bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global Warming and Neurological Practice: Systematic Review
Authors: Peinkhofer C , Amiri M , Othman MH , De Vecchi T , Nersesjan V , Kondziella D 
Published: December 2020

ABSTRACTBackgroundClimate change, including global warming, is expected to cause poorer global health and a rise in the number of environmental refugees. As neurological disorders account for a major share of worldwide morbidity and mortality, climate change and global warming are also destined to alter neurological practice; however, to what extent and by which mechanisms is unknown. We aimed to collect the available information on the effects of ambient temperatures and human migration on the epidemiological and clinical manifestations of major neurological disorders.MethodsWe searched PubMed and Scopus from January 1, 2000 to November 30, 2020 for human studies published in English addressing the influence of ambient temperatures and human migration on Alzheimer’s and non-Alzheimer’s dementia, epilepsy, headache and migraine, multiple sclerosis, Parkinson’s disease, stroke, and tick-borne encephalitis (as a model disease for neuroinfections). The protocol was pre-registered at PROSPERO (2020 CRD42020147543).Results101 studies met inclusion criteria, but we were unable to identify a single study addressing how global warming and human migration will change neurological practice. Still, extracted data suggested multiple ways by which these aspects might alter neurological morbidity and mortality in the future.ConclusionSignificant heterogeneity exists across studies with respect to methodology, outcome measures, control of confounders and study design, but there is enough evidence to suggest climate change will affect the neurological practice of all major neurological disorders. Adequately designed studies to address this issue are urgently needed, which will require concerted efforts from the neurological community.
Tau-first subtype of Alzheimer’s disease consistently identified across in vivo and post mortem studies
Authors: Aksman Leon M. , Oxtoby Neil P. , Scelsi Marzia A. , Wijeratne Peter A. , Young Alexandra L. , Alves Isadora Lopes , Barkhof Frederik , Alexander Daniel C. , Altmann Andre ,   the ADNI
Published: December 2020

AbstractAlzheimer’s disease (AD) is marked by the spread of misfolded amyloid-β and tau proteins throughout the brain. While it is commonly believed that amyloid-β abnormality drives the cascade of AD pathogenesis, several in vivo and post mortem studies indicate that in some subjects localized tau-based neurofibrillary tangles precede amyloid-β pathology. This suggests that there may be multiple distinct subtypes of protein aggregation pathways within AD, with potentially different demographic, cognitive and comorbidity profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post mortem immunohistochemistry and in vivo positron emission tomography (PET) and cerebrospinal fluid (CSF) based measures of protein pathologies in two large observational cohorts. We consistently identified both amyloid-first and tau-first AD subtypes, where tau-first subjects had higher levels of soluble TREM2 compared to amyloid-first subjects. Our work provides insight into AD progression that may be valuable for interventional trials targeting amyloid-β and tau.
A systems biology analysis of lipolysis and fatty acid release from adipocytesin vitroand from adipose tissuein vivo
Authors: Lövfors William , Ekström Jona , Jönsson Cecilia , Strålfors Peter , Cedersund Gunnar , Nyman Elin 
Published: December 2020

AbstractLipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge fromin vitrosystems have not been linked to correspondingin vivodata and knowledgein vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combiningin vivoandin vitrodata into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setupsin silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.
Water stress and nitrogen supply affect floral traits and pollination in the white mustard,Sinapis alba(Brassicaceae)
Authors: Akter Asma , Klečka Jan 
Published: December 2020

AbstractChanges in environmental conditions are likely to have a complex effect on the growth of plants, their phenology, plant-pollinator interactions, and reproductive success. The current world is facing an ongoing climate change along with other human-induced environmental changes. Most research has focused on the impact of increasing temperature as a major driving force for climate change, but other factors may have important impacts on plant traits and pollination too and these effects may vary between different seasons. In addition, it is likely that the effects of multiple environmental factors, such as increasing temperature, water stress, and nitrogen enrichment are not independent. Therefore, we tested the impact of three key factors – season, water, and nitrogen supply – on plant traits, pollination, and seed production inSinapis alba(Brassicaceae). Plants were grown in three seasons with two levels of water and nitrogen supply in a factorial design. We collected data on multiple vegetative and floral traits and assessed the response of pollinators in the field. Additionally, we evaluated the effect of growing conditions on seed set in plants exposed to pollinators and in hand-pollinated plants. Our results show that water stress impaired vegetative growth, decreased flower production, reduced visitation by pollinators and seed set, while nitrogen availability played an important role in nectar production. Seasonality modulated the effect of water and nitrogen availability on vegetative and floral traits and strongly affected flowering phenology and flower production. We demonstrated that changes in water and nitrogen availability alter plant vegetative and floral traits, which impacts flower visitation and consequently plant reproduction. We conclude that ongoing environmental changes such as altered precipitation regimes and nitrogen enrichment may thus affect plant-pollinator interactions with negative consequences for the reproduction of wild plants and insect-pollinated crops.
Optimized guide RNA selection recommendations for usingspCas9 gene editing in human hematopoietic stem and progenitor cells
Authors: Verhagen Han J.M.P. , Kuijk Carlijn , Kokke Anne M. , Rutgers Laurens , van der Meulen Santhe A. , van Mierlo Gerard , Voermans Carlijn , van den Akker Emile 
Published: December 2020

AbstractRibonucleoproteins (RNPs) are frequently applied for therapeutic gene editing as well as fundamental research, because the method is fast, viral free, and does not rely on clonal selection.We evaluated various parameters to genetically engineer human hematopoietic stem progenitor cells (HSPCs) usingspCas9-RNPs and achieve gene editing efficiencies up to 80%. We find that single guide RNA (sgRNA) design is critical to achieve high gene editing efficiencies. However, finding effective sgRNAs for HSPCs can be challenging, while the contribution of numerousin silicomodels is unclear.Here we established a time- and cost-efficientin vitrotranscribed sgRNA screening model in K562 cells to identify sgRNAs that are effective in HSPCs using RNP delivery. We show that this simple screening method outperforms allin silicoprediction models. Our data demonstrates that mostin silicosgRNA prediction models are ineffective and we make recommendations to potentially improve their accuracy.We report that gene editing is equally efficient in distinct CD34+HSPC subpopulations. Furthermore, no effects on cell proliferation, differentiation orin vitrohematopoietic lineage commitment were observed. Finally, no upregulation of p21 expression was found, suggesting unperturbed HSPC homeostasis.Key pointsIn vitro transcribedsingle sgRNAs (IVTsgRNA) screening in K562 outperformsin silicomodelingHematopoietic stem and progenitor cells are equally targeted by Ribonucleoproteins (RNPs)Hematopoietic stem and progenitor cells show no induction of p21 expression or effects on differentiation, proliferation and lineage commitmentGraphical abstract
An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies
Authors: Liu Yafei , Soh Wai Tuck , Tada Asa , Arakawa Akemi , Matsuoka Sumiko , Nakayama Emi E. , Li Songling , Ono Chikako , Torii Shiho , Kishida Kazuki , Jin Hui , Nakai Wataru , Arase Noriko , Nakagawa Atsushi , Shindo Yasuhiro , Kohyama Masako , Nakagami Hironori , Tomii Keisuke , Ohmura Koichiro , Ohshima Shiro , Okada Masato , Matsuura Yoshiharu , Standley Daron M. , Shioda Tatsuo , Arase Hisashi 
Published: December 2020

AbstractSARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.
Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19
Authors: Wilk Aaron J. , Lee Madeline J. , Wei Bei , Parks Benjamin , Pi Ruoxi , Martínez-Colón Giovanny J. , Ranganath Thanmayi , Zhao Nancy Q. , Taylor Shalina , Becker Winston ,   Stanford COVID-19 Biobank, Jimenez-Morales David , Blomkalns Andra L. , O’Hara Ruth , Ashley Euan A. , Nadeau Kari C. , Yang Samuel , Holmes Susan , Rabinovitch Marlene , Rogers Angela J. , Greenleaf William J. , Blish Catherine A. 
Published: December 2020

ABSTRACTOur understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.One Sentence SummarySingle-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity.
Dominant Remodeling of Cattle Rumen Microbiome bySchedonorus arundinaceus(Tall Fescue) KY-31 Carrying a Fungal Endophyte
Authors: Khairunisa Bela Haifa , Susanti Dwi , Loganathan Usha , Teutsch Christopher D. , Campbell Brian T. , Fiske David , Wilkinson Carol A. , Aylward Frank O. , Mukhopadhyay Biswarup 
Published: December 2020

AbstractTall fescue KY-31 feeds ~20% of the beef cattle in the United States. It carries a fungal endophyte that produces ergovaline, which causes toxicosis in cattle, leading to $2 billion revenue loss annually. The MaxQ cultivar of the grass is non-toxic, but less attractive economically. To develop ways of mitigating the toxicity, the rumen microbiome of cattle consuming KY-31 and MaxQ have been analyzed, principally for identifying ergovaline transforming microorganisms and often using fecal microbiome as a surrogate. We have hypothesized that KY-31 not only causes toxicosis, but also impacts rumen metabolism broadly, and tested the hypothesis by analyzing rumen microbiome compositions of cattle that grazed MaxQ with an intervening KY-31 grazing period with 16S rRNA-V4 element as identifier. We found that KY-31 remodeled the cellulolytic and saccharolytic communities substantially. This effect was not evident at whole microbiome levels but in the compositions of sessile and planktonic fractions. A move from MaxQ to KY-31 lowered the Firmicutes abundance in the sessile fraction and increased it in planktonic part and caused an opposite effect for Bacteroidetes, although the total abundances of these dominant rumen organisms remained unchanged. In the sessile fraction, the abundances ofFibrobacter, which degrades less degradable fibers, and certain cellulolytic Firmicutes such asPseudobutyrivibrioandButyrivibrio2, dropped, and these losses were apparently compensated by increased occurrences ofEubacteriumand specificRuminococcaceaeandLachnospiraceae. In planktonic fraction the Tenericutes’ abundance increased as saccharolytic Bacteroidetes’ level dropped. Several potential ergovaline degraders were enriched. A return to MaxQ restored the original Firmicutes and Bacteroidetes distributions. However, theFibrobacterandButyrivibrio2 abundances remained low and their substitutes maintained significant presence. The rumen microbiome was influenced minimally by animals’ fescue toxicosis and was distinct from previously reported fecal microbiomes in composition. In summary, KY-31 and MaxQ cultivars of tall fescue were digested in the cattle rumen with distinct consortia and the KY-31-specific features were dominant. The study highlighted the importance of analyzing sessile and planktonic fractions separately.
Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits
Authors: Whyte Carly E. , Singh Kailash , Burton Oliver T. , Aloulou Meryem , Moudra Alena , Roca Carlos P. , Naranjo Francisco J. , Lombard-Vadnais Félix , Kouser Lubna , Hochepied Tino , Halim Timotheus Y. F. , Schlenner Susan , Lesage Sylvie , Dooley James , Liston Adrian 
Published: December 2020

AbstractInterleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.Graphical abstract
VCFShark: how to squeeze a VCF file
Authors: Deorowicz Sebastian , Danek Agnieszka 
Published: December 2020

AbstractSummaryThe VCF files with results of sequencing projects take a lot of space. We propose VCFShark squeezing them up to an order of magnitude better than the de facto standards (gzipped VCF and BCF).Availability and Implementationhttps://github.com/refresh-bio/vcfsharkContactsebastian.deorowicz@polsl.plSupplementary informationSupplementary data are available at publisher’s Web site.
Apoptosis-resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides
Authors: Deryabin Pavel I. , Shatrova Alla N. , Marakhova Irina I. , Nikolsky Nikolay N. , Borodkina Aleksandra V. 
Published: December 2020

ABSTRACTTargeted elimination of senescent cells – senolysis – is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in ‘cardiac glycosides–sensitive’ A549 and ‘–insensitive’ hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis-resistance in senescent hMSCs. We revealed that apoptosis-resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant compared to their proliferating counterparts.
Glycosylation Limits Forward Trafficking of the Tetraspan Membrane Protein PMP22
Authors: Marinko Justin T. , Wright Madison T. , Heintzman Darren R. , Plate Lars , Sanders Charles R. 
Published: December 2020

AbstractPeripheral myelin protein 22 (PMP22) folds and traffics inefficiently, a phenomenon closely related to the mechanisms by which this tetraspan membrane protein causes Charcot-Marie-Tooth disease (CMTD). We report that elimination of N-glycosylation results in a 3-fold increase in the cell surface trafficking of wild type (WT) PMP22 and a 10-fold increase in trafficking of the unstable L16P disease mutant form. Studies of the interactions of PMP22 with oligosaccharyltransferases A and B as well as quantitative proteomic experiments established that critical endoplasmic reticulum (ER) quality control decisions occur earlier in the biogenesis to cell surface trafficking pathway for the L16P mutant than for WT. CRISPR knock-out cell lines for ER proteins calnexin, RER1, and UGGT1 illuminated the role of each protein in glycosylation dependent and independent surface trafficking of WT PMP22, as well as for a series of disease mutants of varying folding stabilities.One Sentence SummaryN-linked glycosylation was seen to dramatically limit the cell surface trafficking of PMP22, with some key quality control factors in PMP22 biogenesis being identified.
EloR interacts with the lytic transglycosylase MltG at midcell inStreptococcus pneumoniaeR6
Authors: Winther Anja Ruud , Kjos Morten , Herigstad Marie Leangen , Håvarstein Leiv Sigve , Straume Daniel 
Published: December 2020

AbstractThe ellipsoid shape ofStreptococcus pneumoniaeis determined by the synchronized actions of the elongasome and the divisome, which have the task of creating a protective layer of peptidoglycan (PG) enveloping the cell membrane. The elongasome is necessary for expanding PG in the longitudinal direction whereas the divisome synthesizes the PG that divides one cell into two. Although there is still little knowledge about how these two modes of PG synthesis are coordinated, it was recently discovered that two RNA-binding proteins called EloR and KhpA are part of a novel regulatory pathway controlling elongation inS. pneumoniae. EloR and KhpA form a complex that work closely with the Ser/Thr kinase StkP to regulate cell elongation. Here, we have further explored how this regulation occur. EloR/KhpA is found at midcell, a localization fully dependent on EloR. Using a bacterial two-hybrid assay we probed EloR against several elongasome proteins and found an interaction with the lytic transglycosylase homolog MltG. By using EloR as bait in immunoprecipitation assays, MltG was pulled down confirming that they are part of the same protein complex. Fluorescent microscopy demonstrated that the Jag domain of EloR is essential for EloR’s midcell localization and its interaction with MltG. Since MltG is found at midcell independent of EloR, our results suggest that MltG is responsible for recruitment of the EloR/KhpA complex to the division zone to regulate cell elongation.ImportanceBacterial cell division has been a successful target for antimicrobial agents for decades. How different pathogens regulate cell division is, however, poorly understood. To fully exploit the potential for future antibiotics targeting cell division, we need to understand the details of how the bacteria regulate and construct cell wall during this process. Here we have revealed that the newly identified EloR/KhpA complex, regulating cell elongation inS. pneumoniae, forms a complex with the essential peptidoglycan transglycosylase MltG at midcell. EloR, KhpA and MltG are conserved among many bacterial species and the EloR/KhpA/MltG regulatory pathway is most likely a common mechanism employed by many Gram-positive bacteria to coordinate cell elongation and septation.