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  • Wiley-Blackwell  (125,848)
  • Elsevier  (17,224)
  • 2015-2019  (19,676)
  • 1990-1994  (66,091)
  • 1970-1974  (30,762)
  • 1965-1969  (26,548)
Collection
Years
Year
  • 1
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 294 (1992), S. 466-478 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 317 (1993), S. 474-484 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 3
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    New York, NY : Elsevier
    Keywords: Biochemistry ; Enzymes
    Notes: This is a series title, single volumes see link below.
    ISSN: 1557-7988
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  • 4
    Call number: QZ269:203(3)
    Keywords: Radiation Oncology / methods ; Neoplasms / radiotherapy
    Pages: xxviii, 713 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128141281
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    QZ269:203(3) available
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  • 5
    Unknown
    Amsterdam : Elsevier
    Call number: QZ200:575(3)/2
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 577 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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    QZ200:575(3)/2 available
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  • 6
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/1
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 585 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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    QZ200:575(3)/1 available
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  • 7
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/3
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 605 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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    QZ200:575(3)/3 available
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  • 8
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    München : Elsevier
    Call number: WN180:10(5)
    Pages: ix, 141 p. : ill.
    Edition: 5. Aufl.
    ISBN: 9783437422973
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    WN180:10(5) available
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  • 9
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    München : Elsevier
    Call number: QZ269:204(3)
    Keywords: Neoplasms / radiotherapy ; Radiotherapy
    Pages: xxviii, 419 p. : ill.
    Edition: 3. Aufl.
    ISBN: 9783437232923
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    QZ269:204(3) available
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  • 10
    Publication Date: 2018-06-24
    Description: Publication date: 5 October 2018 Source: Gene, Volume 673 Author(s): Tianliu Zhang, Liping Guo, Mingyan Shi, Lingyang Xu, Yan Chen, Lupei Zhang, Huijiang Gao, Junya Li, Xue Gao Incorrect paternity assignment in cattle can significantly influence the accuracy of genetic evaluation. Recent advances in high-throughput technology have facilitated the identification of single nucleotide polymorphism (SNP) markers and their applications for filiation and individual identification. We genotyped 1074 bulls from a reference population of Chinese Simmental cattle for genomic selection using a BovineSNP770K BeadChip. Among them, a total of 136 bulls were randomly selected to design a suitable low-density SNP panel for paternity testing in Simmental cattle. Our results showed that 50 SNPs were determined to be the most informative markers in parental testing, with an accuracy of 99.89% for CPE (cumulative probability of exclusion) in the unknown female parent case. The 50 highly informative SNP markers were distributed across 25 chromosomes, and the mean intermarker distance per chromosome was 26.72 Mb. The average minor allele frequency (MAF), expected heterozygosity (HE), and polymorphic information content (PIC) values were 0.3748, 0.4998, and 0.4818, respectively. Finally, the 50 identified SNPs were used to estimate paternity for the remaining 938 of 1074 bulls from 23 farms. Our results revealed that 76.75% of the 938 bulls were assigned parentage to the pedigree sires with 95% confidence, and the rate of pedigree record mistakes ranged from 9.52%–39.29% in different herds. Our study is the first attempt to provide valuable insights into the extraction of informative markers through the application of high-density SNP chips for paternity testing in Chinese Simmental cattle.
    Print ISSN: 0378-1119
    Electronic ISSN: 1879-0038
    Topics: Biology
    Published by Elsevier
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  • 11
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Sabine Kleinert, Richard Horton
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 12
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Paul Webster
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 13
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Paris Tekkis, Diana Tait, David Cunningham, Gina Brown
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 14
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Talha Burki
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
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  • 15
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Susan Jaffe
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 16
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Amanda McClelland, Thomas R Frieden
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 17
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Geoff Watts
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 18
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Mark Honigsbaum
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 19
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    Elsevier
    In: Lancet
    Publication Date: 2018-06-24
    Description: Publication date: 23–29 June 2018 Source: The Lancet, Volume 391, Issue 10139 Author(s): Tareq Al Saadi, Fatima Abbas, Tarek Turk, Mahmoud Alkhatib, Ibrahem Hanafi, Fares Alahdab
    Print ISSN: 0140-6736
    Electronic ISSN: 1474-547X
    Topics: Medicine
    Published by Elsevier
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  • 20
    Publication Date: 2018-07-10
    Description: Publication date: Available online 7 July 2018 Source: Virus Research Author(s): Zhijun Bai, Li Cheng Liu, Liyun Jiang, Lei Luo, Huahua Feng, Peng Lin, Qinglong Jing, Xincai Xiao, Huiqiong Zhou, Wenzhe Su, Yimin Cao, Yilan Li, Qing Cao, Weijun Chen, Biao Di, Zhicong Yang To determine the evolutionary and phylodynamic history of DENV-1 in Guangdong, the strains detected between 1985 and 2015 were determined with phylogenetic and Bayesian analyses of the E gene. Three DENV-1 genotypes (I, V, and VI) were circulating in Guangdong, and genotype I was detected most frequently. The evolutionary rate of DENV-1 was estimated to be 1.03 × 10 −3 nucleotide substitutions/site/year. The most recent ancestor of the viruses existed approximately 141 years ago. The observed epidemiological dynamics correlated with similar fluctuations in diversity, and the epidemiological dynamics of DENV-1 transmission reflect dramatic changes in the viral population sizes. Two recombination events were identified in those strains. The selection pressures were estimated and revealed an abundance of negatively selected sites but few positively selected sites. These data improve our understanding of the evolution and molecular epidemiology of DENV-1 and provide insights that will facilitate the surveillance and control of DENV-1.
    Print ISSN: 0168-1702
    Electronic ISSN: 1872-7492
    Topics: Medicine
    Published by Elsevier
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  • 21
    Publication Date: 2018-06-25
    Description: Publication date: Available online 23 June 2018 Source: Urology Author(s): Frank C. Lin, Joel T. Funk, Hina Arif Tiwari, Bobby T. Kalb, Christian O. Twiss Objectives To compare dynamic magnetic resonance imaging (dMRI) defecography phase findings with physical examination (PE) grading in the evaluation of pelvic organ prolapse (POP). Methods We retrospectively reviewed 274 consecutive patients who underwent dMRI with defecography. Baden-Walker (B-W) grading of POP, absolute dMRI values, and grading by dMRI were collected for anterior, apical, and posterior compartments. Anatomically significant POP on PE was defined as B-W Grade ≥ 3 and on dMRI by dMRI Grade ≥2. A Spearman's Rank correlation was performed between absolute dMRI values and respective POP grades. Results 178 female patients were included. Anatomically insignificant and significant cystoceles had a 26.4% (19/72) and 84.6% (66/78) agreement respectively. Anatomically insignificant and significant apical prolapse had a 2.0% (2/100) and 62.9% (17/27) agreement respectively. Anatomically insignificant and significant posterior prolapse had a 49.5% (51/103) and 78.7% (59/75) agreement respectively. PE detected only 30% (9/30) of total dMRI detected enteroceles and misdiagnosed 10 % (3/30) of these patients with a rectocele. Conclusions The dMRI defecography phase correlated well for anatomically significant prolapse in anterior and posterior compartments. dMRI was superior to PE for enterocele detection and was better able to distinguish an enterocele from a rectocele. Thus, dMRI may have the greatest diagnostic value in cases where the presence of an enterocele is unclear in apical and/or posterior compartments.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
    Published by Elsevier
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  • 22
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    Elsevier
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Gastroenterology Author(s): Mouen A. Khashab, Petros C. Benias, Lee L. Swanstrom Peroral endoscopic myotomy (POEM) is an advanced endoscopic procedure classically performed for the treatment of achalasia. The procedure is based on principles of submucosal endoscopy and is comprised of a mucosal incision, submucosal tunneling, myotomy and mucosal closure. Multiple published studies that collectively include more than 6000 patients reported clinical success in more than 80-90% of patients. Recent literature also suggested durability of response over a medium-term follow-up. POEM is associated with a low rate of adverse events when performed by experienced operators. Gastroesophageal reflux is not infrequent after POEM but does not seem significantly different from reflux which occurs after Heller myotomy. POEM also seems to be effective in the treatment of spastic esophageal disorders (e.g. Jackhammer and diffuse esophageal spasm). Lastly, the role of gastric POEM (G-POEM) in the treatment of gastroparesis has been investigated in recent studies with promising results.
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
    Published by Elsevier
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  • 23
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    Elsevier
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Gastroenterology Author(s): Nicholas J. Shaheen, M. Brian Fennerty, Jacques J. Bergman A substantial literature documents inappropriate usage of gastrointestinal endoscopy in a variety of clinical settings. Overusage of endoscopy appears to be common, and 30% or more of procedures performed in some clinical settings have questionable indications. The potential reasons for overuse of endoscopy are multiple, and include cancer phobia, fear of medical malpractice litigation, profit motive, the investigation of “incidentalomas” found on other imaging, and under-appreciation of the delayed harms of endoscopy, among other reasons. Clinical guidelines, which should limit overuse of endoscopy, may instead serve to promote it, if authors opt to be “conservative,” recommending endoscopy in situations of unclear utility. Several strategies may decrease overuse of endoscopy, including careful attention to risk stratification when choosing patients to screen, adherence to guidelines for surveillance intervals for colonoscopy, the use of quality indicators to identify outliers in endoscopy utilization, and education on appropriate indications and the risks of overuse at the medical student, residency and fellowship levels.
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
    Published by Elsevier
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  • 24
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    Elsevier
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Gastroenterology Author(s): Evelien Dekker, Douglas K. Rex Colorectal cancer (CRC) is amongst the most commonly diagnosed cancers and causes of death from cancer across the world. CRC can, however, be detected in asymptomatic patients at a curable stage, and several studies have shown lower mortality among patients who undergo screening compared to those who do not. Using colonoscopy in CRC screening also results in the detection of precancerous polyps that can be directly removed during the procedure, thereby reducing the incidence of cancer. In the past decade, convincing evidence has appeared that the effectiveness of colonoscopy as CRC prevention tool is associated with the quality of the procedure. This review aims to provide an up-to-date overview of recent efforts to improve colonoscopy effectiveness of by enhancing detection and improving the completeness and safety of resection of colorectal lesions.
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
    Published by Elsevier
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  • 25
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Gastroenterology Author(s): Long V. Pham, Santseharay Ramirez, Judith M. Gottwein, Ulrik Fahnøe, Yi-Ping Li, Jannie Pedersen, Jens Bukh Background & Aims Chronic liver diseases caused by hepatitis C virus (HCV) genotype 6 are prevalent in Asia, and millions of people require treatment with direct-acting antiviral regimens, such as NS5A inhibitor velpatasvir combined with the NS5B polymerase inhibitor sofosbuvir. We developed infectious cell culture models of HCV genotype 6a infection to study the effects of these inhibitors and the development of resistance. Methods The consensus sequences of prototype strains HK2 (MG717925) and HK6a (MG717928), originating from serum of patients with chronic HCV infection, were determined by Sanger sequencing of genomes amplified by reverse transcription-PCR. In vitro non-infectious full-length clones of these 6a strains were subsequently adapted in Huh7.5 cells, primarily by using substitutions identified in JFH1-based core-NS5A and core-NS5B genotype 6a recombinants. We studied the efficacy of NS5A- and NS5B- inhibitors in concentration–response assays. We examined the effects of long-term culture of Huh7.5 cells incubated with velpatasvir and sofosbuvir singly or combined following infection with passaged full-length HK2 or HK6a recombinant viruses. Resistance-associated substitutions (RAS) were identified by Sanger and next-generation sequencing, and their effects on viral fitness and in drug susceptibility were determined in reverse-genetic experiments. Results Adapted full-length HCV genotype 6a recombinants HK2cc and HK6acc had fast propagation kinetics and high infectivity titers. Compared to a HCV genotype 1a recombinant, HCV genotype 6a recombinants of strains HK2 and HK6a were equally sensitive to daclatasvir, elbasvir, velpatasvir, pibrentasvir, and sofosbuvir, but less sensitive to ledipasvir, ombitasvir, and dasabuvir. Long-term exposure of HCV genotype 6a-infected Huh7.5 cells with a combination of velpatasvir and sofosbuvir resulted in clearance of the virus, but the virus escaped the effects of single inhibitors via emergence of the RAS L31V in NS5A (conferring resistance to velpatasvir) and S282T in NS5B (conferring resistance to sofosbuvir). Engineered recombinant genotype 6a viruses with single RAS mediated resistance to velpatasvir or sofosbuvir. HCV genotype 6a viruses with RAS NS5A-L31V or NS5B-S282T was however able to propagate and escape in Huh7.5 cells exposed to the combination of velpatasvir and sofosbuvir. Further, HCV genotype 6a with NS5A-L31V was able to propagate and escape in the presence of pibrentasvir with emergence of NS5A-L28S, conferring a high level of resistance to this inhibitor. Conclusions Strains of HCV genotype 6a isolated from patients can be adapted to propagate in cultured cells, permitting studies of the complete life cycle for this important genotype. The combination of velpatasvir and sofosbuvir is required to block propagation of original HCV genotype 6a, which quickly becomes resistant to single inhibitors via the rapid emergence and persistence of RAS. These features of HCV genotype 6a could compromise treatment.
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 26
    Publication Date: 2018-02-17
    Description: Suboptimal environmental conditions are ubiquitous in nature and commonly drive the outcome of biological interactions in community processes. Despite the importance of biological interactions for community processes, knowledge on how species interactions are affected by a limiting resource, for example, low food availability, remains limited. Here, we tested whether variation in food supply causes nonadditive consumption patterns, using the macroinvertebrate community of intertidal sandy beaches as a model system. We quantified isotopically labeled diatom consumption by three macroinvertebrate species ( Bathyporeia pilosa , Haustorius arenarius, and Scolelepis squamata ) kept in mesocosms in either monoculture or a three-species community at a range of diatom densities. Our results show that B. pilosa was the most successful competitor in terms of consumption at both high and low diatom density, while H. arenarius and especially S. squamata consumed less in a community than in their respective monocultures. Nonadditive effects on consumption in this macroinvertebrate community were present and larger than mere additive effects, and similar across diatom densities. The underlying species interactions, however, did change with diatom density. Complementarity effects related to niche-partitioning were the main driver of the net diversity effect on consumption, with a slightly increasing contribution of selection effects related to competition with decreasing diatom density. For the first time, we showed that nonadditive effects of consumption are independent of food availability in a macroinvertebrate community. This suggests that, in communities with functionally different, and thus complementary, species, nonadditive effects can arise even when food availability is low. Hence, at a range of environmental conditions, species interactions hold important potential to alter ecosystem functioning. To test whether variation in food supply causes nonadditive consumption patterns, we quantified isotopically labeled diatom consumption by three intertidal macroinvertebrate species kept in mesocosms in either monoculture or a community at a range of diatom densities. Complementarity effects on consumption were the main driver of the net diversity effect, with a slightly increasing contribution of selection effects with decreasing diatom density. For the first time, we have shown that nonadditive effects of consumption are independent from food availability in a macroinvertebrate community.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
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  • 27
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Free Radical Biology and Medicine Author(s): Quach Ngoc Tung, Nico Linzner, Vu Van Loi, Haike Antelmann Gram-negative bacteria utilize glutathione (GSH) as their major LMW thiol. However, most Gram-positive bacteria do not encode enzymes for GSH biosynthesis and produce instead alternative LMW thiols, such as bacillithiol (BSH) and mycothiol (MSH). BSH is utilized by Firmicutes and MSH is the major LMW thiol of Actinomycetes . LMW thiols are required to maintain the reduced state of the cytoplasm, but are also involved in virulence mechanisms in human pathogens, such as Staphylococcus aureus , Mycobacterium tuberculosis , Streptococcus pneumoniae , Salmonella enterica subsp. Typhimurium and Listeria monocytogenes . Infection conditions often cause perturbations of the intrabacterial redox balance in pathogens, which is further affected under antibiotics treatments. During the last years, novel glutaredoxin-fused roGFP2 biosensors have been engineered in many eukaryotic organisms, including parasites, yeast, plants and human cells for dynamic live-imaging of the GSH redox potential in different compartments. Likewise bacterial roGFP2-based biosensors are now available to measure the dynamic changes in the GSH, BSH and MSH redox potentials in model and pathogenic Gram-negative and Gram-positive bacteria. In this review, we present an overview of novel functions of the bacterial LMW thiols GSH, MSH and BSH in pathogenic bacteria in virulence regulation. Moreover, recent results about the application of genetically encoded redox biosensors are summarized to study the mechanisms of host-pathogen interactions, persistence and antibiotics resistance. In particularly, we highlight recent biosensor results on the redox changes in the intracellular food-borne pathogen Salmonella Typhimurium as well as in the Gram-positive pathogens S. aureus and M. tuberculosis during infection conditions and under antibiotics treatments. These studies established a link between ROS and antibiotics resistance with the intracellular LMW thiol-redox potential. Future applications should be directed to compare the redox potentials among different clinical isolates of these pathogens in relation to their antibiotics resistance and to screen for new ROS-producing drugs as promising strategy to combat antimicrobial resistance. Graphical abstract
    Print ISSN: 0891-5849
    Electronic ISSN: 1873-4596
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 28
    Publication Date: 2018-02-17
    Description: Publication date: Available online 15 February 2018 Source: Free Radical Biology and Medicine Author(s): Carolina Prolo, Natalia Rios, Lucia Piacenza, María Noel Álvarez, Rafael Radi In the last two decades, there has been a significant advance in understanding the biochemistry of peroxynitrite, an endogenously-produced oxidant and nucleophile. Its relevance as a mediator in several pathologic states and the aging process together with its transient character and low steady-state concentration, motivated the development of a variety of techniques for its unambiguous detection and estimation. Among these, fluorescence and chemiluminescence approaches have represented important tools with enhanced sensitivity but usual limited specificity. In this review, we analyze selected examples of molecular probes that permit the detection of peroxynitrite by fluorescence and chemiluminescence, disclosing their mechanism of reaction with either peroxynitrite or peroxynitrite-derived radicals. Indeed, probes have been divided into 1) redox probes that yield products by a free radical mechanism, and 2) electrophilic probes that evolve to products secondary to the nucleophilic attack by peroxynitrite. Overall, boronate-based compounds are emerging as preferred probes for the sensitive and specific detection and quantitation. Moreover, novel strategies involving genetically-modified fluorescent proteins with the incorporation of unnatural amino acids have been recently described as peroxynitrite sensors. This review analyzes the most commonly used fluorescence and chemiluminescence approaches for peroxynitrite detection and provides some guidelines for appropriate experimental design and data interpretation, including how to estimate peroxynitrite formation rates in cells. Graphical abstract
    Print ISSN: 0891-5849
    Electronic ISSN: 1873-4596
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 29
    Publication Date: 2018-02-17
    Description: Publication date: Available online 16 February 2018 Source: Free Radical Biology and Medicine Author(s): Leire Almandoz-Gil, Hedvig Welander, Elisabeth Ihse, Payam Emami Khoonsari, Sravani Musunuri, Christofer Lendel, Jessica Sigvardson, Mikael Karlsson, Martin Ingelsson, Kim Kultima, Joakim Bergström
    Print ISSN: 0891-5849
    Electronic ISSN: 1873-4596
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 30
    Publication Date: 2018-02-27
    Description: The purpose of this study was to measure the sodium transverse relaxation time T 2 * in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model. Data were also analysed using a continuous distribution fit with a region of interest-based inverse Laplace transform. Average T 2 * values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi-exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using ultra-short TEs are presented for the first time. Healthy subjects were scanned using 23 Na ultra-short echo time (UTE) magnetic resonance imaging (MRI) with 18 TEs between 0.17 and 67 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model and using a continuous distribution fit with a region of interest-based inverse Laplace transform. Detailed 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using UTEs are presented for the first time.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 31
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    Publication Date: 2018-02-27
    Description: Publication date: Available online 26 February 2018 Source: Seminars in Immunology Author(s): Francesco De Sanctis, Stefano Ugel, John Facciponte, Andrea Facciabene Angiogenesis is a hallmark of cancer and a requisite that tumors must achieve to fulfill their metabolic needs of nutrients and oxygen. As a critical step in cancer progression, the ‘angiogenic switch’ allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic progression and dissemination. Tumor-dependent triggering of the angiogenic switch has critical consequences on tumor progression which extends from an increased nutrient supply and relies instead on the ability of the tumor to hijack the host immune response for the generation of a local immunoprivileged microenvironment. Tumor angiogenic-mediated establishment of endothelial anergy is responsible for this process. However, tumor endothelium can also promote immune tolerance by unbalanced expression of co-stimulatory and co-inhibitory molecules and by releasing soluble factors that restrain T cell function and induce apoptosis. In this review, we discuss the molecular properties of the tumor endothelial barrier and endothelial anergy and discuss the main immunosuppressive mechanisms triggered by the tumor endothelium. Lastly, we describe the current anti-angiogenic therapeutic landscape and how targeting tumor angiogenesis can contribute to improve clinical benefits for patients.
    Print ISSN: 1044-5323
    Electronic ISSN: 1096-3618
    Topics: Medicine
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  • 32
    Publication Date: 2018-02-28
    Description: A patient in whom organs or molecules are affected sequentially by an autoimmune response prompted us to propose a hypothesis that epitope spreading may account for the sequential involvement of different cells. A 27-year old male patient was diagnosed in January 2005 with idiopathic thrombocytopenic purpura (ITP), since all autoantibodies relevant to autoimmune diseases were negative. He was treated with immunosuppression and spenectomy. In 2014, the patient developed transient blurred vision, dizziness and walking instability and autoimmune chylomicronemia was diagnosed, based on the presence of autoantibodies to lipoprotein lipase (LPL) (1). This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 33
    Publication Date: 2018-02-28
    Description: Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. The present study has been designed to evaluate the levels of oxidative and anti-oxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (p〈0.001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant play key role in the severity of sepsis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 34
    facet.materialart.
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    Wiley-Blackwell
    Publication Date: 2018-02-28
    Description: Modern diffusion magnetic resonance imaging (dMRI) acquires intricate volume datasets and biological meaning can only be found in the relationship between its different measurements. Suitable strategies for visualizing these complicated data have been key to interpretation by physicians and neuroscientists, for drawing conclusions on brain connectivity and for quality control. This article provides an overview of visualization solutions that have been proposed to date, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive and dense visualizations. This paper provides an overview of visualization solutions that have been proposed to date for diffusion MRI, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive, and dense visualizations.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 35
    Publication Date: 2018-02-28
    Description: Publication date: June 2018 Source: NeuroImage, Volume 173 Author(s): Alberto Merola, Michael A. Germuska, Kevin Murphy, Richard G. Wise As energy metabolism in the brain is largely oxidative, the measurement of cerebral metabolic rate of oxygen consumption (CMRO 2 ) is a desirable biomarker for quantifying brain activity and tissue viability. Currently, PET techniques based on oxygen isotopes are the gold standard for obtaining whole brain CMRO 2 maps. Among MRI techniques that have been developed as an alternative are dual calibrated fMRI (dcFMRI) methods, which exploit simultaneous measurements of BOLD and ASL signals during a hypercapnic-hyperoxic experiment to modulate brain blood flow and oxygenation. In this study we quantified the repeatability of a dcFMRI approach developed in our lab, evaluating its limits and informing its application in studies aimed at characterising the metabolic state of human brain tissue over time. Our analysis focussed on the estimates of oxygen extraction fraction (OEF), cerebral blood flow (CBF), CBF-related cerebrovascular reactivity (CVR) and CMRO 2 based on a forward model that describes analytically the acquired dual echo GRE signal. Indices of within- and between-session repeatability are calculated from two different datasets both at a bulk grey matter and at a voxel-wise resolution and finally compared with similar indices obtained from previous MRI and PET measurements. Within- and between-session values of intra-subject coefficient of variation (CV intra ) calculated from bulk grey matter estimates 6.7 ± 6.6% (mean ± std.) and 10.5 ± 9.7% for OEF, 6.9 ± 6% and 5.5 ± 4.7% for CBF, 12 ± 9.7% and 12.3 ± 10% for CMRO 2 . Coefficient of variation (CV) and intraclass correlation coefficient (ICC) maps showed the spatial distribution of the repeatability metrics, informing on the feasibility limits of the method. In conclusion, results show an overall consistency of the estimated physiological parameters with literature reports and a satisfactory level of repeatability considering the higher spatial sensitivity compared to other MRI methods, with varied performance depending on the specific parameter under analysis, on the spatial resolution considered and on the study design.
    Print ISSN: 1053-8119
    Electronic ISSN: 1095-9572
    Topics: Medicine , Psychology
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  • 36
    Publication Date: 2018-02-28
    Description: Publication date: June 2018 Source: NeuroImage, Volume 173 Author(s): Antonios Makropoulos, Emma C. Robinson, Andreas Schuh, Robert Wright, Sean Fitzgibbon, Jelena Bozek, Serena J. Counsell, Johannes Steinweg, Katy Vecchiato, Jonathan Passerat-Palmbach, Gregor Lenz, Filippo Mortari, Tencho Tenev, Eugene P. Duff, Matteo Bastiani, Lucilio Cordero-Grande, Emer Hughes, Nora Tusor, Jacques-Donald Tournier, Jana Hutter, Anthony N. Price, Rui Pedro A.G. Teixeira, Maria Murgasova, Suresh Victor, Christopher Kelly, Mary A. Rutherford, Stephen M. Smith, A. David Edwards, Joseph V. Hajnal, Mark Jenkinson, Daniel Rueckert The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity.
    Print ISSN: 1053-8119
    Electronic ISSN: 1095-9572
    Topics: Medicine , Psychology
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  • 37
    Publication Date: 2018-03-05
    Description: Publication date: Available online 2 March 2018 Source: Advances in Cancer Research Author(s): Scott T. Eblen The extracellular-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine–threonine kinases that are involved in regulating cellular signaling in both normal and pathological conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates. In this review I will discuss some of what has been discovered about the members of the Ras to ERK pathway, including regulation of their activation by growth factors and cell adhesion pathways. Looking downstream of ERK activation I will also highlight some of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis.
    Electronic ISSN: 0065-230X
    Topics: Medicine
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  • 38
    Publication Date: 2018-03-05
    Description: Publication date: Available online 2 March 2018 Source: Advances in Cancer Research Author(s): Diana Fang, Eduardo N. Maldonado Cancer metabolism is emerging as a chemotherapeutic target. Enhanced glycolysis and suppression of mitochondrial metabolism characterize the Warburg phenotype in cancer cells. The flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol occur through voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane. Catabolism of respiratory substrates in the Krebs cycle generates NADH and FADH 2 that enter the electron transport chain (ETC) to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The ETC is also the major cellular source of mitochondrial reactive oxygen species (ROS). αβ-Tubulin heterodimers decrease VDAC conductance in lipid bilayers. High constitutive levels of cytosolic free tubulin in intact cancer cells close VDAC decreasing mitochondrial ΔΨ and mitochondrial metabolism. The VDAC–tubulin interaction regulates VDAC opening and globally controls mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a VDAC-binding molecule lethal to some cancer cell types, and erastin-like compounds identified in a high-throughput screening antagonize the inhibitory effect of tubulin on VDAC. Reversal of tubulin inhibition of VDAC increases VDAC conductance and the flux of metabolites into and out of mitochondria. VDAC opening promotes a higher mitochondrial ΔΨ and a global increase in mitochondrial metabolism leading to high cytosolic ATP/ADP ratios that inhibit glycolysis. VDAC opening also increases ROS production causing oxidative stress that, in turn, leads to mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of the VDAC–tubulin interaction promotes cell death by a “double-hit model” characterized by reversion of the proproliferative Warburg phenotype (anti-Warburg) and promotion of oxidative stress.
    Electronic ISSN: 0065-230X
    Topics: Medicine
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  • 39
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    Wiley-Blackwell
    Publication Date: 2018-03-06
    Description: Cover illustration. Additive manufacturing offers the capability to build reactors and components with complex geometries and topologies previously unaccessible to the reactor design engineer. These capabilities could allow a transition from site-built facilities [left, courtesy of Matt Jiggins, https://www.flickr.com/photos/mattjiggins/3948811131 ] to optimized additively manufactured designs [right, examples of metal objects built using Direct Metal Laser Sintering (DMLS) courtesy of Oakridge National Laboratory, https://www.flickr.com/photos/oakridgelab/9067742195 ]. 10.1002/aic.16118
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 40
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    Elsevier
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 3 Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org .
    Print ISSN: 0002-9297
    Electronic ISSN: 1537-6605
    Topics: Biology , Medicine
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  • 41
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 3 Author(s): Arthur L. Beaudet
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    Electronic ISSN: 1537-6605
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  • 42
    Publication Date: 2018-03-06
    Description: Publication date: Available online 2 March 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Nathan R. Blue, Cristina Murray-Krezan, Shana Drake-Lavelle, Daniel Weinberg, Bradley D. Holbrook, Vivek R. Katukuri, Lawrence Leeman, Ellen L. Mozurkewich Background Non-steroidal anti-inflammatory drug use has been shown to increase blood pressure in non-pregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. Objectives Our goal was to test the hypothesis that non-steroidal anti-inflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. Study Design At delivery, we randomized women with preeclampsia with severe features to receive “around-the-clock” oral dosing with either 600mg of ibuprofen or 650mg of acetaminophen every six hours. Dosing began within six hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses and physicians were masked to study allocation. Exclusion criteria were serum AST or ALT > 200mg/dL, serum creatinine >1.0mg/dL, infectious hepatitis, gastroesophageal reflux disease, age 〈 18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours, h) from delivery to the last blood pressure ≥ 160/110 mmHg. Secondary outcomes were time from delivery to last blood pressure ≥ 150/100 mmHg, mean arterial pressure (MAP), need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. Results We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, BMI, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen versus acetaminophen groups (35.3h vs 38.0h, p=0.30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure ≥ 150/100 mmHg, postpartum MAP, maximum postpartum systolic or diastolic blood pressures, any postpartum BP ≥ 160/110 mmHg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.8h and ibuprofen group was 56.7h (p=0.26). At six weeks postpartum, there were no differences between groups in the rates of OB triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. Conclusion The first-line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features.
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    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 43
    Publication Date: 2018-03-06
    Description: Publication date: Available online 28 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Oded Langer Controversies persist over the most efficacious pharmacologic treatment for gestational diabetes mellitus. For purposes of accuracy in this article, the individual American College of Obstetricians and Gynecologists Practice Bulletin and American Diabetes Association Standards of Medical Care positions on each issue are quoted and then deliberated with evidence of counter claims presented in point/counterpoint. This is a review of all the relevant evidence for the most holistic picture possible. The main issues are (1) which diabetic drugs cross the placenta, (2) the quality of evidence and data source validity, (3) the rationale for the designation of glucose control as the primary outcome in gestational diabetes mellitus, and (4) which drugs (metformin, glyburide, or insulin) are most effective in improving secondary outcomes. The concept that 1 drug fits all, whether it be insulin, glyburide, or metformin, is a fallacy. Different drugs provide certain benefits but not all the benefits and not to all patients. In addition, the steps in the gestational diabetes mellitus management decision path and the current cost of the use of insulin, glyburide, or metformin are addressed. In the future, we must consider studying the potential of diabetic drugs that currently are used in nonpregnancy and incorporating the concept of precision medicine in the decision tree to maximize pregnancy outcomes.
    Print ISSN: 0002-9378
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  • 44
    Publication Date: 2018-03-06
    Description: Publication date: Available online 5 March 2018 Source: Analytical Biochemistry Author(s): G. Hawa, Linda Sonnleitner, A. Missbichler, A. Prinz, G. Bauer, C. Mauracher Although Enzyme Linked Immuno Sorbent Assay (ELISA) technology is approaching it's 45th year of existence since first described in 1971, it is still the main diagnostic tool in clinical research and routine diagnostics. However, despite its broad usage it suffers from some drawbacks, limiting its use especially in more advanced assay formats like multiplexing platforms, point of care devices or protein arrays. Those limitations result from the need for an enzyme label, a soluble enzyme substrate, washing steps (multiplexing, point care, arrays) and in some cases also insufficient sensitivity, because the majority of circulating proteins and thus potential biomarkers may be found in lowor sub-picomolar concentrations. We hereby present a new assay platform based on metal enhanced fluorescence (MEF), that remedies these problems since it eliminates the need for washing steps, for using enzyme labels and allows detection of analytes down to sub-picomolar concentrations. In addition this technology is fully compatible to standard fluorescence reader equipment as it is found in many laboratories nowadays. Since our present work is focused on single biomarker evaluation, we chose a 96 well plate format for convenience, but any other formate like antibody arrays, strip-like point of care devices etc. is feasible too.
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 45
    Publication Date: 2018-03-06
    Description: Publication date: 1 May 2018 Source: Analytical Biochemistry, Volume 548 Author(s): Pascal Steffen, Christoph Krisp, Wang Yi, Pengyuan Yang, Mark P. Molloy, Hartmut Schlüter Transporting biological samples such as cells or tissues is complicated by the need to maintain integrity and minimise modification and degradation, but this is economically costly as the samples must be shipped in a frozen state. This multi-laboratory study investigated sample variability introduced by non-cooled transport of dried peptide samples for proteomic analysis using mass spectrometry. Human cancer cell tryptic lysates were proteolysed and dried in Australia and shipped by air to Europe and China. Samples were measured using label free mass spectrometry on similar LC-MS systems at all three sites. Preparation and analysis of the specimens in this manner resulted in only minor differences in protein identification and showed high quantitative reproducibility amongst the participating laboratories. We examined any impact on peptide chemical modification and report no discrepancies compared to the starting, non-shipped sample. We conclude that transport of non-cooled, dried peptides has negligible effect on sample integrity for downstream LC-MS analysis and therefore represents a cost-effective option to facilitate international proteomic collaborations. Data is available via ProteomeXchange with identifier PXD008160.
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 46
    Publication Date: 2018-03-06
    Description: Publication date: Available online 2 March 2018 Source: Analytical Biochemistry Author(s): Iva Turyan, Ruth Frenkel, Zoran Sosic Protein tyrosine sulfation (Tyr-O-SO3) is a common post-translational modification (PTM), which is important for protein function. Absolute quantitation of Tyr-O-SO3 in recombinant therapeutic proteins has been challenging. We report here an MRM method used for absolute quantitation of Tyr-O-SO3 in the hydrolysate of a recombinant Fc-fusion protein. Quantitation is achieved by monitoring the sum of two transitions: the loss of carboxylic acid from tyrosine sulfate (major transition) and sulfate group from tyrosine sulfate sodium salt. The method exhibits a good sensitivity with a limit of quantitation of 1.4 ng/mL, linearity over three orders of magnitude, good repeatability, precision and accuracy.
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 47
    Publication Date: 2018-03-06
    Description: Publication date: Available online 2 March 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Anne M. Ambia, Jamie L. Morgan, C. Edward Wells, Scott W. Roberts, Monika Sanghavi, David B. Nelson, F. Gary Cunningham Background Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes. Objective There were three aims in this study of women with treated chronic hypertension during pregnancy: (1) to apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry. Study Design This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 to January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into four groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry. Results A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P=0.896), habitus (P=0.36), or duration of chronic hypertension (P=0.212) amongst the four groups. Abnormal cardiac remodeling was found in 51% and was significantly associated with increased rates of superimposed preeclampsia (P=0.015), preterm birth (P〈0.001), and neonatal intensive care admission (P=0.003). These outcomes reached the greatest significance when comparisons were made between eccentric hypertrophy and normal geometry. Conclusion Using current American Society of Echocardiography guidelines, 51% of women with treated chronic hypertension during pregnancy have some degree of abnormal cardiac remodeling. Any suggestion of maternal cardiac remodeling, regardless of subtype, was associated with increased risks for superimposed preeclampsia and preterm birth with its resultant perinatal sequelae. Eccentric ventricular hypertrophy, previously thought to mimic exercise physiology, appears to be the most associated with adverse perinatal outcomes. Despite evidence of cardiac remodeling, ejection fraction was preserved.
    Print ISSN: 0002-9378
    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 48
    Publication Date: 2018-03-06
    Description: Publication date: Available online 2 March 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Sharon L. Achilles, Michele N. Austin, Leslie A. Meyn, Felix Mhlanga, Zvavahera M. Chirenje, Sharon L. Hillier Background Data evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent. Objective We hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis-associated microbes with use compared to women initiating and using hormonal contraceptive methods. Study Design Vaginal swabs (N=1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis (BV) and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18-35 in Harare, Zimbabwe who were confirmed to be free of non-study hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate (n=41), norethisterone enanthate (n=44), or medroxyprogesterone acetate and ethinyl estradiol (n=40)), implant (levonorgestrel- (n=45) or etonogestrel-implant (n=48)), or copper intrauterine device (n=48) and repeat vaginal swabs were collected after 30, 90 and 180-days of continuous use. Self-reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus , Lactobacillus jensenii , Lactobacillus gasseri/johnsonii group, Lactobacillus vaginalis , Lactobacillus iners , Gardnerella vaginalis , Atopobium vaginae and Megasphaera -like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use. Results BV prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days and 49% at 180 days (p=.005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in BV prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% CI 0.5-2.0, p=.001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over six months, there was an increase in the log concentration of Gardnerella vaginalis (4.7, 5.2, 5.8, 5.9; p=.046) and Atopobium vaginae (3.0, 3.8, 4.6, 5.1; p=.002) between baseline and 30, 90 and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased Lactobacillus iners (mean decrease log concentration= 0.8; 95% CI: 0.3, 1.5, p=.004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used. Conclusions Copper intrauterine device use may increase colonization by BV-associated microbiota, resulting in increased prevalence of BV. Use of most hormonal contraception does not alter vaginal microbiota.
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  • 49
    Publication Date: 2018-03-06
    Description: Publication date: 11 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 3 Author(s): Yang Liu, Qianzi Zhao, Yuxin Yin, Michael A. McNutt, Tie Zhang, Yongtong Cao Acute gouty arthritis (AGA) is one of the most common forms of auto-inflammatory arthritis. IL-17 is a key proinflammatory cytokine which has been implicated in several autoimmune diseases. However, to date little is known about the role of IL-17 in AGA. In the present study, we show that serum IL-17 levels are significantly elevated in AGA patients early in the onset of symptoms of gout, and decrease gradually as symptoms diminish. Correlation analysis indicated that IL-17 expression is not only positively correlated with disease activity, but is also correlated with serum levels of IL-1β which plays a critical role in the differentiation of IL-17 - γδT cells into IL-17 + γδT cells. Flow cytometry analysis indicated that γδ T cells are a major source of IL-17 production during the early onset of AGA. We therefore identify IL-17 as a potential novel biomarker for AGA and suggest that targeting the γδ T cell/IL-17 immune axis is a potential strategy for treatment of acute flares of AGA. Graphical abstract
    Print ISSN: 0006-291X
    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 50
    Publication Date: 2018-03-06
    Description: Publication date: 11 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 3 Author(s): Wen-Si Yang, Yuan Hong, Ying Zhang, Da-Cheng Wang, De-Feng Li, Yan-Jie Hou Biofilm dispersal is characterized by the cell detachment from biofilms and expected to provide novel “anti-biofilm” approaches of prevention and treatment of biofilms in clinical and industrial settings. The E.coli protein BdcA has been identified as a biofilm dispersal factor and designed to be an important component in engineered applications to control biofilm formation. It belongs to short-chain dehydrogenase/reductase (SDR) family with the specific affinity to NADPH. Here, we show the structure of BdcA in complex with NADPH and confirm that NADPH binding is requisite for BdcA facilitating cell motility and increasing biofilm dispersal. Especially, we observe a potential substrate binding pocket surrounded by hydrophobic residues upon NADPH binding and present evidences that this pocket is essential for BdcA binding NADPH and exerting its biological functions. Our study provides the clues for illuminating the molecular mechanism of BdcA regulating biofilm dispersal and better utilizing BdcA to eliminate the biofilms.
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    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 51
    Publication Date: 2018-03-06
    Description: Publication date: Available online 5 March 2018 Source: Biochemical and Biophysical Research Communications Author(s): Qian Sun, Na-Na Lu, Lei Feng Apigetrin (APG), as a flavonoid, has many cellular bioactivities, including regulation of oxidative stress, and induction of apoptosis. However, the means by which APG suppresses human gastric cancer are still little to be understood. In the present study, the anti-cancer effects of APG on human gastric cancer cells were investigated. The results indicated that APG could suppress the proliferation and induce apoptosis in gastric cancer cells. Its role in apoptosis induction was through reducing Bcl-2, and enhancing Bax, Caspase-9/-3 and poly ADP-ribose polymerase (PARP) cleavage. In addition, APG incubation resulted in the generation of intracellular reactive oxygen species (ROS) in cells. Meanwhile, APG suppressed constitutive and interleukin-6 (IL-6)-stimulated signal transducer and activator of transcription 3 (STAT3), Janus kinase 2 gene (JAK2) and Src activation. However, ROS scavenger, N-acety-l-cysteine (NAC), diminished apoptosis induced by APG. And APG-triggered de-phosphorylation of STAT3/JAK2 was rescued by NAC pre-treatment. In vivo , APG administration significantly inhibited the gastric cancer cell xenograft tumorigenesis through inducing apoptosis and inhibiting STAT3/JAK2 pathways. Taken together, the findings above illustrated that APG might be used as a promising candidate against human gastric cancer progression.
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    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 52
    Publication Date: 2018-03-06
    Description: Publication date: 4 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 2 Author(s): Yongsheng Quan, Yan Zhang, Wei Lin, Zhaohua Shen, Shuai Wu, Changxin Zhu, Xiaoyan Wang Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play a critical role in tumorigenesis of gastric cancer. LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) has been identified as one of gastric cancer-specific lncRNAs. However, its precise role in gastric cancer remains unknown. In this study, we found that lncRNA MLK7-AS1 was significantly increased in gastric cancer tissues compared with in adjacent tissues. Gastric cancer patients with high MLK7-AS1 expression had a shorter survival and poorer prognosis. By loss-function assay, we demonstrated that knockdown of MLK7-AS1 inhibited cell proliferation and induced apoptosis in HGC27and MKN-45 cells. Furthermore, we identified miR-375 as a target of MLK7-AS1. MLK7-AS1 interacted with Dnmt1 and recruited it to miR-375 promotor, hyper-methylating miR-375 promotor and repressing miR-375 expression. Taken together, our findings demonstrate that knockdown of MLK7-AS1 by siRNA inhibits gastric cancer growth by epigenetically regulating miR-375. Thus, MLK7-AS1 may be a useful prognostic marker and therapeutic target for gastric cancer patients.
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    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 53
    Publication Date: 2018-03-06
    Description: Publication date: 4 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 2 Author(s): Ji-qiang Liu, Li Zhang, Ji Yao, Shuo Yao, Ting Yuan Chronic obstructive pulmonary disease (COPD), is characterized by inflammation of airways accompanied by a progressive destruction of lung parenchyma. This process is initiated in most cases by cigarette smoking. In this study we investigated the role of AMP activated protein kinase (AMPK) in cigarette smoke extract (CSE)-induced airway epithelial cell apoptosis as a consequence of endoplasmic reticulum stress (ER stress). Exposure of human bronchial epithelial cells (HBEpC) to CSE resulted in apoptosis as detected using Annexin V-PI flow cytometry. However, co-treatment with N 1 -(β- d -ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly increased cell protection against ER stress-induced apoptosis by upregulating the 150 kDa oxygen-regulated protein (ORP150), which functions as an ER-associated chaperone, with concomitant elevation of FOXO1, a critical transcription factor regulating ORP150 expression. Lentiviral silencing of AMPK or FOXO1 using short hairpin (sh) RNA resulted in a significant decrease of ORP150 and an elevation of CCAAT/enhancer-binding protein-homologous protein (CHOP) resulting in ER stress and apoptosis of HBEpC. Together, our results strongly suggest that AMPK can activate ORP150 through FOXO1 pathway and confer protection against ER stress-induced apoptosis of airway epithelial cells following exposure to CSE. Thus, AMPK may serve as a likely therapeutic target for clinical and sub-clinical interventions in COPD.
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  • 54
    Publication Date: 2018-03-06
    Description: Publication date: 4 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 2 Author(s): Jun Cao, Yijun Mi, Cuilin Shi, Yicong Bian, Chenrong Huang, Zhijian Ye, Linsheng Liu, Liyan Miao Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis -4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis -aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications. Graphical abstract
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  • 55
    Publication Date: 2018-03-06
    Description: Publication date: 4 March 2018 Source: Biochemical and Biophysical Research Communications, Volume 497, Issue 2 Author(s): Jinyu Chi, Lei Wang, Xiaohui Zhang, Yu Fu, Yue Liu, Wenjia Chen, Wenxiu Liu, Zhiyu Shi, Xinhua Yin Cardiac fibrosis is one of the primary mechanisms of ventricular remodeling, and there is no effective method for reversal. Activation of calcium sensing receptor (CaSR) has been reported to be involved in the development of myocardial fibrosis, but the molecular mechanism for CaSR activation has not yet been clarified and needs to be further explored. Here, we found that AngII induces cardiac fibroblast proliferation and phenotypic transformation in a dose-dependent manner with increased CaSR and autophagy related protein (Beclin1, LC3B) expression. CaSR activation results in intracellular calcium release, MEK1/2 pathway phosphorylation, autophagy activation and collagen formation induced by AngII in cardiac fibroblasts. However, pretreating the cells with Calhex 231 , PD98059 or 3-MA partially blocked AngII-induced cardiac fibrosis. Our data indicate that the activation of CaSR-mediated MEK/ERK and autophagic pathways is involved in AngII-induced cardiac fibrosis in vitro.
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  • 56
    Publication Date: 2018-03-06
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part A Author(s): Amber Ou, Ben J. Gu, James S. Wiley Activation of P2X7 receptors is widely recognised to initiate proinflammatory responses. However P2X7 also has a dual function as a scavenger receptor which is active in the absence of ATP and plasma proteins and may be important in central nervous system (CNS) diseases. Here, we investigated both P2X7 pore formation and its phagocytic function in fresh human monocytes (as a model of microglia) by measuring ATP-induced ethidium dye uptake and fluorescent bead uptake respectively. This was studied in monocytes expressing various polymorphic variants as well as in the presence of different P2X7 antagonists and ionic media. P2X7-mediated phagocytosis was found to account for about half of Latrunculin (or Cytochalasin D)-sensitive bead engulfment by fresh human monocytes. Monocytes harbouring P2X7 Ala348Thr or Glu496Ala polymorphic variants showed increase or loss of ethidium uptake respectively, but these changes in pore formation did not always correspond to the changes in phagocytosis of YG beads. Unlike pore function, P2X7-mediated phagocytosis was not affected by three potent selective P2X7 antagonists and remained identical in Na + and K + media. Taken together, our results show that P2X7 is a scavenger receptor with important function in the CNS but its phagocytic function has features distinct from its pore function. Both P2X7 pore formation and P2X7-mediated phagocytosis should be considered in the design of new P2X7 antagonists for the treatment of CNS diseases.
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
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  • 57
    Publication Date: 2018-03-06
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part A Author(s): Hyeong Jun Ku, Jung Hyun Park, Sung Hwan Kim, Jeen-Woo Park Isocitrate dehydrogenase 2 (IDH2) is a key enzyme that maintains the balance of mitochondrial redox status by generating NADPH as a reducing factor, which is used to reduce oxidized antioxidant proteins and oxidized glutathione. Therefore, the role of IDH2 is crucial in organs that are easily influenced by reactive oxygen species (ROS) or mechanical damage. Humans are constantly exposed to ultraviolet (UV) radiation throughout their lifetime, which can cause various cutaneous diseases, such skin carcinoma, dermatitis, and sunburn. ROS play an important role in the initial step of these diseases; therefore, IDH2 deficient mice ( Idh2 −/− ) could be a useful model to investigate UV-mediated skin damage. When we exposed the dorsal skin of Idh2 −/− mice to UVB, pyrimidine dimers and (6-4) photoproducts (6-4PPs), marker of photoproducts generated by UVB, were found in the dermis of the knockout mice. Increased collagen degradation, apoptosis, inflammation, and ROS levels in the dermis were also observed. These results indicated that UVB could reach the dermis by penetrating the epidermis. We then attempted to determine how the epidermis was breached, and observed a decrease in the expression level of ΔNp63, a major protein required for epidermis generation, in the Idh2 −/− mice. The mito-TEMPO supplement significantly ameliorates UVB-induced damage in the skin of Idh2 −/− mice. In the present study, we provided a role for IDH2 in protection against UVB-induced skin damage and a new connection between IDH2 and ΔNp63. Graphical abstract
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  • 58
    Publication Date: 2018-03-06
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part A Author(s): Kahli Zietlow, Lefko Charalambous, Isaac Ng, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L. Rock, Ann Saunders, Allen D. Roses, W. Kirby Gottschalk
    Print ISSN: 0925-4439
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  • 59
    Publication Date: 2018-03-06
    Description: Publication date: Available online 3 March 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Author(s): Meiting Zhang, Yi Zhao, Youli Zhang, Dawei Wang, Shuming Gu, Wen Feng, Wanxin Peng, Aihua Gong, Min Xu Although overexpression of the long non-coding RNA (lncRNA) UCA1 has been implicated in several human cancers, its biological function in pancreatic cancer remains to be clarified. In this study, we reported that UCA1 expression was significantly increased in pancreatic cancer tissues and correlated with clinicopathological features, tumor stage, and poorer patient outcome. We further showed that UCA1 promoted cell migration and invasion of pancreatic cancer cells. Importantly, we found that UCA1 overexpression inhibited YAP phosphorylation, and increased YAP expression. Mechanistically, UCA1 interacted with MOB1, Lats1, and YAP, forming shielding composites. Moreover, we demonstrated that UCA1 increased YAP nuclear localization and stabilization, and improved TEAD luciferase activity. In turn, YAP promotes UCA1 expression. Collectively, the present study provides insights into the mechanistic regulation of UCA1 promoting pancreatic cancer progression through the Hippo signaling pathway. UCA1 may serve as a candidate biomarker for poor prognosis and a target for new pancreatic cancer therapies.
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  • 60
    Publication Date: 2018-03-06
    Description: Publication date: Available online 28 February 2018 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): David J. Birnbaum, François Bertucci, Pascal Finetti, Daniel Birnbaum, Emilie Mamessier Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for oancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter and intra tumor genetic heterogeneity. A molecular classification should help reduce heterogeneity among patients, with the consequences of better predicting evolution and better orienting the treatment. This review summarizes the information that should be retained in clinical practice from all the molecular analyses. PDAC can be classified based on mutational subtypes and gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Different molecular classifications have been established by using gene expression analyses to reduce PDAC heterogeneity. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions.
    Print ISSN: 0304-419X
    Electronic ISSN: 1879-2561
    Topics: Medicine
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  • 61
    Publication Date: 2018-03-06
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part A Author(s): Mi-Jeong Lee Accumulation of dysfunctional white adipose tissues increases risks for cardiometabolic diseases in obesity. In addition to white, brown or brite adipose tissues are also present in adult humans and increasing their amount may be protective. Therefore, understanding factors regulating the amount and function of each adipose depot is crucial for developing therapeutic targets for obesity and its associated metabolic diseases. The transforming growth factor beta (TGFβ) superfamily, which consists of TGFβ, BMPs, GDFs, and activins, controls multiple aspects of adipose biology. This review focuses on the recent development in understanding the role of TGFβ superfamily in the regulation of white, brite and brown adipocyte differentiation, adipose tissue fibrosis, and adipocyte metabolic and endocrine functions. TGFβ family and their antagonists are produced locally within adipose tissues and their expression levels are altered in obesity. We also discuss their potential contribution to adipose tissue dysfunction in obesity.
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  • 62
    Publication Date: 2018-03-06
    Description: Publication date: Available online 4 March 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Author(s): Karolina Losenkova, Mariachiara Zuccarini, Mikko Helenius, Guillaume Jacquemet, Evgenia Gerasimovskaya, Camilla Tallgren, Sirpa Jalkanen, Gennady G. Yegutkin Intravascular ATP and adenosine have emerged as important regulators of endothelial barrier function, vascular remodeling and neovascularization at various pathological states, including hypoxia, inflammation and oxidative stress. By using human umbilical vein endothelial cells (HUVEC) and bovine vasa vasorum endothelial cells (VVEC) as representatives of macro- and microvessel phenotypes, this study was undertaken to evaluate cellular mechanisms contributing to physiological adaptation of vascular endothelium to hypoxia, with a particular emphasis on ectoenzymatic purine-converting activities and their link to intracellular ATP homeostasis and signaling pathways. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), ecto-5′-nucleotidase/CD73 and ecto-adenylate kinase activities were determined by thin-layer chromatography (TLC) with 3 H-labelled nucleotide substrates. Exposure of HUVEC and VVEC to 1% O 2 for 4–24 h triggered rather moderate activation of ATP breakdown into adenosine via the CD39-CD73 axis. Additional TLC analysis of salvage pathways revealed the enhanced ability of hypoxic HUVEC to convert cell-incorporated [ 3 H]adenosine into [ 3 H]ADP/ATP. Furthermore, following a period of hypoxia, HUVEC underwent concurrent changes in intracellular signaling manifested in the depletion of putative ATP stores and targeted up-regulation of phospho-p53, p70S6K/mTOR and other tyrosine kinases. The revealed complex implication of both extrinsic and intrinsic mechanisms into a tuned hypoxia-induced control of purine homeostasis and signaling may open up further research for the development of pharmacological treatments to improve endothelial cell function under disease conditions associated with a loss of cellular ATP during oxygen deprivation. Graphical abstract
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  • 63
    Publication Date: 2018-03-06
    Description: The cartwheel is a striking structure critical for building the centriole, a microtubule-based organelle fundamental for organizing centrosomes, cilia, and flagella. Over the last 50 years, the cartwheel has been described in many systems using electron microscopy, but the molecular nature of its constituent building blocks and their assembly mechanisms have long remained mysterious. Here, we review discoveries that led to the current understanding of cartwheel structure, assembly, and function. We focus on the key role of SAS-6 protein self-organization, both for building the signature ring-like structure with hub and spokes, as well as for their vertical stacking. The resemblance of assembly intermediates in vitro and in vivo leads us to propose a novel registration step in cartwheel biogenesis, whereby stacked SAS-6-containing rings are put in register through interactions with peripheral elements anchored to microtubules. We conclude by evoking some avenues for further uncovering cartwheel and centriole assembly mechanisms. The cartwheel is crucial for centriole assembly. Despite this fundamental role, cartwheel structure and assembly mechanisms remain unclear for a long time. Here we review five decades of research that led to our current understanding of these questions, highlighting the central role of the SAS-6 protein family.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
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  • 64
    Publication Date: 2018-03-06
    Description: Publication date: Available online 1 March 2018 Source: Cell Author(s): Jeffrey N. Carey, Erin L. Mettert, Manuela Roggiani, Kevin S. Myers, Patricia J. Kiley, Mark Goulian Microbial populations can maximize fitness in dynamic environments through bet hedging, a process wherein a subpopulation assumes a phenotype not optimally adapted to the present environment but well adapted to an environment likely to be encountered. Here, we show that oxygen induces fluctuating expression of the trimethylamine oxide (TMAO) respiratory system of Escherichia coli , diversifying the cell population and enabling a bet-hedging strategy that permits growth following oxygen loss. This regulation by oxygen affects the variance in gene expression but leaves the mean unchanged. We show that the oxygen-sensitive transcription factor IscR is the key regulator of variability. Oxygen causes IscR to repress expression of a TMAO-responsive signaling system, allowing stochastic effects to have a strong effect on the output of the system and resulting in heterogeneous expression of the TMAO reduction machinery. This work reveals a mechanism through which cells regulate molecular noise to enhance fitness. Graphical abstract Teaser Environmental oxygen regulates the cell-to-cell variability of an E. coli signal transduction system that controls anaerobic respiration but leaves the population mean unchanged, thereby revealing a distinct form of bet hedging that provides a fitness advantage when oxygen availability rapidly drops.
    Print ISSN: 0092-8674
    Electronic ISSN: 1097-4172
    Topics: Biology , Medicine
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  • 65
    Publication Date: 2018-03-06
    Description: Publication date: Available online 1 March 2018 Source: Cell Author(s): David Oliveira Dias, Hoseok Kim, Daniel Holl, Beata Werne Solnestam, Joakim Lundeberg, Marie Carlén, Christian Göritz, Jonas Frisén CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury. Graphical abstract Teaser Attenuation of fibrotic tissue generation by a subset of pericytes promotes regeneration of serotonergic and corticospinal tract axons and improves functional recovery after spinal cord injury.
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    Topics: Biology , Medicine
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  • 66
    Publication Date: 2018-03-06
    Description: Publication date: Available online 1 March 2018 Source: Cell Host & Microbe Author(s): Kyung-Ah Lee, Kyu-Chan Cho, Boram Kim, In-Hwan Jang, Kibum Nam, Young Eun Kwon, Myungjin Kim, Do Young Hyeon, Daehee Hwang, Jae-Hong Seol, Won-Jae Lee DUOX, a member of the NADPH oxidase family, acts as the first line of defense against enteric pathogens by producing microbicidal reactive oxygen species. DUOX is activated upon enteric infection, but the mechanisms regulating DUOX activity remain incompletely understood. Using Drosophila genetic tools, we show that enteric infection results in “pro-catabolic” signaling that initiates metabolic reprogramming of enterocytes toward lipid catabolism, which ultimately governs DUOX homeostasis. Infection induces signaling cascades involving TRAF3 and kinases AMPK and WTS, which regulate TOR kinase to control the balance of lipogenesis versus lipolysis. Enhancing lipogenesis blocks DUOX activity, whereas stimulating lipolysis via ATG1-dependent lipophagy is required for DUOX activation. Drosophila with altered activity in TRAF3-AMPK/WTS-ATG1 pathway components exhibit abolished infection-induced lipolysis, reduced DUOX activation, and enhanced susceptibility to enteric infection. Thus, this work uncovers signaling cascades governing inflammation-induced metabolic reprogramming and provides insight into the pathophysiology of immune-metabolic interactions in the microbe-laden gut epithelia. Graphical abstract Teaser DUOX, a member of the NADPH oxidase family, acts as the first line of host defense in the Drosophila intestine. Lee et al. show that pathogen infection stimulates pro-catabolic signaling that initiates metabolic reprogramming toward lipid catabolism, which is required for DUOX activation and host resistance to enteric infection.
    Print ISSN: 1931-3128
    Electronic ISSN: 1934-6069
    Topics: Biology
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  • 67
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    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): Senthil K. Muthuswamy Organoids have tremendous promise for modeling human cancers and revealing new biological insights. Sachs et al. (2018), Seino et al. (2018) (in this issue of Cell Stem Cell ), and Broutier et al. (2017) derive cancer organoids from breast, pancreas, and liver, respectively, not only reporting new methodologies but also showing their utility for translational and clinical cancer research. Teaser Organoids have tremendous promise for modeling human cancers and revealing new biological insights. Sachs et al. (2018), Seino et al. (2018) (in this issue of Cell Stem Cell ), and Broutier et al. (2017) derive cancer organoids from breast, pancreas, and liver, respectively, not only reporting new methodologies but also showing their utility for translational and clinical cancer research.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
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  • 68
    Publication Date: 2018-03-06
    Description: Publication date: Available online 1 March 2018 Source: Cell Host & Microbe Author(s): Enzo Z. Poirier, Bertsy Goic, Lorena Tomé-Poderti, Lionel Frangeul, Jérémy Boussier, Valérie Gausson, Hervé Blanc, Thomas Vallet, Hyelee Loyd, Laura I. Levi, Sophie Lanciano, Chloé Baron, Sarah H. Merkling, Louis Lambrechts, Marie Mirouze, Susan Carpenter, Marco Vignuzzi, Maria-Carla Saleh The RNAi pathway confers antiviral immunity in insects. Virus-specific siRNA responses are amplified via the reverse transcription of viral RNA to viral DNA (vDNA). The nature, biogenesis, and regulation of vDNA are unclear. We find that vDNA produced during RNA virus infection of Drosophila and mosquitoes is present in both linear and circular forms. Circular vDNA (cvDNA) is sufficient to produce siRNAs that confer partially protective immunity when challenged with a cognate virus. cvDNAs bear homology to defective viral genomes (DVGs), and DVGs serve as templates for vDNA and cvDNA synthesis. Accordingly, DVGs promote the amplification of vDNA-mediated antiviral RNAi responses in infected Drosophila . Furthermore, vDNA synthesis is regulated by the DExD/H helicase domain of Dicer-2 in a mechanism distinct from its role in siRNA generation. We suggest that, analogous to mammalian RIG-I-like receptors, Dicer-2 functions like a pattern recognition receptor for DVGs to modulate antiviral immunity in insects. Graphical abstract Teaser Poirier et al. show that during RNA virus infection of insects, circular viral DNA is produced, regulated by Dicer-2 helicase domain. The main template for viral DNA is defective viral genomes, which appear to be key viral products modulating the host immune response and the establishment of viral persistence.
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    Electronic ISSN: 1934-6069
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  • 69
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): Thomas A. Rando, Fabrisia Ambrosio The emerging field of regenerative rehabilitation integrates biological and bioengineering advances in regenerative medicine with rehabilitative sciences. Here we highlight recent stem cell-based examples of the regenerative rehabilitation paradigm to promote tissue repair and regeneration, and we discuss remaining challenges and future directions for the field. Teaser The emerging field of regenerative rehabilitation integrates biological and bioengineering advances in regenerative medicine with rehabilitative sciences. Here we highlight recent stem cell-based examples of the regenerative rehabilitation paradigm to promote tissue repair and regeneration, and we discuss remaining challenges and future directions for the field.
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  • 70
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic Organs-on-a-chip (OOCs) are miniature tissues and organs grown in vitro that enable modeling of human physiology and disease. The technology has emerged from converging advances in tissue engineering, semiconductor fabrication, and human cell sourcing. Encompassing innovations in human stem cell technology, OOCs offer a promising approach to emulate human patho/physiology in vitro , and address limitations of current cell and animal models. Here, we review the design considerations for single and multi-organ OOCs, discuss remaining challenges, and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine. Teaser Ronaldson-Bouchard and Vunjak-Novakovic discuss the design considerations for single and multi-organ organs-on-a-chip (OOCs) and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine.
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  • 71
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): Laura E. Niklason The extracellular matrix is a biologically critical entity that has historically been poorly understood. Here we discuss how new tools for characterizing matrix composition and function enable us to design and deliver advanced matrices in vitro , to optimize regeneration, and in vivo , within a variety of tissues and organs. Teaser The extracellular matrix is a biologically critical entity that has historically been poorly understood. Here we discuss how new tools for characterizing matrix composition and function enable us to design and deliver advanced matrices in vitro , to optimize regeneration, and in vivo , within a variety of tissues and organs.
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  • 72
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): H.-H. Greco Song, Rowza T. Rumma, C. Keith Ozaki, Elazer R. Edelman, Christopher S. Chen Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology. Teaser Song et al. explore recent bioengineering advances in creating functional blood macro- and microvessels, particularly featuring stem cells as a seed source. They highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
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    Topics: Biology
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  • 73
    Publication Date: 2018-03-06
    Description: Publication date: 1 March 2018 Source: Cell Stem Cell, Volume 22, Issue 3 Author(s): Madeline N. Hayes, Karin McCarthy, Alexander Jin, Mariana L. Oliveira, Sowmya Iyer, Sara P. Garcia, Sivasish Sindiri, Berkley Gryder, Zainab Motala, G. Petur Nielsen, Jean-Paul Borg, Matt van de Rijn, David Malkin, Javed Khan, Myron S. Ignatius, David M. Langenau Tumor growth and relapse are driven by tumor propagating cells (TPCs). However, mechanisms regulating TPC fate choices, maintenance, and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway, affects TPC self-renewal in rhabdomyosarcoma (RMS)—a pediatric cancer of muscle. VANGL2 is expressed in a majority of human RMS and within early mononuclear progenitor cells. VANGL2 depletion inhibited cell proliferation, reduced TPC numbers, and induced differentiation of human RMS in vitro and in mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS), we determined that Vangl2 expression enriches for TPCs and promotes their self-renewal. Expression of constitutively active and dominant-negative isoforms of RHOA revealed that it acts downstream of VANGL2 to regulate proliferation and maintenance of TPCs in human RMS. Our studies offer insights into pathways that control TPCs and identify new potential therapeutic targets. Graphical abstract Teaser Hayes et al. find that Vangl2 specifically labels progenitors that sustain growth and self-renewal in both zebrafish and human rhabdomyosarcoma and is required for their maintenance. This work reveals direct regulation of stem cell programs and tumor growth by Vangl2/RhoA signaling, offering opportunities for direct assessment and therapeutic targeting.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 74
    Publication Date: 2018-03-06
    Description: Despite the existence of well-established international environmental and nature conservation policies (e.g., the Ramsar Convention and Convention on Biological Diversity) ponds are largely missing from national and international legislation and policy frameworks. Ponds are among the most biodiverse and ecologically important freshwater habitats, and their value lies not only in individual ponds, but more importantly, in networks of ponds (pondscapes). Ponds make an important contribution to society through the ecosystem services they provide, with effective conservation of pondscapes essential to ensuring that these services are maintained. Implementation of current pond conservation through individual site designations does not function at the landscape scale, where ponds contribute most to biodiversity. Conservation and management of pondscapes should complement current national and international nature conservation and water policy/legislation, as pondscapes can provide species protection in landscapes where large-scale traditional conservation areas cannot be established (e.g., urban or agricultural landscapes). We propose practical steps for the effective incorporation or enhancement of ponds within five policy areas: through open water sustainable urban drainage systems in urban planning, increased incentives in agri-environment schemes, curriculum inclusion in education, emphasis on ecological scale in mitigation measures following anthropogenic developments, and the inclusion of pondscapes in conservation policy. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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