bluuebunny/crossref_metadata_2025_split huggingface dataset:
COMplex mental health PAThways (COMPAT) Study: a mixed methods study to inform an evidence-based service delivery model for people with complex needs: Study protocol
Authors: Saini Pooja , Martin Antony , McIntyre Jason , Balmer Anna , Burton Sam , Roks Hana , Sambrook Laura , Shetty Amrith , Nathan Rajan 
Published: April 2021

AbstractBackgroundMental health services for adults, as they are currently configured, have been designed to provide predominantly community-based interventions. It has long been recognised that some patients have such significant clinical and/or risk needs that those needs cannot be adequately met within standard service delivery models, resulting in a pressing need to consider the best models for this group of people. This paper shares a protocol for a mixed methods study that aims to understand: the profile and history of service users described as having complex needs; the decision-making processes by clinicians that lead to complex needs categorisation; service users and carers experience of service use; and, associated economic impact. This protocol describes a comprehensive evaluation that aims to inform an evidence-based service delivery model for people with complex needs.MethodsWe will use a mixed methods design, combining quantitative and qualitative methods using in-depth descriptive and inferential analysis of patient records, written medical notes and in-depth interviews with service users, carers, and clinicians. The study will include five components: (1) a quantitative description and analysis of the demographic clinical characteristics of the patient group; (2) an economic evaluation of alternative patient pathways; (3) semi-structured interviews about service user and carer experiences; (4) using data from components 1-3 to co-produce vignettes jointly with relevant stakeholders involved in the care of service users with complex mental health needs; and, (5) semi-structured interviews about clinical decision-making by clinicians in relation to this patient group, using the vignettes as example case studies.DiscussionThe study’s key outcomes will be to: examine the resource use and cost-impact associated with alternative care pathways to the NHS and other sectors of the economy (including social care); explore patient health and non-health outcomes associated with alternative care pathways; and, gain an understanding of a complex service user group and how treatment decisions are made to inform consistent and person-centred future service delivery.
Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
Authors: Pagadala Meghana , Wu Victoria H. , Pérez-Guijarro Eva , Kim Hyo , Castro Andrea , Talwar James , Sears Timothy , Gonzalez-Colin Cristian , Cao Steven , Schmiedel Benjamin J. , Goudarzi Shervin , Kirani Divya , Salem Rany M. , Morris Gerald P. , Harismendy Olivier , Patel Sandip Pravin , Mesirov Jill P. , Zanetti Maurizio , Day Chi-Ping , Fan Chun Chieh , Thompson Wesley K. , Merlino Glenn , Gutkind J. Silvio , Vijayanand Pandurangan , Carter Hannah 
Published: April 2021

AbstractWith the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were withPD-L1andCTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibitedCTSS,a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survivalin vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics.SignificanceA systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.
Dietary, Cultural and Pathogens-related Selective Pressures Shaped Differential Adaptive Evolution Among Native Mexican Populations
Authors: Ojeda-Granados Claudia , Abondio Paolo , Setti Alice , Sarno Stefania , Gnecchi-Ruscone Guido Alberto , González-Orozco Eduardo , De Fanti Sara , Jiménez-Kaufmann Andres , Rangel-Villalobos Héctor , Moreno-Estrada Andrés , Sazzini Marco 
Published: April 2021

AbstractNative American genetic ancestry has been remarkably implicated with increased risk of diverse health issues in several Mexican populations, especially in relation to the dramatic changes in environmental, dietary and cultural settings they have recently undergone. In particular, the effects of these ecological transitions and Westernization of lifestyles have been investigated so far predominantly on Admixed individuals. Nevertheless, indigenous groups, rather than admixed Mexicans, have plausibly retained the highest proportions of genetic components shaped by natural selection in response to the ancient milieu experienced by Mexican ancestors during their pre-Columbian evolutionary history. These formerly adaptive alleles/haplotypes have the potential to represent the genetic determinants of some biological traits peculiar to the Mexican people and a reservoir of loci with potential biomedical relevance. To test such a hypothesis, we used high-resolution genomic data to infer the unique adaptive evolution of 15 Native Mexican groups selected as reasonable descendants of the main pre-Columbian Mexican civilizations. A combination of haplotype-based and gene-network analyses enabled us to detect genomic signatures ascribable to polygenic adaptive traits evolved by the main genetic clusters of indigenous Mexican populations to cope with local environmental and/or cultural conditions. Some of them were also found to play a role in modulating the susceptibility/resistance of these groups to certain pathological conditions, thus providing new evidence for diverse selective pressures having contributed to shape current biological and disease-risk patterns in present-day Native and Mestizo Mexican populations.
The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells
Authors: Mann-Nüttel Ritu , Ali Shafaqat , Petzsch Patrick , Köhrer Karl , Alferink Judith , Scheu Stefanie 
Published: April 2021

AbstractTranscription factors (TFs) control gene expression by direct binding to regulatory regions of target genes but also by impacting chromatin landscapes and thereby modulating DNA accessibility for other TFs. To date, the global TF reservoir in plasmacytoid dendritic cells (pDCs), a cell type with the unique capacity to produce unmatched amounts of type I interferons, has not been fully characterized. To fill this gap, we have performed a comprehensive analysis in naïve and TLR9-activated pDCs in a time course study covering early timepoints after stimulation (2h, 6h, 12h) integrating gene expression (RNA-Seq), chromatin landscape (ATAC-Seq) and Gene Ontology studies. We found that 70% of all described TFs are expressed in pDCs for at least one stimulation time point and that activation predominantly “turned on” the chromatin regions associated with TF genes. We hereby define the complete set of TLR9-regulated TFs in pDCs. Further, this study identifies the AP-1 family of TFs as potentially important but so far less well characterized regulators of pDC function.
BioNetComp: a Python package for biological network development and comparison
Authors: Carvalho Lucas M. 
Published: April 2021

AbstractDue to the large generation of omics data on a large scale in the last few years, the extraction of information from biological data has become more complex and its integration or comparison as well. One of the ways to represent interactions of biological data is through networks, which summarize information on interactions between their nodes through edges. The comparison of two biological networks using network metrics, biological enrichment, and visualization consists of data that allows us to understand differences in the interactomes of contrasting conditions. We describe BioNetComp, a python package to compare two different interactomes through different metrics and data visualization without the need for a web platform or software, just by command-line. As a result, we present a comparison made between the interactomes generated from the differentially expressed genes at two different points during a typical bioethanol fermentation. BioNetComp is available at github.com/lmigueel/BioNetComp.
Profiling the Human Phosphoproteome to Estimate the True Extent of Protein Phosphorylation
Authors: Kalyuzhnyy Anton , Eyers Patrick A. , Eyers Claire E. , Sun Zhi , Deutsch Eric W. , Jones Andrew R. 
Published: April 2021

AbstractMass spectrometry-based phosphoproteomics allows large-scale generation of phosphorylation site data. However, analytical pipelines need to be carefully designed and optimised to minimise incorrect identification of phosphopeptide sequences or wrong localisation of phosphorylation sites within those peptides. Public databases such as PhosphoSitePlus (PSP) and PeptideAtlas (PA) compile results from published papers or openly available MS data, but to our knowledge, there is no database-level control for false discovery of sites, subsequently leading to the likely overestimation of true phosphosites. It is therefore difficult for researchers to assess which phosphosites are “real” and which are likely to be artefacts of data processing. By profiling the human phosphoproteome, we aimed to estimate the false discovery rate (FDR) of phosphosites based on available evidence in PSP and/or PA and predict a more realistic count of true phosphosites. We ranked sites into phosphorylation likelihood sets based on layers of accumulated evidence and then analysed them in terms of amino acid conservation across 100 species, sequence properties and functional annotations of associated proteins. We demonstrated significant differences between the sets and developed a method for independent phosphosite FDR estimation. Remarkably, we estimated a false discovery rate of 86.1%, 95.4% and 82.2% within sets of described phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr) sites respectively for which only a single piece of identification evidence is available (the vast majority of sites in PSP). Overall, we estimate that ∼56,000 Ser, 10,000 Thr and 12,000 Tyr phosphosites in the human proteome have truly been identified to date, based on evidence in PSP and/or PA, which is lower than most published estimates. Furthermore, our analysis estimated ∼91,000 Ser, 49,000 Thr and 26,000 Tyr sites that are likely to represent false-positive phosphosite identifications. We conclude that researchers should be aware of the significant potential for false positive sites to be present in public databases and should evaluate the evidence behind the phosphosites used in their research.
Development of a rapid LC-MS/MS method for the simultaneous quantification of various flavonoids and phytohormones extracted fromMedicago Truncatulaleaves
Authors: Bisht Neema , Gupta Arunima , Awasthi Pallavi , Goel Atul , Chandran Divya , Sharma Neha , Singh Nirpendra 
Published: April 2021

ABSTRACTFlavonoids are small metabolites of plants, which are involved in the regulation of plant development as well as defence against pathogens. Quantitation of these flavonoids in plant samples is highly important and essential in the food and herbal industry. Hence, robust, reliable and sensitive methods are required for the analysis of these compounds in plant samples. In the present study, a high performance liquid chromatographic-tandem mass spectrometric (HPLC– ESI-MS/MS) method was developed and validated for the determination of nine flavonoids, including Liquiritigenin, Naringenin, Genistein, Daidzein, Formononetin, Biochanin A, 2’-hydroxy formononetin, 2’-methoxyformononetin, Medicarpin, and two phytohormones, Salicylic acid and Jasmonic acid, inMedicago truncatula. The analytes were separated by means of C-18, reversed-phase chromatography and detected using QTRAP mass spectrometer. Molecules were quantified using different transitions in positive and negative ion modes simultaneously in 12 minutes. The on-column limit of detection of all the analytes was as low as 0.03 pg, whereas the limit of quantification of all the compounds was observed upto 0.1 pg levels. Further the method was also validated in terms of specificity, linearity (r2> 0.99), average recovery (90.6 – 110.3%), accuracy (RE% ≤ 3%) and precision (RSD% ≤ 3%). As a proof of concept, the developed method was successfully used for the quantitation of these flavonoids and phytohormones from leaf extract ofMedicago truncatula.
Angiopoietin 1 and integrin beta 1b are vital for zebrafish brain development
Authors: Chen Yu-Chia , Martins Tomás A. , Marchica Valentina , Panula Pertti 
Published: April 2021

AbstractThis study aimed at identifying the role of angiopoietin 1 (angpt1) in brain development, the mode of action of angpt1, and the main targets in the zebrafish brain. We investigated embryonic brain angiogenesis and neural development in theangpt1sa14264,itgb1bmi371,tekhu1667mutant fish, and the effects of transgenic overexpression ofangpt1in the larval brain. Lack ofangpt1was associated with downregulation oftekand upregulation ofitgb1b. We found deficiencies in the patterning of proliferation, the vascular network and reticulospinal neurons in the hindbrain, and selective deficiencies in specific neurotransmitter systems. In theangpt1sa14264anditgb1bmi371larval brains, using microangiography, retrograde labeling, and immunostaining, we demonstrated that the targeted destruction ofangpt1sa14264anditgb1bmi371mutant fish caused severe irregular cerebrovascular development, aberrant hindbrain patterning, downregulation of neural proliferation, expansion of the radial glial progenitors, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the larval brain. In contrast, thetekhu1667mutants regularly grew with no such apparent phenotypes. Neurally overexpressedangpt1promoted opposite effects by increasing the vascular branching, increasing cell proliferation, and neuronal progenitors. Notably, zebrafishangpt1showed neurogenic activity independent of its typical receptortek, indicating the novel role of a dual regulation byangpt1in embryonic neurogenesis and angiogenesis in zebrafish. The results show that angpt1 and its interaction with itgb1b are crucial in zebrafish brain neuronal and vascular development and suggest that angpt1 through itgb1b can act as a neurogenic factor in the neural proliferation fate in the developing brain.
Phylogeny Reveals Novel HipA-Homologous Kinase Families and Toxin – Antitoxin Gene Organizations
Authors: Gerdes Kenn , Bærentsen Rene , Brodersen Ditlev E. 
Published: April 2021

AbstractToxin – Antitoxin modules function in the genetic stability of mobile genetic elements, bacteriophage defense, and antibiotic tolerance. A gain-of-function mutation of the Escherichia coli K-12 hipBA module can induce antibiotic tolerance in a subpopulation of bacterial cells, a phenomenon known as persistence. HipA is a Ser/Thr kinase that phosphorylates and inactivates glutamyl tRNA synthetase, inhibiting cellular translation and inducing the stringent response. Additional characterized HipA homologues include HipT from pathogenic E. coli O127 and YjjJ of E. coli K-12, which are encoded by tri-cistronic hipBST and monocistronic operons, respectively. The apparent diversity of HipA homologues in bacterial genomes inspired us to investigate overall phylogeny. Here we present a comprehensive phylogenetic analysis of the Hip kinases in bacteria and archaea that expands on this diversity by revealing seven novel kinase families. Kinases of one family, encoded by monocistronic operons, consist of an N-terminal core kinase domain, a HipS-like domain and a HIRAN (HIP116 Rad5p N-terminal) domain. HIRAN domains bind single or double-stranded DNA ends. Moreover, five types of bicistronic kinase operons encode putative antitoxins with HipS-HIRAN, HipS, γδ-resolvase or Stl repressor-like domains. Finally, our analysis indicates that reversion of hipBA gene-order happened independently several times during evolution.ImportanceBacterial multidrug tolerance and persistence are problems of increasing scientific and medical significance. The first gene discovered to confer persistence was hipA, encoding the kinase toxin of the hipBA toxin-antitoxin (TA) module of E. coli. HipA-homologous kinases phosphorylate and thereby inactivate specific tRNA synthetases, thus inhibiting protein translation and cell proliferation. Here, we present a comprehensive phylogenetic analysis of bacterial Hip kinases and discover seven new families with novel operon structures and domains. Overall, Hip kinases are encoded by TA modules with at least 10 different genetic organizations, seven of which have not been described before. These results open up exciting avenues for the experimental analysis of the superfamily of Hip kinases.
Multiplex Fragment Analysis Identifies SARS-CoV-2 Variants
Authors: Clark A.E. , Wang Z. , Cantarel B. , Kanchwala M. , Xing C. , Chen L. , Irwin P. , Xu Y. , Oliver D. , Lee F. , Gagan J.R. , Filkins L. , Muthukumar A. , Park J.Y. , Sarode R. , SoRelle J.A. 
Published: April 2021

AbstractThe rapid spread of SARS-CoV-2 Variants of Concern (VOC) necessitates systematic efforts for epidemiological surveillance. The current method for identifying variants is viral whole genome sequencing (WGS). Broad clinical adoption of sequencing is limited by costly equipment, bioinformatics support, technical expertise, and time for implementation. Here we describe a scalable, multiplex, non-sequencing-based capillary electrophoresis assay to affordably screen for SARS-CoV-2 VOC.
Patterns and Changes in Expectation of Life at Birth in India: 1998-2017
Authors: Chaurasia Aalok Ranjan 
Published: April 2021

AbstractThis paper analyses patterns and changes in the expectation of life at birth in India and decomposes the increase in the expectation of life at birth between 1998-2002 and 2013-2017. The analysis reveals considerable volatility in the increase in the expectation of life at birth in the country and in its different population groups and states. In recent years, there is considerable deceleration in the increase in the expectation of life at birth in the country because of the deceleration in the increase in female expectation of life at birth. The decomposition exercise reveals that most of the increase in the expectation of life at birth is attributed to the improvement in the survival probability in the first five years of life. The analysis also suggests that the recent deceleration in the increase in female expectation of life at birth may be attributed to the decrease in the person-years lived in the age group 40-65 years.
SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8
Authors: Salvi Valentina , Nguyen Hoang Oanh , Sozio Francesca , Schioppa Tiziana , Laffranchi Mattia , Scapini Patrizia , Passari Mauro , Barbazza Ilaria , Tiberio Laura , Tamassia Nicola , Garlanda Cecilia , Del Prete Annalisa , Cassatella Marco A. , Mantovani Alberto , Sozzani Silvano , Bosisio Daniela 
Published: April 2021

AbstractThe inflammatory and IFN pathways of innate immunity play a key role in both resistance and pathogenesis of Coronavirus Disease 2019 (COVID-19). Innate sensors and SARS-CoV-2-Associated Molecular Patterns (SAMPs) remain to be completely defined. Here we identify single-stranded RNA (ssRNA) fragments from SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and functions, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identify TLR7/8 as crucial cellular sensors of ssRNAs encoded by SARS-CoV-2 involved in host resistance and disease pathogenesis of COVID-19.
A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer
Authors: Lovell Scott , Zhang Leran , Kryza Thomas , Neodo Anna , Bock Nathalie , Williams Elizabeth D. , Engelsberger Elisabeth , Xu Congyi , Bakker Alexander T. , De Vita Elena , Maneiro Maria , Tanaka Reiko J. , Bevan Charlotte L. , Clements Judith A. , Tate Edward W. 
Published: April 2021

AbstractKallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network – the KLK activome – with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.