, operation time, blood loss, and hernia recurrence were assessed.Results: Twenty-one cases of umbilical hernia were successfully completed. The size of the hernia ring was 1.5–3 cm2, with an average of 2.39 ± 0.47 cm2. The operation time was 120–240 min (average, 177.3 ± 42.15 min), and the blood loss volume was 30–40 ml (average, 33.73 ± 3.55 ml). The mean follow-up period was 6 months, and there were no short-term complications and no cases of recurrence.Conclusion: A laparoscopic cephalic approach plus a posterior sheath and extraperitoneal approach is a safe alternative for the repair of an umbilical hernia. The intraoperative complication rate was low.

Description: BackgroundSepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown.MethodsPeripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro.ResultsOur results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1β, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-β.ConclusionsCollectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.

Description: Low bone mineral density (BMD) is an emerging health issue in adults with cerebral palsy (CP). This cross-sectional study aimed to describe the characteristics of BMD in adults with CP, and to elucidate the risk factors for low BMD in this population. People aged ≥20 years and diagnosed with CP were recruited from February 2014 to November 2014. We assessed BMD using dual-energy X-ray absorptiometry (DXA) for the lumbar spine, femoral neck, and total femur. Moreover, the body composition was assessed using DXA. We included a total of 87 adults with CP (mean age 42.01 years; 52 men). The prevalence of low BMD was 25.3%. Male sex and age were associated with lower BMD. BMD was significantly lower in the non-ambulatory group than that in the ambulatory group for both lumbar spine and femoral neck. The total fat mass demonstrated a positive correlation with the Z-score and BMD for the femur neck and total femur. Body mass index (BMI) and total fat mass were positively correlated with BMD in the lumbar spine, femoral neck, and total femur. However, the Gross Motor Function Classification Scale levels were negatively correlated with BMD at the aforementioned three sites. In conclusion, adults with CP revealed decreased BMD, which was associated with male sex, age, decreased gross motor function, loss of ambulatory function, low BMI, decreased total fat mass, and decreased total fat-free mass.

Description: A larger number of patients with stages I–III hepatocellular carcinoma (HCC) experience late recurrence (LR) after surgery. We sought to develop a novel tool to stratify patients with different LR risk for tailoring decision-making for postoperative recurrence surveillance and therapy modalities. We retrospectively enrolled two independent public cohorts and 103 HCC tissues. Using LASSO logical analysis, a six-gene model was developed in the The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) and independently validated in GSE76427. Further experimental validation using qRT-PCR assays was performed to ensure the robustness and clinical feasible of this signature. We developed a novel LR-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in three cohorts TCGA-LIHC, GSE76427, and qPCR assays [HR: 2.007 (1.200–3.357), p = 0.008; HR: 2.171 (1.068, 4.412), p-value = 0.032; HR: 3.383 (2.100, 5.450), p-value

Description: CD8 T cell memory offers critical antiviral protection, even in the absence of neutralizing antibodies. The paradigm is that CD8 T cell memory within the lung tissue consists of a mix of circulating TEM cells and non-circulating TRM cells. However, based on our analysis, the heterogeneity within the tissue is much higher, identifying TCM, TEM, TRM, and a multitude of populations which do not perfectly fit these classifications. Further interrogation of the populations shows that TRM cells that express CD49a, both with and without CD103, have increased and diverse effector potential compared with CD49a negative populations. These populations function as a one-man band, displaying antiviral activity, chemokine production, release of GM-CSF, and the ability to kill specific targets in vitro with delayed kinetics compared with effector CD8 T cells. Together, this study establishes that CD49a defines multiple polyfunctional CD8 memory subsets after clearance of influenza infection, which act to eliminate virus in the absence of direct killing, recruit and mature innate immune cells, and destroy infected cells if the virus persists.

Description: Lightweight structures produced by additive manufacturing (AM) technology such as the selective laser melting (SLM) process enable the fabrication of 3D structures with a high degree of freedom. A printed component can be tailored to have specific properties and render possible applications for industries such as the aerospace and automotive industries. Here, AlSi10Mg is one of the alloys that is currently used for SLM processes. Although the research with the aim improving the strength of AM aluminum alloy components is rapidly progressing, corrosion protection is scarcely addressed in this field. Plasma electrolytic oxidation (PEO) is an advanced electrolytical process for surface treatment of light metals such as aluminum, magnesium, and titanium. This process produces an oxide ceramic-like layer, which is extremely hard but also ductile, and significantly improves the corrosion and wear behavior. The aim of this study is to understand the corrosion behavior of 3D-printed AlSi10Mg alloy and to improve its corrosion resistance. For this reason, the properties of CERANOD®—PEO coating on an AlSi10Mg alloy produced by SLM were investigated on different AM surfaces, i.e., as-built, polished and stress relieved specimens. The corrosion performance of these surfaces was analyzed using electrochemical impedance spectroscopy (EIS), potentiodynamic polarization, and long-term immersion tests. Moreover, the microstructure and morphology of the resulting coatings were characterized by SEM/EDS, taking into account the corrosive attacks. The results exhibited a high amount of localized corrosion in the case of the uncoated specimens, while the PEO process conducted on the aluminum AM surfaces led to enclosed homogeneous coatings by protecting the material’s pores, which are typically observed in AM process. Thereby, high corrosion protection could be achieved using PEO surfaces, suggesting that this technology is a promising candidate for unleashing the full potential of 3D light metal printing.

Description: Despite the use of gear requirements and access restrictions to manage lobster fishery interactions with north Atlantic right whales since 1997, the population is likely below 370 animals. The Dynamic Area Management (DAM) program (2002–2009) used “real-time” right whale sightings data to provide temporary protection using closures or whale-modified-gear to reduce entanglement. Our ex-post evaluation uses a flexible framework to identify strengths and weaknesses of the program. Biological and economic implications of the program are evaluated using a relative risk of entanglement index (RREI) calculated with spatially and temporally explicit data on density of right whales and fishing effort. An illustrative closure optimization model demonstrates the trade-offs between the non-monetary benefits of risk reduction and the opportunity cost of closures under alternative decision rules (benefit-ranking and cost-effectiveness). Annual aerial sampling to detect DAM areas was low (

Description: Mucosa-associated lymphoid tissue (MALT) lymphoma arises in extra-nodal sites from the malignant transformation of B lymphocytes that are mainly triggered by infection or autoimmune process. MALT lymphoma is frequently detected in the gastrointestinal tract. As the causal relationship between Helicobacter pylori (H. pylori) infection and gastric MALT lymphoma, it was well-established that early-stage gastric MALT lymphoma could be cured by H. pylori eradication, and about 50–95% of cases achieved complete response with anti-H. pylori treatment. Compared to the stomach which is the most involved site due to the high prevalence of H. pylori infection, the colorectum is rarely affected. Primary rectal MALT lymphoma is a rare malignancy, and there are no specific therapeutic strategies so far. Here we report a case of rectal MALT lymphoma successfully resected by endoscopic submucosal dissection (ESD). ESD serves as a novel strategy to cure small localized rectal MALT lymphomas to avoid unnecessary surgery or chemo-radiotherapy.

Description: Patients with human papillomavirus (HPV) negative oral squamous cell carcinoma (OSCC) generally have poor clinical outcomes and worse responses to radiotherapy. It is urgent to explore the underlining mechanisms of the distinct prognoses between HPV negative and HPV positive OSCC and to develop effective therapy strategy to increase the survival rate of HPV negative OSCC patients. We conducted a retrospective cohort of 99 resected OSCC patients to evaluate the prognosis of HPV negative and HPV positive OSCC patients receiving radiation or not. We further addressed the association of CD68+ macrophage infiltration with HPV status and the effects on survival of OSCC patients. We also used the TCGA-OSCC cohort for further verification. Based on the cohort study, we applied a synthetic dsRNA polymer, polyriboinosinic-polyribocytidylic acid (poly(I:C)), on CAL-27 (HPV negative OSCC cells). We co-cultured its condition medium with THP-1 derived macrophage and examined the cytokines and macrophage migration. We found that high CD68+ macrophage infiltration associated with poor overall survival in HPV negative OSCC patients receiving radiation. In vitro, poly(I:C) could induce apoptosis and enhance the radiosensitivity, but increase macrophage recruitment. Targeting HMGB1 could inhibit IL-6 induction and macrophage recruitment. Our findings indicated that CD68+ macrophage might play an important role in the outcomes of HPV negative OSCC patients receiving radiation. Our findings also suggested that radiation combined poly(I:C) might be a potential therapy strategy to increase the radiation response and prognosis of HPV negative OSCC. Notably, HMGB1 should be targeted to inhibit macrophage recruitment and enhance overall therapy effects.

Description: Introduction: As non-small cell lung cancer (NSCLC) seriously threatens human health, several clinical studies have reported that Chinese herbal injections (CHIs) in combination with and gemcitabine plus cisplatin (GP) are beneficial. This multidimensional network meta-analysis aimed to compare the clinical efficacy and safety of different CHIs in combination with GP against NSCLC.Methods: Randomized controlled trials (RCTs) for the treatment of NSCLC were retrieved from seven electronic databases from inception to April 30, 2020. Study selection and data extraction were based on a priori criteria. Data analysis was performed using Stata 13.0, WinBUGS 14.0 software. Multidimensional cluster analysis was performed using the “scatterplot3d” package in R 3.6.1 software.Results: This network meta-analysis included 71 eligible RCTs and 10 Chinese herbal injections. Delisheng injection and Kangai injection had the highest probability in terms of clinical effectiveness rate (94.60%) and gastrointestinal reactions (82.62%) when combined with GP compared with the other interventions. Compound Kushen injection combined with GP ranked ahead of the other interventions in terms of performance status (73.36%) and abnormal liver function (87.17%). Shenmai injection combined with GP had the highest probability in terms of leukopenia (94.59%) and thrombocytopenia (99.18%).Conclusion: The current evidence revealed that CHIs combined with GP have a better impact on patients with NSCLC than GP alone. Aidi injection, Compound kushen injection, and Kanglaite injection deserve more attention of clinicians when combined with GP in patients with NSCLC. Additionally, due to the limitations of this network meta-analysis, further well-designed, large-sample, multicenter RCTs are required to support our findings adequately.

Description: BackgroundRecently, albumin–globulin ratio (AGR), a serological indicator that reflects nutritional status and systemic inflammatory, has been reported to be associated with the prognosis of various cancers. However, there is currently no research report on its relationship with cancer cachexia.ObjectivesThis study aimed to explore the prognostic value of AGR in patients with cancer cachexia through a multicenter retrospective analysis.MethodsWe recruited 2,364 patients with cancer cachexia and randomly divided the patients into training and validation cohorts at a ratio of 7:3. The optimal stratification method was used to determine the optimal cutoff value of AGR. The survival curve was evaluated by the Kaplan–Meier method. Cox regression proportional-hazards model was used to determine independent prognostic factors in patients with cancer cachexia. The time-dependent receiver operating characteristic curve was used to compare the prognostic performance of different malnutrition evaluation tools.ResultsThe optimal cutoff value of AGR is 1.24 in patients with cancer cachexia. Increasing AGR was associated with survival in a dose–response manner with a forward L-shape. Compared with the high AGR group, the low AGR group had a shorter overall survival; and there was consistency in training and validation cohorts. In the stratified analysis of TNM stage, AGR has good prognostic distinguishing ability for advanced patients. Multivariate survival analysis determined that low AGR was an independent risk factor affecting all-cause mortality in patients with cancer cachexia. In addition, compared with other malnutrition evaluation tools, AGR could effectively stratify the prognosis of patients with cancer cachexia.ConclusionAGR was an independent prognostic factor affecting patients with cancer cachexia, especially in advanced patients. Compared with other malnutrition evaluation tools, AGR can effectively stratify the prognosis of patients with cancer cachexia.

Description: The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC.

Description: The Wlds mutation, which arose spontaneously in C57Bl/6 mice, remarkably delays the onset of Wallerian degeneration of axons. This remarkable phenotype has transformed our understanding of mechanisms contributing to survival vs. degeneration of mammalian axons after separation from their cell bodies. Although there are numerous studies of how the Wlds mutation affects axon degeneration, especially in the peripheral nervous system, less is known about how the mutation affects degeneration of CNS synapses. Here, using electron microscopy, we explore how the Wlds mutation affects synaptic terminal degeneration and withering and re-growth of dendritic spines on dentate granule cells following lesions of perforant path inputs from the entorhinal cortex. Our results reveal that substantial delays in the timing of synapse degeneration in Wlds mice are accompanied by paradoxical hypertrophy of spine heads with enlargement of post-synaptic membrane specializations (PSDs) and development of spinules. These increases in the complexity of spine morphology are similar to what is seen following induction of long-term potentiation (LTP). Robust and paradoxical spine growth suggests yet to be characterized signaling processes between amputated but non-degenerating axons and their postsynaptic targets.

Description: Systemic antifungal agents are increasingly used for prevention or treatment of invasive fungal infections, whose prognosis remains poor. At the same time, emergence of resistant or even multi-resistant strains is of concern as the antifungal arsenal is limited. Antifungal susceptibility testing (AFST) is therefore of key importance for patient management and antifungal stewardship. Current AFST methods, including reference and commercial types, are based on growth inhibition in the presence of an antifungal, in liquid or solid media. They usually enable Minimal Inhibitory Concentrations (MIC) to be determined with direct clinical application. However, they are limited by a high turnaround time (TAT). Several innovative methods are currently under development to improve AFST. Techniques based on MALDI-TOF are promising with short TAT, but still need extensive clinical validation. Flow cytometry and computed imaging techniques detecting cellular responses to antifungal stress other than growth inhibition are also of interest. Finally, molecular detection of mutations associated with antifungal resistance is an intriguing alternative to standard AFST, already used in routine microbiology labs for detection of azole resistance in Aspergillus and even directly from samples. It is still restricted to known mutations. The development of Next Generation Sequencing (NGS) and whole-genome approaches may overcome this limitation in the near future. While promising approaches are under development, they are not perfect and the ideal AFST technique (user-friendly, reproducible, low-cost, fast and accurate) still needs to be set up routinely in clinical laboratories.

Description: Mycobacterium lepromatosis was identified as a new species and second causal agent of Hansen’s disease (HD, or leprosy) in 2008, 150years after the disease was first attributed to Mycobacterium leprae. M. lepromatosis has been implicated in a small number of HD cases, and clinical aspects of HD caused by M. lepromatosis are poorly characterized. HD is a recognized zoonosis through transmission of M. leprae from armadillos, but the role of M. lepromatosis as a zoonotic agent of HD is unknown. M. lepromatosis was initially associated with diffuse lepromatous leprosy, but subsequent case reports and surveys have linked it to other forms of HD. HD caused by M. lepromatosis has been reported from three endemic countries: Brazil, Myanmar, and Philippines, and three non-endemic countries: Mexico, Malaysia, and United States. Contact with armadillos in Mexico was mentioned in 2/21 M. lepromatosis HD case reports since 2008. M. lepromatosis in animals has been investigated only in non-endemic countries, in squirrels and chipmunks in Europe, white-throated woodrats in Mexico, and armadillos in the United States. To date, there have only been a small number of positive findings in Eurasian red squirrels in Britain and Ireland. A single study of environmental samples found no M. lepromatosis in soil from a Scottish red squirrel habitat. Future studies must focus on endemic countries to determine the true proportion of HD cases caused by M. lepromatosis, and whether viable M. lepromatosis occurs in non-human sources.

Description: The newborns of women infected with the parasite Trypanosoma cruzi (the agent of Chagas disease) can be infected either before birth (congenitally), or after birth (as e.g., by vector route). Congenital Chagas disease can induce high levels of neonatal morbidity and mortality. Parasite-infected pregnant women transmit antibodies to their fetus. Antibodies, by opsonizing parasites, can promote phagocytosis and killing of T. cruzi by cells expressing FcγR, on the mandatory condition that such cells are sufficiently activated in an inflammatory context. Antibody-dependent enhancement (ADE) is a mechanism well described in viral infections, by which antibodies enhance entry of infectious agents into host cells by exploiting the phagocytic FcγR pathway. Previously reported Chagas disease studies highlighted a severe reduction of the maternal-fetal/neonatal inflammatory context in parasite-transmitting pregnant women and their congenitally infected newborns. Otherwise, experimental observations brought to light ADE of T. cruzi infection (involving FcγR) in mouse pups displaying maternally transferred antibodies, out of an inflammatory context. Herein, based on such data, we discuss the previously unconsidered possibility of a role of ADE in the trans-placental parasite transmission, and/or the development of severe and mortal clinical forms of congenital/neonatal Chagas disease in newborns of T. cruzi-infected mothers.

Description: The relative importance of different ecological processes controlling biofilm community assembly over time on membranes with different surface characteristics has never been investigated in membrane bioreactors (MBRs). In this study, five ultrafiltration hollow-fiber membranes – having identical nominal pore size (0.1μm) but different hydrophobic or hydrophilic surface characteristics – were operated simultaneously in the same MBR tank with a constant flux of 10 liters per square meter per hour (LMH). In parallel, membrane modules operated without permeate flux (0 LMH) were submerged in the same MBR tank, to investigate the passive microbial adsorption onto different hydrophobic or hydrophilic membranes. Samples from the membrane biofilm were collected after 1, 10, 20, and 30days of continuous filtration. The membrane biofilm microbiome were investigated using 16S rRNA gene amplicon sequencing from DNA and cDNA samples. Similar beta diversity trends were observed for both DNA- and cDNA-based analyses. Beta diversity analyses revealed that the nature of the membrane surface (i.e., hydrophobic vs. hydrophilic) did not seem to have an effect in shaping the bacterial community, and a similar biofilm microbiome evolved for all types of membranes. Similarly, membrane modules operated with and without permeate flux did not significantly influence alpha and beta diversity of the membrane biofilm. Nevertheless, different-aged membrane biofilm samples exhibited significant differences. Proteobacteria was the most dominant phylum in early-stage membrane biofilm after 1 and 10days of filtration. Subsequently, the relative reads abundance of the phyla Bacteroidetes and Firmicutes increased within the membrane biofilm communities after 20 and 30days of filtration, possibly due to successional steps that lead to the formation of a relatively aged biofilm. Our findings indicate distinct membrane biofilm assembly patterns with different-aged biofilm. Ecological null model analyses revealed that the assembly of early-stage biofilm community developed after 1 and 10days of filtration was mainly governed by homogenous selection. As the biofilm aged (days 20 and 30), stochastic processes (e.g., ecological drift) started to become important in shaping the assembly of biofilm community.

Description: Background: Maximum oxygen uptake (VO2max) is an important respiratory physiological index of the aerobic endurance of the body, especially for special groups such as drug addicts, and it is an important indicator for assessing the cardiopulmonary function and formulating exercise prescriptions. Although the cardiopulmonary exercise test (CPX) is a classic method to directly measure VO2max, this method is limited by factors such as cumbersome operating procedures and expensive equipment, resulting in its relatively low applicability. Recently, many studies have begun to focus on the estimation of VO2max in different groups of people, but few studies have focused on drug addicts.Methods: Fifteen chemically synthesized drug addicts (such as amphetamines) and Fifteen plant-derived drug addicts (such as heroin) were recruited at the Chongqing Compulsory Isolation and Drug Rehabilitation Center in China. First, the VO2max of subjects was directly measured through the CPX. Second, after subjects were fully rested, they were required to complete the 30-s high-leg raise, 1,000-m walk, and 3-min step experiment. Finally, SPSS 21.0 software was used to perform the correlation and linear regression analysis to verify the estimated effectiveness.Results: (1) Regardless of chemically synthesized or natural plant-derived drug addicts, the years of drug use and walking time of 1,000 m were significantly negatively correlated with VO2max (chemically synthesized: P 〈 0.01 and natural plant-derived: P 〈 0.05), the number of 30-s high-leg raises was a significantly positive correlation with VO2max (P 〈 0.05 and P 〈 0.01), and the 3-min step index was significantly positively correlated with VO2max (P 〈 0.01 and P 〈 0.01). (2) Regression analysis shows that the 30-s high-leg lift, 1,000-m walking, and 3-min step experiment could effectively estimate the VO2max of chemically synthesized and natural plant-derived drug addicts. (3) Multiple linear regression constructed by the years of drug use combined with the step index has the highest estimated accuracy for the VO2max of chemically synthesized drug addicts (96.48%), while the unary regression equation established by a single step index has the highest prediction accuracy for the VO2max of natural plant-derived addicts (94.30%).Conclusion: The indirect measurement method could effectively estimate the VO2max of drug addicts, but different measurement methods have certain differences in the estimation accuracy of VO2max of different drug addicts. In the future, the physical characteristics of drug users can be fully considered, combined with more cutting-edge science and technology, to make the estimation accuracy of VO2max closer to the real level.

Description: Background: Hospital wastewater is a major source of antimicrobial resistance (AMR) outflow into the environment. This study uses metagenomics to study how hospital clinical activity impacts antimicrobial resistance genes (ARGs) abundances in hospital wastewater.Methods: Sewage was collected over a 24-h period from multiple wastewater collection points (CPs) representing different specialties within a tertiary hospital site and simultaneously from community sewage works. High throughput shotgun sequencing was performed using Illumina HiSeq4000. ARG abundances were correlated to hospital antimicrobial usage (AMU), data on clinical activity and resistance prevalence in clinical isolates.Results: Microbiota and ARG composition varied between CPs and overall ARG abundance was higher in hospital wastewater than in community influent. ARG and microbiota compositions were correlated (Procrustes analysis, p=0.014). Total antimicrobial usage was not associated with higher ARG abundance in wastewater. However, there was a small positive association between resistance genes and antimicrobial usage matched to ARG phenotype (IRR 1.11, CI 1.06–1.16, p

Description: Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.

Description: The most likely cause of lower-leg swelling is prolonged sitting, which sometimes induces deep vein thrombosis, also known as, economy class syndrome. We aimed to clarify the influence of intake of 4G-α-glucopyranosyl hesperidin (G-Hsp) beverage on the lower-leg swelling caused by 6 h of sitting in six healthy women. All subjects ingested 100 mL of G-Hsp or Placebo beverages with 100 mL of mineral water after 10 min of rest in a chair. Subsequently, subjects were requested to sit in the chair in a relaxed position for 6 h with two breaks to walk for urination. Calf water content measured by impedance plethysmography, calf circumference, and calf skin temperature by infrared thermography were measured, along with assessment of calf swelling sensation on a visual analog scale. Increase in ankle % circumference was significantly less after the G-Hsp ingestion (101.8 ± 1.5%) than after placebo (103.3 ± 0.8%; P = 0.004). A significant difference was found between percent circumference after the G-Hsp and the placebo, that is, the calf swelling after the placebo was significantly larger (P = 0.043). A gradual increase in skin temperature at the lower limb was observed after G-Hsp ingestion, while there was no change after placebo. Gravity-induced calf and ankle swelling resulted by prolonged sitting can be ameliorated by oral ingestion of hesperidin-derived G-Hsp through production of nitric oxide. It might be helpful in preventing economy-class syndrome caused by enforced sitting for a long duration.

Description: A novel treatment involving enzymatic hydrolysis using an acidic xylanase coupled with ultrasound was performed to improve the xylo-oligosaccharides (XOS) yield from corncob bran. The acidic xylanase (XynB) was purified to a most suitable pH, temperature, and operational parameters for ultrasound-assisted hydrolysis were determined. A preliminary mechanistic investigation was performed through circular dichroism (CD) spectroscopy, scanning electron microscope (SEM) and a laser particle size analyzer, and the effects of ultrasound on enzyme (XynB) and substrate (corncob bran) were assessed. The results show that the maximum XOS yield was 20.71% when the reaction pH and temperature were 4.3 and 50°C, the ultrasonic parameters were 50 kHz and 0.40 W/cm2, which was 2.55 fold higher than that obtained using a non-ultrasound-assisted enzymatic preparation. Mechanism studies indicated that ultrasonic pretreatment could reduce the β-fold content and increase the random coil content. Changes in structure and size of substrate were observed. The specific surface area of the XAC molecules is easy to carry out enzymatic reaction, which is beneficial to the production of XOS.

Description: Flowering is an integral part of the life cycle of flowering plants, which is essential for plant survival and crop production. Most woody fruit trees such as apples and pears bloom in spring, but loquat blooms in autumn and winter. Gibberellin (GA) plays a key role in the regulation of plant flower formation. In this study, we sprayed loquat plants with exogenous GA3, which resulted in vigorous vegetative growth rather than floral bud formation. We then performed a comprehensive RNA-seq analysis on GA3-treated and control-treated leaves and buds over three time periods to observe the effects of exogenous GA3 application on floral initiation and development. The results showed that 111 differentially expressed genes (DEGs) and 563 DEGs were down-regulated, and 151 DEGs and 506 DEGs were up-regulated in buds and leaves, respectively, upon treatment with GA3. Among those that are homologs of the DELLA-mediated GA signal pathway genes, some may be involved in the positive regulation of flower development, including EjWRKY75, EjFT, EjSOC1, EjAGL24, EjSPL, EjLFY, EjFUL, and EjAP1; while some may be involved in the negative regulation of flower development, including EjDELLA, EjMYC3, EjWRKY12, and EjWRKY13. Finally, by analyzing the co-expression of DEGs and key floral genes EjSOC1s, EjLFYs, EjFULs, EjAP1s, 330 candidate genes that may be involved in the regulation of loquat flowering were screened. These genes belong to 74 gene families, including Cyclin_C, Histone, Kinesin, Lipase_GDSL, MYB, P450, Pkinase, Tubulin, and ZF-HD_dimer gene families. These findings provide new insights into the regulation mechanism of loquat flowering.

Description: It is known that the microbiome affects human physiology, emotion, disease, growth, and development. Most humans exhibit reduced appetites under high temperature and high humidity (HTHH) conditions, and HTHH environments favor fungal growth. Therefore, we hypothesized that the colonic mycobiota may affect the host’s appetite under HTHH conditions. Changes in humidity are also associated with autoimmune diseases. In the current study mice were fed in an HTHH environment (32°C ± 2°C, relative humidity 95%) maintained via an artificial climate box for 8 hours per day for 21 days. Food intake, the colonic fungal microbiome, the feces metabolome, and appetite regulators were monitored. Components of the interleukin 17 pathway were also examined. In the experimental groups food intake and body weight were reduced, and the colonic mycobiota and fecal metabolome were substantially altered compared to control groups maintained at 25°C ± 2°C and relative humidity 65%. The appetite-related proteins LEPT and POMC were upregulated in the hypothalamus (p 〈 0.05), and NYP gene expression was downregulated (p 〈 0.05). The expression levels of PYY and O-linked β-N-acetylglucosamine were altered in colonic tissues (p 〈 0.05), and interleukin 17 expression was upregulated in the colon. There was a strong correlation between colonic fungus and sugar metabolism. In fimo some metabolites of cholesterol, tromethamine, and cadaverine were significantly increased. There was significant elevation of the characteristic fungi Solicoccozyma aeria, and associated appetite suppression and interleukin 17 receptor signaling activation in some susceptible hosts, and disturbance of gut bacteria and fungi. The results indicate that the gut mycobiota plays an important role in the hypothalamus endocrine system with respect to appetite regulation via the gut-brain axis, and also plays an indispensable role in the stability of the gut microbiome and immunity. The mechanisms involved in these associations require extensive further studies.

Description: Objectives: To systematically review studies on the effect of treatment of subjective tinnitus in children.Data Sources: We searched for studies in MEDLINE and EMBASE databases, after which additional studies were hand searched using Scopus databases. The methods are described in the study protocol, which has been registered in the PROSPERO register. PRISMA guidelines were followed in the reporting of this study.Eligibility Criteria: We considered for inclusion randomized controlled trials (RCTs), observational studies, case reports, and case series, with tinnitus as primary outcome in children (0–18 years old) with acute or chronic subjective tinnitus. We excluded studies in which both children and adults participated but outcomes were not specifically reported for children, as well as animal studies, studies with a non-original study design and studies about children with pulsatile or objective tinnitus.Data Selection: Two reviewers independently assessed studies for eligibility and quality, collected and extracted data. Statistical analyses were performed in case of homogeneous outcomes.Results: The search yielded a total of 4,447 studies. Of these, 147 eligible studies were selected. One case report and five observational studies met the eligibility criteria. Three studies applied counseling and (simplified-)TRT and reported improvement in tinnitus outcome in 68 out of 82 children after 3–6 months of treatment. Two studies used pharmacological treatments and reported improvement in 74 out of 86 patients after 10 days to 3 months of treatment. One study reported the outcome of biofeedback therapy, describing an improvement in tinnitus loudness and annoyance after 2 months of treatment.Conclusion: Due to the high risk of bias of the included studies, we cannot determine the effectiveness of the treatment of subjective tinnitus in children. Also, owing to brief follow-up periods, it is not possible to draw conclusions regarding long-term effects. Randomized controlled trials with longer follow-up periods are necessary to provide substantial evidence of the effects of therapies for children affected by tinnitus. https://www.crd.york.ac.uk/prospero/Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier [CRD42020178134].

Description: In the past decade, the Deepwater Horizon oil spill triggered a spike in investigatory effort on the effects of crude oil chemicals, most notably polycyclic aromatic hydrocarbons (PAHs), on marine organisms and ecosystems. Oysters, susceptible to both waterborne and sediment-bound contaminants due to their filter-feeding and sessile nature, have become of great interest among scientists as both a bioindicator and model organism for research on environmental stressors. It has been shown in many parts of the world that PAHs readily bioaccumulate in the soft tissues of oysters. Subsequent experiments have highlighted the negative effects associated with exposure to PAHs including the upregulation of antioxidant and detoxifying gene transcripts and enzyme activities such as Superoxide dismutase, Cytochrome P450 enzymes, and Glutathione S-transferase, reduction in DNA integrity, increased infection prevalence, and reduced and abnormal larval growth. Much of these effects could be attributed to either oxidative damage, or a reallocation of energy away from critical biological processes such as reproduction and calcification toward health maintenance. Additional abiotic stressors including increased temperature, reduced salinity, and reduced pH may change how the oyster responds to environmental contaminants and may compound the negative effects of PAH exposure. The negative effects of acidification and longer-term salinity changes appear to add onto that of PAH toxicity, while shorter-term salinity changes may induce mechanisms that reduce PAH exposure. Elevated temperatures, on the other hand, cause such large physiological effects on their own that additional PAH exposure either fails to cause any significant effects or that the effects have little discernable pattern. In this review, the oyster is recognized as a model organism for the study of negative anthropogenic impacts on the environment, and the effects of various environmental stressors on the oyster model are compared, while synergistic effects of these stressors to PAH exposure are considered. Lastly, the understudied effects of PAH photo-toxicity on oysters reveals drastic increases to the toxicity of PAHs via photooxidation and the formation of quinones. The consequences of the interaction between local and global environmental stressors thus provide a glimpse into the differential response to anthropogenic impacts across regions of the world.

Description: The worldwide spread of COVID-19 dramatically influences the world economic landscape. In this paper, we have quantitatively investigated the time-frequency co-movement impact of COVID-19 on U.S. and China stock market since early 2020 in terms of daily observation from National Association of Securities Dealers Automated Quotations Index (NDX), Dow Jones Industrial Average (DJIA), Standard & Poor's 500 Index (SPX), Shanghai Securities Composite Index (SSEC), Shenzhen Securities Component Index (SZI), in favor of spatiotemporal interactions over investor sentiment index, and propose to explore the divisibility and the predictability to the volatility of stock market during the development of COVID-19. We integrate evidence yielded from wavelet coherence and phase difference to suggest the responses of stock market indexes to the COVID-19 epidemic in a long-term band, which could be roughly divided into three distinguished phases, namely, 30–75, 110–150, and 220–280 business days for China, and 80–125 and 160–175 after 290 business days for the U.S. At the first phase, the reason for the extreme volatility of stock market mainly attributed to the sudden emergence of the COVID-19 epidemic due to the pessimistic expectations from investors; China and U.S. stock market shared strongly negative correlation with the growing number of COVID-19 cases. At the second phase, the revitalization of stock market shared strong simultaneous moves but exhibited opposite responses to the COVID-19 impact on China and U.S. stock market; the former retained a significant negative correlation, while the latter turned to positively correlated throughout the period. At the third phase, the progress in vaccine development and economic stimulus began to impose forces to stock market; the vulnerability to COVID-19 diminished to some extent as the investor sentiment indexes rebounded. Finally, we attempted to initially establish a coarse-grained representation to stock market indexes and investor sentiment indexes, which demonstrated the homogenous spacial distribution in the vectorgraph after normalization and quantization, implying the strong consistency when filtering the frequent small fluctuations during the evolution of the COVID-19 pandemic, which might help insights into the prediction of possible status transition in stock market performance under the public health issues, potentially performing as the quantitative references in reasonably deducing the economic influences.

Description: Denitrifying microbes sequentially reduce nitrate (NO3–) to nitrite (NO2–), NO, N2O, and N2 through enzymes encoded by nar, nir, nor, and nos. Some denitrifiers maintain the whole four-gene pathway, but others possess partial pathways. Partial denitrifiers may evolve through metabolic specialization whereas complete denitrifiers may adapt toward greater metabolic flexibility in nitrogen oxide (NOx–) utilization. Both exist within natural environments, but we lack an understanding of selective pressures driving the evolution toward each lifestyle. Here we investigate differences in growth rate, growth yield, denitrification dynamics, and the extent of intermediate metabolite accumulation under varying nutrient conditions between the model complete denitrifier Pseudomonas aeruginosa and a community of engineered specialists with deletions in the denitrification genes nar or nir. Our results in a mixed carbon medium indicate a growth rate vs. yield tradeoff between complete and partial denitrifiers, which varies with total nutrient availability and ratios of organic carbon to NOx–. We found that the cultures of both complete and partial denitrifiers accumulated nitrite and that the metabolic lifestyle coupled with nutrient conditions are responsible for the extent of nitrite accumulation.

Description: Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer’s disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.

Description: Multi-omics data is frequently measured to enrich the comprehension of biological mechanisms underlying certain phenotypes. However, due to the complex relations and high dimension of multi-omics data, it is difficult to associate omics features to certain biological traits of interest. For example, the clinically valuable breast cancer subtypes are well-defined at the molecular level, but are poorly classified using gene expression data. Here, we propose a multi-omics analysis method called MONTI (Multi-Omics Non-negative Tensor decomposition for Integrative analysis), which goal is to select multi-omics features that are able to represent trait specific characteristics. Here, we demonstrate the strength of multi-omics integrated analysis in terms of cancer subtyping. The multi-omics data are first integrated in a biologically meaningful manner to form a three dimensional tensor, which is then decomposed using a non-negative tensor decomposition method. From the result, MONTI selects highly informative subtype specific multi-omics features. MONTI was applied to three case studies of 597 breast cancer, 314 colon cancer, and 305 stomach cancer cohorts. For all the case studies, we found that the subtype classification accuracy significantly improved when utilizing all available multi-omics data. MONTI was able to detect subtype specific gene sets that showed to be strongly regulated by certain omics, from which correlation between omics types could be inferred. Furthermore, various clinical attributes of nine cancer types were analyzed using MONTI, which showed that some clinical attributes could be well explained using multi-omics data. We demonstrated that integrating multi-omics data in a gene centric manner improves detecting cancer subtype specific features and other clinical features, which may be used to further understand the molecular characteristics of interest. The software and data used in this study are available at: https://github.com/inukj/MONTI.

Description: Background and Purpose: Robot-assisted cochlear implantation has recently been implemented in clinical practice; however, its effect on hearing outcomes is unknown. The aim of this preliminary study was to evaluate hearing performance 1 year post-implantation whether the electrode array was inserted manually or assisted by a robot.Methods: Forty-two profoundly deaf adults were implanted either manually (n = 21) or assisted by a robot (RobOtol®, Collin, Bagneux, France) with three different electrode array types. Participants were paired by age, and electrode array type. The scalar position of the electrode array in the cochlea was assessed by 3D reconstruction from the pre- and post-implantation computed tomography. Pure-tone audiometry and speech perception in silence (percentage of disyllabic words at 60 dB) were tested on the implanted ear 1 year post-implantation in free-field conditions. The pure-tone average was calculated at 250–500–750 Hz, 500–1,000–2,000–3,000 Hz, and 3,000–4,000–8,000 Hz for low, mid, and high frequencies, respectively.Results: One year after cochlear implantation, restoration of the high-frequency thresholds was associated with better speech perception in silence, but not with low or mid frequencies (p 〈 0.0001; Adjusted R2 = 0.64, polynomial non-linear regression). Although array translocation was similar using either technique, the number of translocated electrodes was lower when the electrode arrays had been inserted with the assistance of the robot compared with manual insertion (p = 0.018; Fisher's exact test).Conclusion: The restoration of high-frequency thresholds (3,000–4,000–8,000 Hz) by cochlear implantation was associated with good speech perception in silence. The numbers of translocated electrodes were reduced after a robot-assisted insertion.

Description: Over 90% of colorectal cancer (CRC) patients have mutations in the Wnt/β-catenin pathway, making the development of biomarkers difficult based on this critical oncogenic pathway. Recent studies demonstrate that CRC tumor niche-stromal cells can activate β-catenin in cancer-initiating cells (CICs), leading to disease progression. We therefore sought to elucidate the molecular interactions between stromal and CRC cells for the development of prognostically relevant biomarkers. Assessment of CIC induction and β-catenin activation in CRC cells with two human fibroblast cell-conditioned medium (CM) was performed with subsequent mass spectrometry (MS) analysis to identify the potential paracrine factors. In vitro assessment with the identified factor and in vivo validation using two mouse models of disease dissemination and metastasis was performed. Prediction of additional molecular players with Ingenuity pathway analysis was performed, with subsequent in vitro and translational validation using human CRC tissue microarray and multiple transcriptome databases for analysis. We found that fibroblast-CM significantly enhanced multiple CIC properties including sphere formation, β-catenin activation, and drug resistance in CRC cells. MS identified galectin-1 (Gal-1) to be the secreted factor and Gal-1 alone was sufficient to induce multiple CIC properties in vitro and disease progression in both mouse models. IPA predicted SOX9 to be involved in the Gal-1/β-catenin interactions, which was validated in vitro, with Gal-1 and/or SOX9—particularly Gal-1high/SOX9high samples—significantly correlating with multiple aspects of clinical disease progression. Stromal-secreted Gal-1 promotes CIC-features and disease dissemination in CRC through SOX9 and β-catenin, with Gal-1 and SOX9 having a strong clinical prognostic value.

Description: Porcine epidemic diarrhea virus (PEDV) is a causative agent of a highly contagious enteric disease in swine of all ages, leading to severe economic losses for the swine industry in many countries. One of the most effective approaches in controlling PEDV infection is vaccination. The ORF3 accessory protein has been proposed as a crucial viral virulence factor in a natural host. However, due to the lack of an extensive comparative study of ORF3, exactly how the ORF3 takes part in virus replication and pathogenesis as well as its role in host-virus interaction is unclear. In this review, we aim to discuss the current knowledge of ORF3 concerning its dispensability for viral replication in vitro, ability to modulate host responses, contribution to virus pathogenicity, and research gaps among ORF3 functional studies. These will be beneficial for further studies to a better understanding of PEDV biology and PEDV vaccine development.

Description: Anatomical proximity and functional correlations between the exocrine and endocrine pancreas warrant reciprocal effects between the two parts. Inflammatory diseases of the exocrine pancreas, such as acute or chronic pancreatitis, or the presence of cystic fibrosis disrupt endocrine function, resulting in diabetes of the exocrine pancreas. Although novel mechanisms are being increasingly identified, the intra- and intercellular pathways regulating exocrine–endocrine interactions are still not fully understood, making the development of new and more effective therapies difficult. Therefore, this review sought to accumulate current knowledge regarding the pathogenesis of diabetes in acute and chronic pancreatitis, as well as cystic fibrosis.

Description: The development of multicellular organisms and the uniqueness of each cell are achieved by distinct transcriptional programs. Multiple processes that regulate gene expression converge at the core promoter region, an 80 bp region that directs accurate transcription initiation by RNA polymerase II (Pol II). In recent years, it has become apparent that the core promoter region is not a passive DNA component, but rather an active regulatory module of transcriptional programs. Distinct core promoter compositions were demonstrated to result in different transcriptional outputs. In this mini-review, we focus on the role of the core promoter, particularly its downstream region, as the regulatory hub for developmental genes. The downstream core promoter element (DPE) was implicated in the control of evolutionarily conserved developmental gene regulatory networks (GRNs) governing body plan in both the anterior-posterior and dorsal-ventral axes. Notably, the composition of the basal transcription machinery is not universal, but rather promoter-dependent, highlighting the importance of specialized transcription complexes and their core promoter target sequences as key hubs that drive embryonic development, differentiation and morphogenesis across metazoan species. The extent of transcriptional activation by a specific enhancer is dependent on its compatibility with the relevant core promoter. The core promoter content also regulates transcription burst size. Overall, while for many years it was thought that the specificity of gene expression is primarily determined by enhancers, it is now clear that the core promoter region comprises an important regulatory module in the intricate networks of developmental gene expression.

Description: Background:Kodamaea ohmeri, previously known as Pichia ohmeri or Yamadazyma ohmeri, has been regarded as an emerging human pathogen in recent decades, and has caused various types of infections with high mortality. This study systematically reviewed all the published cases of K. ohmeri infection, aiming to have a better understanding of the clinical and epidemiological characteristics of the organism.Methods: All the published literature (as of March 31, 2021) on K. ohmeri, in four databases: PubMed, Embase, Web of Science, and CNKI, were systematically reviewed to select appropriate studies for summarizing the demographic information, clinical and microbiological characteristics of relevant infections.Results: A total of 51 studies involving 67 patients were included for final analysis, including 49 sporadic cases and two clusters of outbreaks. Neonates and the elderly constituted the majority of patients, and fungemia was the dominant infection type. Comorbidities (like malignancy, diabetes, and rheumatism), invasive operations, previous antibiotic use and prematurity, were commonly described in patients. Gene sequencing and broth microdilution method, were the most reliable way for the identification and antifungal susceptibility testing of K. ohmeri, respectively. Amphotericin B and fluconazole were the commonest antifungal therapies administered. The calculated mortality rates for K. ohmeri infection was higher than that of common candidemia.Conclusion: In this study, we systematically reviewed the epidemiology, clinical characteristics, microbiological features, treatment, and outcomes, of all the published cases on K. ohmeri. Early recognition and increased awareness of K. ohmeri as an emerging human pathogen by clinicians and microbiologists is important for effective management of this organism.

Description: Interfering with the ability of pathogenic bacteria to import glucose may represent a new promising antibacterial strategy, especially for the treatment of infections occurring in diabetic and other hyperglycemic patients. Such patients are particularly susceptible to infections caused by a variety of bacteria, among which opportunistic pathogens like Pseudomonas aeruginosa. In P. aeruginosa, glucose can be directly imported into the cytoplasm or after its periplasmic oxidation into gluconate and 2-ketogluconate (2-KG). We recently demonstrated that a P. aeruginosa mutant lacking the 2-KG transporter KguT is less virulent than its kguT+ parental strain in an insect infection model, pointing to 2-KG branch of glucose utilization as a possible target for anti-Pseudomonas drugs. In this work, we devised an experimental protocol to find specific inhibitors of the 2-KG pathway of P. aeruginosa glucose utilization and applied it to the screening of the Prestwick Chemical Library. By exploiting mutants lacking genes involved in the transport of glucose derivatives in the primary screening and in the secondary assays, we could identify sanguinarine as an inhibitor of 2-KG utilization. We also demonstrated that sanguinarine does not prevent 2-KG formation by gluconate oxidation or its transport, suggesting that either KguD or KguK is the target of sanguinarine in P. Aeruginosa.

Description: BackgroundGlioblastoma multiforme (GBM) is characterized by widespread genetic and transcriptional heterogeneity. Aberrant DNA methylation plays a vital role in GBM progression by regulating gene expression. However, little is known about the role of methylation and its association with prognosis in GBM. Our aim was to explore DNA methylation-driven genes (DMDGs) and provide evidence for survival prediction and individualized treatment of GBM patients.MethodsUse of the MethylMix R package identified DMDGs in GBM. The prognostic signature of DMDGs based on the risk score was constructed by multivariate Cox regression analysis. Receiver operating characteristics (ROC) curve and C-index were applied to assess the predictive performance of the DMDG prognostic signature. The predictive ability of the multigene signature model was validated in TCGA and CGGA cohorts. Finally, the role of DMDG β-Parvin (PARVB) was explored in vitro.ResultsThe prognostic signature of DMDGs was constructed based on six genes (MDK, NMNAT3, PDPN, PARVB, SERPINB1, and UPP1). The low-risk cohort had significantly better survival than the high-risk cohort (p 〈 0.001). The area under the curve of the ROC of the six-gene signature was 0.832, 0.927, and 0.980 within 1, 2, and 3 years, respectively. The C-index of 0.704 indicated superior specificity and sensitivity. The six-gene model has been demonstrated to be an independent prognostic factor for GBM. In addition, joint survival analysis indicated that the MDK, NMNAT3, PARVB, SERPINB1, and UPP1 genes were significantly associated with prognosis and therapeutic targets for GBM. Importantly, our DMDG prognostic model was more suitable and accurate for low-grade gliomas. Finally, we verified that PARVB induced epithelial-mesenchymal transition partially through the JAK2/STAT3 pathway, which in turn promoted GBM cell proliferation, migration, and invasion.ConclusionThis study demonstrated the potential value of the prognostic signature of DMDGs and provided important bioinformatic and potential therapeutic target data to facilitate individualized treatment for GBM, and to elucidate the specific mechanism by which PARVB promotes GBM progression.

Description: The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.

Description: ObjectiveThis prospective randomized trial aimed to assess the impact of the uterine manipulator in terms of lymph vascular space invasion (LVSI) in patients undergoing minimally invasive staging for early-stage endometrial cancer.MethodsIn this multicentric randomized trial, enrolled patients were randomly allocated in two groups according to the no use (arm A) or the use (arm B) of the uterine manipulator. Inclusion criteria were G1-G2 early-stage endometrial cancer at preoperative evaluation. The variables collected included baseline demographic characteristics, perioperative data, final pathology report, adjuvant treatment, and follow-up.ResultsIn the study, 154 patients (76 in arm A and 78 in arm B) were finally included. No significant differences were recorded regarding the baseline characteristics. A statistically significant difference was found in operative time for the laparoscopic staging (p=0.005), while no differences were reported for the robotic procedures (p=0.419). The estimated blood loss was significantly lower in arm A (p=0.030). No statistically significant differences were recorded between the two study groups in terms of peritoneal cytology, LVSI (p=0.501), and pattern of LVSI (p=0.790). No differences were detected in terms of overall survival and disease-free survival (p=0.996 and p=0.480, respectively). Similarly, no differences were recorded in the number of recurrences, 6 (7.9%) in arm A and 4 (5.2%) in arm B (p=0.486). The use of the uterine manipulator had no impact on DFS both at univariable and multivariable analyses.ConclusionsThe intrauterine manipulator does not affect the LVSI in early-stage endometrial cancer patients undergoing laparoscopic/robotic staging.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier (NCT: 02762214)

Description: Background: The impact of viral burden on severity and prognosis of patients hospitalized for Coronavirus Disease 2019 (COVID-19) is still a matter of debate due to controversial results. Herein, we sought to assess viral load in the nasopharyngeal swab and its association with severity score indexes and prognostic parameters.Methods: We included 127 symptomatic patients and 21 asymptomatic subjects with a diagnosis of SARS-CoV-2 infection obtained by reverse transcription polymerase chain reaction and presence of cycle threshold. According to the level of care needed during hospitalization, the population was categorized as high-intensity (HIMC, n = 76) or low intensity medical care setting (LIMC, n = 51).Results: Viral load did not differ among asymptomatic, LIMC, and HIMC SARS-CoV-2 positive patients [4.4 (2.9–5.3) vs. 4.8 (3.6–6.1) vs. 4.6 (3.9–5.7) log10 copies/ml, respectively; p = 0.31]. Similar results were observed when asymptomatic individuals were compared to hospitalized patients [4.4 (2.9–5.3) vs. 4.68 (3.8–5.9) log10 copies/ml; p = 0.13]. When the study population was divided in High (HVL, n = 64) and Low Viral Load (LVL, n = 63) group no differences were observed in disease severity at diagnosis. Furthermore, LVL and HVL groups did not differ with regard to duration of hospital stay, number of bacterial co-infections, need for high-intensity medical care and number of deaths. The viral load was not an independent risk factor for HIMC in an adjusted multivariate regression model (OR: 1.59; 95% CI: 0.46–5.55, p = 0.46).Conclusions: Viral load at diagnosis is similar in asymptomatic and hospitalized patients and is not associated with either worse outcomes during hospitalization. SARS CoV-2 viral load might not be the right tool to assist clinicians in risk-stratifying hospitalized patients.

Description: Estuaries have historically been subject to considerable habitat loss, and continue to be subjected to such in areas where the natural landward migration of intertidal habitats is constrained by hard coastal defences. Thus, in estuaries where direct (e.g., port development) or indirect (e.g., sea level rise) processes are predicted to threaten intertidal habitats and associated waterbird species, there is a regulatory requirement to produce compensatory intertidal habitats. Managed realignment (MR) is a shoreline management practise that is undertaken to build sustainable coastal defences and create intertidal habitats in estuaries. This nature-based solution brings multiple benefits in the form of carbon storage, increased resilience to flooding, and, potentially, the formation of new habitats, which is the topic of this study. A 75-ha site at the Paull Holme Strays (Humber Estuary, United Kingdom) was monitored over a 10-year period following MR to examine the change in the abundance of waterbirds in the chosen site in response to the physical processes occurring there. Using digital terrain models (DTMs) collected via light detection and ranging (LiDAR), we examined how four compensatory target species responded to changes in elevation after the creation of the site. It was shown that the very rapid accretion of estuarine sediment occurred in the first decade of the new re-created intertidal, which, over time, led to changes in the numbers of benthic foraging birds supported. Furthermore, elevation change was also driven by this sediment accretion, the rate of which depended on the initial bed elevation of the sectors within the site. Ten years after the recreation of the habitat, the spatial heterogeneity in the bed elevation remained high; however, the sectors with the lowest elevations accreted the most over the 10-year period. The foraging number of the four waterbird species that colonised the MR site significantly declined above a certain elevation, with this effect being most pronounced for the Eurasian curlew (Numenius arquata). The number of common shelducks (Tadorna tadorna), dunlins (Calidris alpina), and common redshanks (Tringa totanus) declined significantly after initial peaks 5–7 years after the creation of the site, reflecting the ongoing elevation changes. Thus, this study highlighted the need for long-term studies to understand how species respond to large-scale habitat construction. It can also aid in predicting the suitability of an MR site for waterbirds in the medium and long term.

Description: The lack of clarity in turbid coastal waters interferes with light attenuation and hinders remotely sensed studies in aquatic ecology such as benthic habitat mapping and bathymetry estimation. Although turbid water column corrections can be applied on regions with seasonal turbidity by performing multi-temporal analysis, different approaches are needed in regions where the water is constantly turbid or only exhibits subtle turbidity variations through time. This study aims to detect these turbid zones (TZs) in optically shallow coastal waters using multi-temporal Sentinel-2 surface reflectance datasets to improve the aforementioned studies. The herein framework can be paired with other aquatic ecology remote sensing studies to establish the clear water focus area and can also be used by decision makers to identify rehabilitation areas. We selected the coastlines of Guinea-Bissau, Tunisia, and west Madagascar as our case studies which feature wide-ranging turbidity intensities across tropical, subtropical, and Mediterranean waters and applied three different methods for the TZ detection: Otsu’s method for bimodal thresholding, linear spectral unmixing, and Random Forest (RF) machine learning method on Google Earth Engine as an end-to-end process. Based on our experiments, the RF method yields good results in all study regions with overall accuracies ranging between 88 and 96% and F1-scores between 0.87 and 0.96. TZ detection is highly site-specific due to the inter-class variability that is mainly affected by the nature of the suspended materials and the environmental characteristics of the site.

Description: Emerging studies have showed irreversible electroporation (IRE) focused on pancreatic cancer (PC). However, the effects of IRE treatment on the immune response of PC remain unknown. Moreover, there are few studies on the therapeutic effect of IRE combining with immunotherapy on PC. Thus, we review recent advances in our understanding of IRE alone and its working with immunotherapy towards the immune response of PC, discussing potential opportunities for exploring future treatment strategies.

Description: During summer, phytoplankton blooms occur frequently off the southeast Vietnam coast in the western South China Sea (WSCS). Using multi-source remote sensing data, such as sea surface temperature (SST), sea surface wind (SSW), aerosol optical thickness (AOT), sea level anomalies (SLA), and chlorophyll-a (Chl-a) data from 1998 to 2020 and in situ observations of analyzed data, we report the patterns of spatial variation of summer phytoplankton blooms in this region. The partial correlation and multiple stepwise linear regression analyses reveal that Ekman transport (ET) and Ekman pumping velocity (EPV) exert a greater impact on the summer phytoplankton blooms than the other environmental factors, suggesting that the phytoplankton blooms in the region may be mainly triggered by the enhanced nutrients by wind-induced upwelling and vertical mixing. AOT only weakly correlates with Chl-a concentration in the region, probably these prominent abundant nutrients in the region come from upwelling and convective-overturn. A northeastward jet causes the distribution of high Chl-a in the WSCS to be plume-shaped. A new finding in this study is that the northward current in this area may cause the northward deviation of phytoplankton blooms from the areas of upwelling.

Description: Reactive oxygen species (ROS) and dissolved oxygen play key roles across many biological processes, and fluorescent stains and dyes are the primary tools used to quantify these species in vitro. However, spatio-temporal monitoring of ROS and dissolved oxygen in biological systems are challenging due to issues including poor photostability, lack of reversibility, and rapid off-site diffusion. In particular, ROS monitoring is hindered by the short lifetime of ROS molecules and their low abundance. The combination of nanomaterials and fluorescent detection has led to new opportunities for development of imaging probes, sensors, and theranostic products, because the scaffolds lead to improved optical properties, tuneable interactions with cells and media, and ratiometric sensing robust to environmental drift. In this review, we aim to critically assess and highlight recent development in nanosensors and nanomaterials used for the detection of oxygen and ROS in biological systems, and their future potential use as diagnosis tools.

Description: Cardiac autonomic modulation, assessed by heart rate variability (HRV), is associated with tumor pathogenesis and development as well as invasion and metastasis. This study aimed to examine this association in breast cancer (BC) patients. A total of 133 patients (average age 49.2years) with BC or benign breast tumors were divided into three groups: benign group, early-stage group, and advanced-stage group. About 5-min resting ECG was collected for the analysis of linear and nonlinear HRV parameters. Multiple logistic regression models were performed to test the independent contribution of HRV to breast tumor stage. The advanced-stage group had significantly reduced HRV compared to the benign and early-stage groups. In particular, for each 1-SD increase in SD2, SD of normal-to-normal intervals, very-low frequency, total power, and low frequency, the odds of having advanced staging decreased by 69.3, 64.3, 58.3, 53.3, and 65.9%, respectively. These associations were independent of age, body mass index, mean heart rate (HR), and respiratory rate (RR). These findings suggest an association between HRV and breast tumor stage, and HRV parameters may help construct an effective early diagnostic and clinical prognostic model.

Description: Bacteria and fungi present during pile-fermentation of Sichuan dark tea play a key role in the development of its aesthetic properties, such as color, taste, and fragrance. In our previous study, high-throughput sequencing of dark tea during fermentation revealed Aspergillus was abundant, but scarce knowledge is available about bacterial communities during pile-fermentation. In this study, we rigorously explored bacterial diversity in Sichuan dark tea at each specific stage of piling. Analysis of cluster data revealed 2,948 operational taxonomic units, which were divided into 42 phyla, 98 classes, 247 orders, 461 families, 1,052 genera, and 1,888 species. Certain members of the family Enterobacteriaceae were dominant at early stages of fermentation YC, W1, and W2; Pseudomonas at middle stage W3; and the highest bacterial diversity was observed at the final quality-determining stage W4. Noticeably, probiotics, such as Bacillus, Lactobacillus, Bifidobacterium, and Saccharopolyspora were also significantly higher at the quality-determining stage W4. Our findings might help in precise bacterial inoculation for probiotic food production by increasing the health benefits of Sichuan dark tea. This research also falls under the umbrella of the “Establish Good Health and Well-Being” Sustainable Development Goals of the United Nations Organization.

Description: Digital health consultations in primary care have the advantage of offering equal healthcare for people residing in the countryside. While it is gaining acceptance among young- and middle-aged people, the elderly are reluctant to use it. The aim of this study was hence to identify reasons for non-use among elderly in the countryside and describe perceived possible challenges and opportunities with digital health consultations. Semi-structured interviews were conducted with 13 persons over 65 years old residing in the Swedish countryside. There was a mistrust for services offered by private companies and their public funding, a lack of knowledge of available services, and a lack of perceived usefulness. Personal interaction and continuity was more important than time or travel conveniences, although these advantages were recognized. To prevent digital exclusion, caregivers need to offer information, encouragement, or tools for the elderly. Digital primary care also needs to offer familiarity, with continuity and personal connections.

Description: Primary brainstem hemorrhage (PBSH) is the most fatal subtype of intracerebral hemorrhage and is invariably associated with poor prognosis. Several prognostic factors are involved, of which the two most predominant and consistent are the initial level of consciousness and hemorrhage size. Other predictors, such as age, hyperthermia, and hydrocephalus, are generally not dependable indicators for making prognoses. Scoring systems have now been developed that can predict mortality and functional outcomes in patients suffering from PBSH, which can thus guide treatment decision-making. A novel grading scale, entitled “the new primary pontine hemorrhage (PPH) score,” represents the latest approach in scoring systems. In this system, patients with a score of 2–3 points appear to benefit from surgical management, although this claim requires further verification. The four main surgical options for the treatment of PBSH are craniotomy, stereotactic hematoma puncture and drainage, endoscopic hematoma removal, and external ventricular drainage. Nevertheless, the management of PBSH still primarily involves conservative treatment methods and surgery is generally not recommended, according to current practice. However, the ongoing clinical trial, entitled Safety and Efficacy of Surgical Treatment in Severe Primary Pontine Hemorrhage Evacuation (STIPE), should provide additional evidence to support the surgical treatment of PBSH. Therefore, we advocate the update of epidemiological data and re-evaluation of PBSH treatment in a contemporary context.

Description: Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.

Description: BackgroundThe SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes.MethodsWe conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality.ResultsFour clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group.ConclusionThese findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.

Description: Due to the alarming speed of global warming, greenhouse gas removal from atmosphere will be absolutely necessary in the coming decades. Methane is the second most harmful greenhouse gas in the atmosphere. There is an emerging technology proposed to incorporating photocatalysis with solar updraft Towers (SUT) to remove methane from the air at a planetary scale. In this study, we present a deep analysis by calculating the potential of methane removal in relation to the dimensions and configuration of SUT using different photocatalysts. The analysis shows that the methane removal rate increases with the SUT dimensions and can be enhanced by changing the configuration design. More importantly, the low methane removal rate on conventional TiO2 photocatalyst can be significantly improved to, for example, 42.5% on a more effective Ag-doped ZnO photocatalyst in a 200 MW SUT while the photocatalytic reaction is the rate limiting step. The factors that may further affect the removal of methane, such as more efficient photocatalysts, night operation and reaction zone are discussed as possible solutions to further improve the system.

Description: We demonstrate that colloidal quantum dots of CdSe and CdSe/ZnS are detected during the photooxidation of MeOH, under broad spectrum illumination (250 mW/cm2). The stepwise photocurrent vs. time response corresponds to single entities adsorbing to the Pt electrode surface irreversibly. The adsorption/desorption of the QDs and the nature of the single entities is discussed. In suspensions, the QDs behave differently depending on the solvent used to suspend the materials. For MeOH, CdSe is not as stable as CdSe/ZnS under constant illumination. The photocurrent expected for single QDs is discussed. The value of the observed photocurrents, 〉 1 pA is due to the formation of agglomerates consistent with the collision frequency and suspension stability. The observed frequency of collisions for the stepwise photocurrents is smaller than the diffusion-limited cases expected for single QDs colliding with the electrode surface. Dynamic light scattering and scanning electron microscopy studies support the detection of aggregates. The results indicate that the ZnS layer on the CdSe/ZnS material facilitates the detection of single entities by increasing the stability of the nanomaterial. The rate of hole transfer from the QD aggregates to MeOH outcompetes the dissolution of the CdSe core under certain conditions of electron injection to the Pt electrode and in colloidal suspensions of CdSe/ZnS.

Description: The multidimensional framework to the study of consciousness, which comes as an alternative to a single sliding scale model, offers a set of experimental paradigms for investigating dimensions of animal consciousness, acknowledging the compelling urge for a novel approach. One of these dimensions investigates whether non-human animals can flexibly and spontaneously plan for a future event, and for future desires, without relying on reinforcement learning. This is a critical question since different intentional structures for action in non-human animals are described as served by different neural mechanisms underpinning the capacity to represent temporal properties. And a lack of appreciation of this variety of intentional structures and neural correlates has led many experts to doubt that animals have access to temporal reasoning and to not recognize temporality as a mark of consciousness, and as a psychological resource for their life. With respect to this, there is a significant body of ethological evidence for planning abilities in non-human animals, too often overlooked, and that instead should be taken into serious account. This could contribute to assigning consciousness profiles, across and within species, that should be tailored according to an implemented and expansive use of the multidimensional framework. This cannot be fully operational in the absence of an additional tag to its dimensions of variations: the experience-specificity of consciousness.

Description: Fragile X Syndrome is a neuro-developmental disorder caused by the silencing of the FMR1 gene, resulting in the loss of its protein product, FMRP. FMRP binds mRNA and represses general translation in the brain. Transcriptome analysis of the Fmr1-deficient mouse hippocampus reveals widespread dysregulation of alternative splicing of pre-mRNAs. Many of these aberrant splicing changes coincide with those found in post-mortem brain tissue from individuals with autism spectrum disorders (ASDs) as well as in mouse models of intellectual disability such as PTEN hamartoma syndrome (PHTS) and Rett Syndrome (RTT). These splicing changes could result from chromatin modifications (e.g., in FXS, RTT) and/or splicing factor alterations (e.g., PTEN, autism). Based on the identities of the RNAs that are mis-spliced in these disorders, it may be that they are at least partly responsible for some shared pathophysiological conditions. The convergence of splicing aberrations among these autism spectrum disorders might be crucial to understanding their underlying cognitive impairments.

Description: Maturity degree and quality evaluation are important for strawberry harvest, trade, and consumption. Deep learning has been an efficient artificial intelligence tool for food and agro-products. Hyperspectral imaging coupled with deep learning was applied to determine the maturity degree and soluble solids content (SSC) of strawberries with four maturity degrees. Hyperspectral image of each strawberry was obtained and preprocessed, and the spectra were extracted from the images. One-dimension residual neural network (1D ResNet) and three-dimension (3D) ResNet were built using 1D spectra and 3D hyperspectral image as inputs for maturity degree evaluation. Good performances were obtained for maturity identification, with the classification accuracy over 84% for both 1D ResNet and 3D ResNet. The corresponding saliency maps showed that the pigments related wavelengths and image regions contributed more to the maturity identification. For SSC determination, 1D ResNet model was also built, with the determination of coefficient (R2) over 0.55 of the training, validation, and testing sets. The saliency maps of 1D ResNet for the SSC determination were also explored. The overall results showed that deep learning could be used to identify strawberry maturity degree and determine SSC. More efforts were needed to explore the use of 3D deep learning methods for the SSC determination. The close results of 1D ResNet and 3D ResNet for classification indicated that more samples might be used to improve the performances of 3D ResNet. The results in this study would help to develop 1D and 3D deep learning models for fruit quality inspection and other researches using hyperspectral imaging, providing efficient analysis approaches of fruit quality inspection using hyperspectral imaging.

Description: Purpose: Non-infectious uveitis is a leading cause of vision loss in the developed world. The purpose of this systematic review is to investigate the epidemiology and risk factors of non-infectious uveitis over the last 50 years.Methods: A systematic literature search of Pubmed/MEDLINE database was performed in the 50-year period from January 1971 to January 2021, according to the PRISMA guidelines. Studies that assessed the epidemiology and risk factors for non-infectious uveitis were included.Results: Few epidemiologic studies focus specifically on non-infectious uveitis. In the Unites States, the estimated prevalence of non-infectious uveitis is 121/100,000. The incidence and prevalence varies considerably worldwide. Females and the working age group (20–50 years) appear to be the most affected. Smoking and vitamin D deficiency are the biggest risk factors for non-infectious uveitis, while pregnancy appears to be protective. Additional risk factors include presence of other autoimmune diseases (thyroid disease, diabetes, celiac), pre-eclampsia/eclampsia, psychological stress, and certain medications (bisphosphonates, immune checkpoint inhibitors, female hormone therapy, and etanercept).Discussion: Our systematic review summarizes the incidence and prevalence of non-infectious uveitis and associated modifiable and non-modifiable risk factors.

Description: Natural killer/T cell lymphoma (NKTCL) most frequently affects the nasal cavity and upper aerodigestive tract (UAT) and is often mistaken for reactive disease processes, such as chronic rhinosinusitis (CRS). Recently, alterations of the nasal resident microbiota have been found in CRS. However, nasal microbial features in NKTCL have never been reported. This case-control study collected 46 NKTCL patients, 25 CRS patients and 24 matched healthy controls (HCs) to analyze nasal microbial profiles via 16S rRNA sequencing technology to improve our understanding of changes in the nasal microbiota in NKTCL. We found that alpha diversity was significantly decreased, while beta diversity was significantly increased in NKTCL compared with those in CRS and HCs. The genus Corynebacterium was significantly depleted in CRS and NKTCL versus that in HCs, while genus Staphylococcus was the most abundant in the NKTCL compared to that in the other two groups. The nasal microbial community was significantly different between UAT-NKTCL and non-UAT NKTCL patients. Importantly, based on a panel of taxa, excellent classification power with an AUC of 0.875 between UAT-NKTCL and CRS was achieved. Furthermore, the alpha diversity of the nasal microbiota was associated with several clinical covariates of NKTCL. Finally, PICRUSt analysis implicated an array of distinct functions in NKTCL that might be involved in the pathogenesis of the disease. In conclusion, the nasal microbial profile was unique in NKTCL. The nose-microbiota-UAT NKTCL axis represents a panel of promising biomarkers for clinical practice and contributes to revealing the potential pathogenesis of this malignancy.

Description: Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different