bluuebunny/crossref_metadata_2025_split huggingface dataset:
SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway
Authors: Wang Menghao , Yuan Fangchao , Bai He , Zhang Jie , Wu Hao , Zheng Kaiwen , Zhang Wenfeng , Miao Mingyong , Gong Jianping 
Published: April 2019

Background.
The development of liver transplantation (LT) is increasingly being limited by the unavailability of liver grafts. Unique regenerative capacity of liver in response to injuries makes living-donor liver transplantation (LDLT) a feasible strategy to meet clinical demands. Serine hydroxymethyl-transferase 2 (SHMT2) serves as the key enzyme in the biosynthesis of glycine. Glycine affects the activity of mammalian target of rapamycin (mTOR), which is important for cellular growth and proliferation. In this study, the effects of SHMT2 on mouse liver regeneration were investigated using a classical partial hepatectomy (PH) model.

Methods.
In vivo, PH was performed on mice with or without knockdown of SHMT2. In vitro, SHMT2 was overexpressed in primary hepatocytes, which were cultured in customized Dulbecco’s modified eagle media and LY294002 (an Akt inhibitor). Relevant indexes of liver regeneration, cell proliferation, and Akt/mTOR signal pathways were analyzed.

Results.
After PH, the expression levels of SHMT2 fluctuated with time and knockdown of SHMT2 in vivo lowered the regenerative ability of liver, with reduced glycine levels compared to the scramble group. In addition, overexpression of SHMT2 in hepatocytes boosted glycine production while enhancing Akt/mTOR pathway activity. These results were validated by the application of LY294002 in vitro.

Conclusions.
SHMT2 can contribute to liver regeneration after PH, and this is likely related to the activation of Akt/mTOR signaling pathway by its metabolic product, glycine, in hepatocytes. These results might have therapeutic implications for the prognosis of patients undergoing hepatic resection or transplantation.
An epithelial organoid model with Langerhans cells for assessing virus-host interactions
Authors: Jackson Robert , Eade Statton , Zehbe Ingeborg 
Published: April 2019

Persistent infection with oncogenic human papillomavirus (HPV) may lead to cancer in mucosal and skin tissue. Consequently, HPV must have developed strategies to escape host immune surveillance. Nevertheless, most HPV infections are cleared by the infected host. Our laboratory investigates Langerhans cells (LCs), acting at the interface between innate and adaptive immunity. We hypothesize that this first line of defence is vital for potential HPV elimination. As an alternative to animal models, we use smaller-scale epithelial organoids grown from human primary keratinocytes derived from various anatomical sites. This approach is amenable to large sample sizes—an essential aspect for scientific rigour and statistical power. To evaluate LCs phenotypically and molecularly during the viral life cycle and onset of carcinogenesis, we have included an engineered myeloid cell line with the ability to acquire an LC phenotype. This model is accurately tailored for the crucial time-window of early virus elimination in a complex organism and will shed more light on our long-standing research question of how naturally occurring HPV variants influence disease development. It may also be applied to other microorganism–host interaction research or enquiries of epithelium immunobiology. Finally, our continuously updated pathogen–host analysis tool enables state-of-the-art bioinformatics analyses of next-generation sequencing data.
This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Integrating measures of viral prevalence and seroprevalence: a mechanistic modelling approach to explaining cohort patterns of human papillomavirus in women in the USA
Authors: Brouwer Andrew F. , Meza Rafael , Eisenberg Marisa C. 
Published: April 2019

Incidence of human papillomavirus (HPV) related cancers is increasing, generating substantial interest in understanding how trends in population prevalence of HPV infection are changing. However, there are no direct, population-scale measurements of HPV prevalence prior to 2003. Previous work using models to reconstruct historical trends have focused only on genital infection or seroprevalence (prevalence of antibodies) separately, and the results of these single-measure studies have been hard to reconcile. Here, we develop a mechanistic disease model fit jointly to cervicogential prevalence and seroprevalence in unvaccinated women in the USA using National Health and Nutrition Examination Survey data (2003–2010) and compare it to fits of statistical age–cohort models. We find that including a latent HPV state in our model significantly improves model fit and that antibody waning may be an important contributor to observed patterns of seroprevalence. Moreover, we find that the mechanistic model outperforms the statistical model and that the joint analysis prevents the inconsistencies that arise when estimating historical cohort trends in infection from genital prevalence and seroprevalence separately. Our analysis suggests that while there is substantial uncertainty associated with the estimation of historic HPV trends, there has likely been an increase in the force of infection for more recent birth cohorts.
This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Essential role of inverted repeat in Epstein–Barr virus IR-1 in B cell transformation; geographical variation of the viral genome
Authors: Bridges Ray , Correia Samantha , Wegner Fanny , Venturini Cristina , Palser Anne , White Robert E. , Kellam Paul , Breuer Judith , Farrell Paul J. 
Published: April 2019

Many regions of the Epstein–Barr virus (EBV) genome, repeated and unique sequences, contribute to the geographical variation observed between strains. Here we use a large alignment of curated EBV genome sequences to identify major sites of variation in the genome of type 1 EBV strains; the CAO deletion in latent membrane protein 1 (LMP1) is the most frequent major indel present in the unique regions of EBV strains from various parts of the world. Principal component analysis was used to identify patterns of sequence variation and nucleotide positions in the sequences that can distinguish EBV from some different geographical regions. Viral genome sequence variation also affects interpretation of genetic content; known genes, origins of replication and gene expression control regions explain most of the viral genome but there are still a few sections of unknown function. One of these EBV genome regions contains a large inverted repeat sequence (invR) within the IR-1 major internal repeat array. We deleted this invR sequence and showed that this abolished the ability of the virus to transform human B cells into lymphoblastoid cell lines.This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Small size, big impact: how studies of small DNA tumour viruses revolutionized biology
Authors: DiMaio Daniel 
Published: April 2019

Intense study of three families of small tumour viruses with double-stranded DNA genomes, carried out over 50 years, has had a profound impact on biology. The polyomaviruses and papillomaviruses have circular DNA genomes of approximately 5000 and approximately 8000 base-pairs, respectively, and thus encode only a handful of proteins. Adenoviruses have a 32 000-base-pair linear DNA genome, still far smaller than the three billion-base-pair human genome. Members of all three virus families can transform cultured cells to tumorigenicity and cause tumours in experimental animals. Several human papillomaviruses (HPV) and at least one polyomavirus are oncogenic in humans. Early analysis of these viruses, particularly the polyomavirus SV40, led to the development of many powerful experimental tools, including restriction mapping, site-directed mutagenesis, gene transfer, genome-wide sequencing and recombinant DNA. These tools have since been refined and used to study cellular genes, revolutionizing our understanding of biology. These tools were also applied to the viruses themselves. Analysis of the virus life cycle and the effect of these viruses on cells yielded important new insights into many aspects of gene expression, DNA replication, cell biology and carcinogenesis. These studies have also led to vaccination strategies to prevent infection and cancer in humans.
This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Intra-patient viral evolution in polyomavirus-related diseases
Authors: McIlroy Dorian , Halary Franck , Bressollette-Bodin Céline 
Published: April 2019

Human polyomaviruses show relatively little genetic polymorphism between isolates, indicating that these viruses are genetically stable between hosts. However, it has become increasingly clear that intra-host molecular evolution is a feature of some polyomavirus (PyV) infections in humans. Mutations inducing premature stop codons in the early region of the integrated Merkel cell PyV genome lead to the expression of a truncated form of the large tumour (LT) antigen that is critical for the transformation of Merkel cell carcinoma (MCC) cells. Non-coding control region (NCCR) rearrangements and point mutations in virion protein (VP) 1 have been described in both JCPyV and BKPyV infections. In the context of JCPyV infection, molecular evolution at both these loci allows the virus to replicate effectively in the central nervous system, thereby leading to the development of progressive multifocal leukoencephalopathy (PML). In BKPyV infection, NCCR rearrangements have been linked to higher rates of virus replication in the kidney, and are proposed to play a direct causal role in the development of PyV-associated nephropathy. In all three of these infections, therefore, intra-host viral evolution appears to be an essential component of the disease process.
This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Detection of SHV, CTX-M and TEM genes in extended spectrum beta lactamase producing multi-drug resistant Escherichia coli from clinical isolates in Calabar, Nigeria
Authors: Ogba Ofonime , Esiere Miracle , Esiere Rosemary 
Published: April 2019

Background
The emergence of multi-drug resistant strains of Escherichia coli complicates the treatment of infections. The detection of ESBL genes in bacteria and their antimicrobial resistance patterns can provide information about their epidemiology and transmission. The study aimed to detect ESBL genes that encode; CTX-M, TEM and SHV in E. coli isolatesin our locality.

Methods
Clinical E. coli isolates were obtained from public and private clinics within Calabar metropolis. Biochemical method was used to re-identify the isolates. Antibiotics susceptibility testing was done using Kirby-Bauer disc diffusion method. Phenotypic detection of ESBL in isolates was done by double disc synergy test (DDST). The ESBL genes were detected using conventional PCR method.

Results
The ESBL phenotypic positive isolates was (56.6 %). The most prevalent gene in the study was CTX-M gene. Antibiotic susceptibility of E. coli isolates to commonly used antibiotics was low. Isolates were most susceptible to quinolones (54.7 %) and fluoroquinolones (34.0 %). The ESBL producing isolates were more susceptible to quinolones but less susceptible to the third generation cephalosporins. There was significant association between gene expression by isolates and antibiotic resistance (P≤0.05). Isolates with the SHV and TEM genes showed 100 % resistance to some tested antibiotics. Isolates with CTX-M genes were also highly resistant.

Conclusion
The SHV, CTX-M and TEM genes were detected in Escherichia coli isolates in our locality. These may have resulted in the high resistance of isolates to commonly used antibiotics which may pose challenges to patient’s management.
Association of milk microbiome in bovine clinical mastitis and their functional implications in cows in Bangladesh
Authors: Hoque M. Nazmul , Istiaq Arif , Clement Rebecca A. , Sultana Munawar , Crandall Keith A. , Siddiki Amam Zonaed , Hossain M. Anwar 
Published: April 2019

AbstractMilk microbiomes impose a significant influence on the pathophysiology of bovine mastitis. To assess the association, we compared the microbiome of clinical mastitis (CM) and healthy (H) milk samples through whole metagenomic deep sequencing. A total of 483.38 million reads generated from both metagenomes were analyzed through PathoScope and MG-RAST, and mapped to 380 bacterial, 56 archaeal, and 39 viral genomes. We observed distinct shifts and differences in abundance between the microbiome of CM and H milk in phyla Proteobacteria, Bacteroidetes, Firmicutes and Actinobacteria with an inclusion of 68.04% unreported and/or opportunistic species in CM milk. Additionally, 14 archaeal and 14 viral genera were found to be solely associated with CM. The functional metagenomics identified several pathways related to bacterial proliferation and colonization such as metabolism, chemotaxis and invasion, immune-diseases, oxidative stress, regulation and cell signaling, phage and prophases, antibiotic and heavy metal resistance to be associated with CM. Therefore, the present study provides conclusive data on milk microbiome diversity associated with bovine CM and its role in udder health.
Infectious disease phylodynamics with occurrence data
Authors: Featherstone Leo A. , Di Giallonardo Francesca , Holmes Edward C. , Vaughan Timothy G. , Duchêne Sebastián 
Published: April 2019

AbstractPoint 1Phylodynamic models use pathogen genome sequence data to infer epidemiological dynamics. With the increasing genomic surveillance of pathogens, especially amid the SARS-CoV-2 outbreak, new practical questions about their use are emerging.Point 2One such question focuses on the inclusion of un-sequenced case occurrence data alongside sequenced data to improve phylodynamic analyses. This approach can be particularly valuable if sequencing efforts vary over time.Point 3Using simulations, we demonstrate that birth-death phylodynamic models can employ occurrence data to eliminate bias in estimates of the basic reproductive number due to misspecification of the sampling process. In contrast, the coalescent exponential model is robust to such sampling biases, but in the absence of a sampling model it cannot exploit occurrence data. Subsequent analysis of the SARS-CoV-2 epidemic in the northwest USA supports these results.Point 4We conclude that occurrence data are a valuable source of information in combination with birth-death models. These data should be used to bolster phylodynamic analyses of infectious diseases and other rapidly spreading species in the future.
Short Neurorobotics Workshop for High School Students Promotes Competence and Confidence in Computational Neuroscience
Authors: Harris Christopher A. , Mircic Stanislav , Reining Zachary , Amorim Marcio , Jović Đorđe , Guerri Lucia , Wallace William , Gage Gregory J. 
Published: April 2019

ABSTRACTUnderstanding the brain is a fascinating challenge, captivating the scientific community and the public alike. The lack of effective treatment for most brain disorders makes the training of the next generation of neuroscientists, engineers and physicians a key concern. Over the past decade there has been a growing effort to introduce neuroscience in primary and secondary schools, however hands-on laboratories have been limited to anatomical or electrophysiological activities. Modern neuroscience research labs are increasingly using computational tools to model circuits of the brain to understand information processing. Here we introduce the use of neurorobots - robots controlled by computer models of biological brains - as an introduction to computational neuroscience in the K-12 classroom. Neurorobotics has enormous potential as an education technology because it combines multiple activities with clear educational benefits including neuroscience, active learning, and robotics. We describe an introductory neurorobot workshop that teaches high school students how to use neurorobots to investigate key concepts in neuroscience, including spiking neural networks, synaptic plasticity, and adaptive action selection. Our do-it-yourself (DIY) neurorobot uses wheels, a camera, a speaker, and a distance sensor to interact with its environment, and can be built from generic parts costing about $150 in under 4 hrs. Our Neurorobot App visualizes the neurorobot's visual input and brain activity in real-time, and enables students to design new brains and deliver dopamine-like reward signals to reinforce chosen behaviors. We have tested the Neurorobot Workshop with high school students (n = 3 workshops, 9 students total) and have found that students were able to complete all exercises in under 3 hrs. In a post-workshop survey, students reported having gained the ability to develop neural networks that perform specific functions, including goal-directed behavior and memory. Here we provide DIY hardware assembly instructions, discuss our open-source Neurorobot App and demonstrate how to teach the Neurorobot Workshop. By doing this we hope to accelerate research in educational neurorobotics and promote the use of neurorobots to teach computational neuroscience in high school.
Cholesterol binding to the transmembrane region of a group 2 HA of Influenza virus is essential for virus replication affecting both virus assembly and HA’s fusion activity
Authors: Hu Bodan , Höfer Chris Tina , Thiele Christoph , Veit Michael 
Published: April 2019

ABSTRACTHemagglutinin (HA) of Influenza virus is incorporated into cholesterol enriched, nanodomains of the plasma membrane. Phylogenetic group 2 HAs contain the conserved cholesterol consensus motif (CCM) YKLW in the transmembrane region. We previously reported that mutations in the CCM retarded intracellular transport of HA and decreased its nanodomain association. Here we analyzed whether cholesterol interacts with the CCM. Incorporation of photocholesterol into HA was significantly reduced if the whole CCM is replaced by alanine, both using immunoprecipitated HA and when HA is embedded in the membrane. Next, we used reverse genetics to investigate the significance of the CCM for virus replication. No virus was rescued if the whole motif is exchanged (YKLW4A); single (LA) or double (YK2A and LW2A) mutated virus showed decreased titers and a comparative fitness disadvantage. In polarized cells transport of HA mutants to the apical membrane was not disturbed. Reduced amounts of HA and cholesterol were incorporated into the viral membrane. Mutant viruses exhibit a decrease in hemolysis, which is only partially corrected if the membrane is replenished with cholesterol. More specifically, viruses have a defect in hemifusion as demonstrated by fluorescence dequenching. Cells expressing HA-YKLW4A fuse with erythrocytes, but the number of events are reduced. Even after acidification unfused erythrocytes remain cell-bound, a phenomenon not observed with wildtype HA. We conclude that cholesterol-binding to a group 2 HA is essential for virus replication. It has pleiotropic effects on virus assembly and membrane fusion, mainly on lipid mixing and possibly a preceding step.IMPORTANCEThe glycoprotein hemagglutinin (HA) is a major pathogenicity factor of Influenza viruses. Whereas the structure and function of HA’s ectodomain is known in great detail, similar data for the membrane-anchoring part of the protein are missing. Here we demonstrate that the transmembrane region of a group 2 HA interacts with cholesterol, the major lipid of the plasma membrane and the defining element of the viral budding site nanodomains of the plama membrane. The cholesterol binding motif is essential for virus replication. Its partial removal affects various steps of the viral life cycle, such as assembly of new virus particles and their subsequent cell entry via membrane fusion. A cholesterol-binding pocket in group 2 HAs might be a promising target for a small lipophilic drug that inactivates the virus.
Implications of data-driven analyses for personalized therapy in psychosis: a systematic review of cluster- and trajectory-based modelling studies
Authors: Habtewold Tesfa Dejenie , Rodijk Lyan H. , Liemburg Edith J. , Sidorenkov Grigory , Boezen H. Marike , Bruggeman Richard , Alizadeh Behrooz Z. 
Published: April 2019

AbstractIntroductionTo tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its (sub)clinical symptoms though there is no systematic review.AimsTo summarize the evidence from cluster- and trajectory-based studies of positive, negative and cognitive symptoms in patients with schizophrenia spectrum disorders, their siblings and healthy people. Additionally, we aimed to highlight knowledge gaps and point out future directions to optimize the translatability of cluster- and trajectory-based studies.MethodsA systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE, and Web of Science electronic databases. Both cross-sectional and longitudinal studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data.ResultsOf 2,285 studies retrieved, 50 studies (17 longitudinal and 33 cross-sectional) conducted in 30 countries were selected for review. Longitudinal studies discovered two to five trajectories of positive and negative symptoms in patient, and four to five trajectories of cognitive deficits in patient and sibling. In cross-sectional studies, three clusters of positive and negative symptoms in patient, four clusters of positive and negative schizotypy in sibling, and three to five clusters of cognitive deficits in patient and sibling were identified. These studies also reported multidimensional predictors of clusters and trajectories.ConclusionsOur findings indicate that (sub)clinical symptoms of schizophrenia are more heterogeneous than currently recognized. Identified clusters and trajectories can be used as a basis for personalized psychiatry.
Peptidoglycan layer and disruption processes inBacillus subtiliscells visualized using quick-freeze, deep-etch electron microscopy
Authors: Tulum Isil , Tahara Yuhei O , Miyata Makoto 
Published: April 2019

ABSTRACTPeptidoglycan, which is the main component of the bacterial cell wall, is a heterogeneous polymer of glycan strands crosslinked with short peptides and is synthesized in cooperation with the cell division cycle. Although it plays a critical role in bacterial survival, its architecture is not well understood. Herein, we visualized the architecture of the peptidoglycan surface inBacillus subtilisat the nanometer resolution, using quick-freeze, deep-etch electron microscopy. Filamentous structures were observed on the entire surface of the cell, where filaments about 11-nm wide formed concentric circles on cell poles, filaments about 13-nm wide formed a circumferential mesh-like structure on the cylindrical part, and a “piecrust” structure was observed at the boundary. When growing cells were treated with lysozyme, the entire cell mass migrated to one side and came out from the cell envelope. Fluorescence labeling showed that lysozyme preferentially bound to a cell pole and cell division site, where the peptidoglycan synthesis was not complete. Ruffling of surface structures was observed during electron microscopy. When cells were treated with penicillin, the cell mass came out from a cleft around the cell division site. Outward curvature of the protoplast at the cleft seen using electron microscopy suggested that turgor pressure was applied as the peptidoglycan was not damaged at other positions. When muropeptides were depleted, surface filaments were lost while the rod shape of the cell was maintained. These changes can be explained on the basis of the working points of the chemical structure of peptidoglycan.