bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning
Authors: Mušo Milan , Bentley Liz , Vizor Lucie , Yon Marianne , Burling Keith , Barker Peter , Zolkiewski Louisa A K , Cox Roger D , Dumbell Rebecca 
Published: May 2022

1.AbstractBackgroundIncreased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The TBX15-WARS2 locus has consistently been associated with increased WHR. Previous study of the hypomorphic Wars2V117L/V117L mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting Wars2 could be a potential modulator of fat distribution and WAT browning.MethodsTo test for differences in browning induction across different adipose depots of Wars2V117L/V117L mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed Wars2V117L/V117L mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age.ResultsThe chow-fed Wars2V117L/V117L mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the Wars2V117L/V117L mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT : iWAT ratio.ConclusionSevere reduction of Wars2 gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.
Design of Peptide-Based Protein Degraders via Contrastive Deep Learning
Authors: Palepu Kalyan , Ponnapati Manvitha , Bhat Suhaas , Tysinger Emma , Stan Teodora , Brixi Garyk , Koseki Sabrina R.T. , Chatterjee Pranam 
Published: May 2022

AbstractTherapeutic modalities targeting pathogenic proteins are the gold standard of treatment for multiple disease indications. Unfortunately, a significant portion of these proteins are considered “undruggable” by standard small molecule-based approaches, largely due to their disordered nature and instability. Designing functional peptides to undruggable targets, either as standalone binders or fusions to effector domains, thus presents a unique opportunity for therapeutic intervention. In this work, we adapt recent models for contrastive language-image pre-training (CLIP) to devise a unified, sequence-based framework to design target-specific peptides. Furthermore, by leveraging known experimental binding proteins as scaffolds, we create a streamlined inference pipeline, termed Cut&CLIP, that efficiently selects peptides for downstream screening. Finally, we experimentally fuse candidate peptides to E3 ubiquitin ligase domains and demonstrate robust intracellular degradation of pathogenic protein targets in human cells, motivating further development of our technology for future clinical translation.
Divergent evolution of genetic sex determination mechanisms along environmental gradients
Authors: Schenkel Martijn A. , Billeter Jean-Christophe , Beukeboom Leo W. , Pen Ido 
Published: May 2022

AbstractSex determination (SD) is a crucial developmental process, but its molecular underpinnings are very diverse, both between and within species. SD mechanisms have traditionally been categorized as either genetic (GSD) or environmental (ESD), depending on the type of cue that triggers sexual differentiation. However, mixed systems, with both genetic and environmental components, are more prevalent than previously thought. Here, we show theoretically that environmental effects on expression levels of genes within SD regulatory mechanisms can easily trigger within-species evolutionary divergence of SD mechanisms. This may lead to the stable coexistence of multiple SD mechanisms and to spatial variation in the occurrence of different SD mechanisms along environmental gradients. We applied the model to the SD system of the housefly, a global species with world-wide latitudinal clines in the frequencies of different SD systems, and found that it correctly predicted these clines if specific genes in the housefly SD system were assumed to have temperature-dependent expression levels. We conclude that environmental sensitivity of gene regulatory networks may play an important role in diversification of SD mechanisms.
Influence of culturing media components on the growth and microbial induced calcium carbonate precipitation (MICP) activity of Lysinibacillus sphaericus
Authors: Rahmaninezhad Seyed Ali , Farnam Yaghoob A. , Schauer Caroline L. , Raeisi Najafi Ahmad , Sales Christopher M. 
Published: May 2022

AbstractIn order to identify appropriate environmental conditions and media components that are either essential or that enhance its growth and Microbial induced calcium carbonate precipitation (MICP) activity, in this study, a series of experiments were conducted to investigate the effects of media components and oxygen conditions on the growth rate and MICP activity of Lysinibacillus sphaericus strain MB 284. From these experiments, it was observed that aerobic conditions could lead to increased calcium carbonate production and up to three times faster growth rates by strain MB284 when compared to anoxic conditions. It was also determined that considering the measured growth rate, final biomass concentration, ureolysis activity, amount of calcium carbonate precipitation, and cost of media components for designing undefined culture media for industrial applications, yeast extract is the most economically appropriate option. In our attempts to grow strain MB284 in urea, sucrose, and ammonium acetate as its sole carbon source in minimal media, it was observed it is auxotrophic and that casamino acids and casein are essential for its growth. Even though our experiments agree with the literature that the addition of urea enhances the growth and MICP activity of L. sphaericus, it was discovered that when the initial urea concentration was greater than 3 g/l, the growth rate of strain MB284 can be temporarily inhibited until enough cells and urease are produced. These results reveal that the growth and MICP activity of strain MB284 during its application for bio-self healing can be highly dependent on environmental and nutrient conditions.ImportanceAerobic conditions increase calcium carbonate production by strain MB284yeast extract is the most economically appropriate option for industrial applications of MICPLysinibacillus sphaericus strain MB 284 is auxotroph and casamino acids and casein are essential for its growththe growth rate of strain MB284 can be temporarily inhibited with urea
Systematic approach to outcome assessment from coded electronic healthcare records in the DaRe2THINK NHS-embedded randomised trial
Authors: Wang Xiaoxia , Mobley Alastair R , Tica Otilia , Okoth Kelvin , Ghosh Rebecca E , Myles Puja , Williams Tim , Haynes Sandra , Nirantharakumar Krishnarajah , Shukla David , Kotecha Dipak 
Published: May 2022

ABSTRACTBackgroundImproving the efficiency of clinical trials is key to their continued importance in directing evidence-based patient care. Digital innovations, in particular the use of electronic healthcare records (EHR), allow for large-scale screening and follow-up of participants. However, it is critical these developments are accompanied by robust and transparent methods that can support high quality and high clinical value research.MethodsThe DaRe2THINK trial includes a series of novel processes, including nationwide pseudonymised pre-screening of the primary care EHR across England, digital enrolment, remote e-consent, and ‘no-visit’ follow-up by linking all primary and secondary care health data with patient-reported outcomes.FindingsDaRe2THINK is a pragmatic, healthcare-embedded randomised trial testing whether earlier use of direct oral anticoagulants in patients with prior or current atrial fibrillation can prevent thromboembolic events and cognitive decline (www.birmingham.ac.uk/dare2think). This paper outlines the systematic approach and methodology employed to define patient information and outcome events. This includes transparency on all medical code lists and phenotypes used in the trial across a variety of national data sources, including Clinical Practice Research Datalink Aurum (primary care), Hospital Episode Statistics (secondary care) and the Office for National Statistics (mortality).InterpretationCo-designed by a patient and public involvement team, DaRe2THINK presents an opportunity to transform the approach to randomised trials in the setting of routine healthcare, providing high-quality evidence generation in populations representative of the community at-risk.
A multivariate genetic analysis of environmental sensitivity, anxiety sensitivity and reported life events in adolescents
Authors: Peel Alicia J. , Oginni Olakunle , Assary Elham , Krebs Georgina , Lockhart Celestine , McGregor Thomas , Palaiologou Elisavet , Ronald Angelia , Danese Andrea , Eley Thalia C. 
Published: May 2022

AbstractBackgroundDespite being considered a measure of environmental risk, reported life events are partly heritable. One mechanism that may contribute to their heritability is genetic influences on sensitivity. These sensitivity biases can relate to how individuals process the contextual aspects of their environment (environmental sensitivity) or how they interpret their own physical and emotional responses (anxiety sensitivity). The aim of this study was to explore the genetic and environmental overlap between self-reported life events and measures of sensitivity.MethodsAt age 17, individuals (N = 2,939) from the Twins Early Development Study (TEDS) completed measures of environmental sensitivity (Highly Sensitive Child Scale) and anxiety sensitivity (Children’s Anxiety Sensitivity Index), as well as reporting on their experience of 20 recent life events. Using multivariate Cholesky decomposition models, we investigated the shared genetic and environmental influences on the associations between these measures of sensitivity and the number of reported life events, as well as both negative and positive ratings of life events.ResultsThe majority of the associations between anxiety sensitivity, environmental sensitivity and reported life events were explained by shared genetic influences (59%-75%), with the remainder explained by non-shared environmental influences (25%-41%). Environmental sensitivity showed comparable genetic correlations with both negative and positive ratings of life events (rA= .21 and .15), anxiety sensitivity only showed a significant genetic correlation with negative ratings of life events (rA= .33). Approximately 10% of the genetic influences on reported life events were accounted for by genetic influences shared with anxiety sensitivity and environmental sensitivity.ConclusionsA proportion of the heritable component of reported life events is captured by measures of sensitivity. Differences in how individuals process the contextual aspects of the environment or interpret their own physical and emotional response to environmental stimuli may be one mechanism through which genetic liability influences the subjective experience of life events.
Episodic memory formation in unrestricted viewing
Authors: Nikolaev Andrey R. , Bramão Inês , Johansson Roger , Johansson Mikael 
Published: May 2022

AbstractThe brain systems of episodic memory and oculomotor control are tightly linked, suggesting a crucial role of eye movements in memory. But little is known about the neural mechanisms of memory formation across eye movements in unrestricted viewing behavior. Here, we leverage simultaneous eye tracking and EEG recording to examine episodic memory formation in free viewing. Participants memorized multi-element events while their EEG and eye movements were concurrently recorded. Each event comprised elements from three categories (face, object, place), with two exemplars from each category, in different locations on the screen. A subsequent associative memory test assessed participants’ memory for the between-category associations that specified each event. We used a deconvolution approach to overcome the problem of overlapping EEG responses to sequential saccades in free viewing. Brain activity was time-locked to the fixation onsets, and we examined EEG power in the theta and alpha frequency bands, the putative oscillatory correlates of episodic encoding mechanisms. Three modulations of fixation-related EEG predicted high subsequent memory performance: 1) theta increase at fixations afterbetween-categorygaze transitions, 2) theta and alpha increase at fixations afterwithin-elementgaze transitions, 3) alpha decrease at fixations afterbetween-exemplargaze transitions. Thus, event encoding with unrestricted viewing behavior was characterized by three neural mechanisms, manifested in fixation-locked theta and alpha EEG activity that rapidly turned on and off during the unfolding eye movement sequences. These three distinct neural mechanisms may be the essential building blocks that subserve the buildup of coherent episodic memories during unrestricted viewing behavior.
Design and off-target prediction for antisense oligomers targeting bacterial mRNAs with the MASON webserver
Authors: Jung Jakob , Popella Linda , Do Phuong Thao , Pfau Patrick , Vogel Jörg , Barquist Lars 
Published: May 2022

ABSTRACTAntisense oligomers (ASOs) such as peptide nucleic acids (PNAs), designed to inhibit the translation of essential bacterial genes, have emerged as attractive sequence- and species-specific programmable RNA antibiotics. Yet, potential drawbacks include unwanted side effects caused by their binding to transcripts other than the intended target. To facilitate the design of PNAs with minimal off-target effects, we developed MASON (MakeAntiSenseOligomersNow), a webserver for the design of PNAs that target bacterial mRNAs. MASON generates PNA sequences complementary to the translational start site of a bacterial gene of interest and reports critical sequence attributes and potential off-target sites. We based MASON’s off-target predictions on experiments in which we treatedSalmonella entericaserovar Typhimurium with a series of 10mer PNAs derived from a PNA targeting the essential geneacpPbut carrying two serial mismatches. Growth inhibition and RNA-sequencing (RNA-seq) data revealed that PNAs with terminal mismatches are still able to targetacpP, suggesting wider off-target effects than anticipated. Comparison of these results to an RNA-seq dataset from uropathogenicEscherichia coli(UPEC) treated with eleven different PNAs confirmed our findings are not unique toSalmonella. We believe that MASON’s off-target assessment will improve the design of specific PNAs and other ASOs.
Compound specific stable isotope analysis of amino acid nitrogen reveals detrital support of microphytobenthos in the Dutch Wadden Sea benthic food web
Authors: Riekenberg Philip M. , van der Heide Tjisse , Holthuijsen Sander J. , van der Veer Henk W. , van der Meer Marcel T.J. 
Published: May 2022

AbstractThe Wadden Sea is the world’s largest intertidal ecosystem and provides vital food resources for a large number of migratory bird and fish species during seasonal stopovers. Previous work using bulk stable isotope analysis of carbon found that microphytobenthos was the dominant resource use fueling the food web with particulate organic matter making up the remainder. However, this work was unable to account for the trophic structure of the food web or the considerable increase in δ15N values of bulk tissue throughout the benthic food web occurring in the Eastern regions of the Dutch Wadden Sea. Here, we combine compound specific and bulk analytical stable isotope techniques to further resolve the trophic structure and resource use throughout the benthic food web in the Wadden Sea. Analysis of δ15N for trophic and source amino acids allowed for better identification of trophic relationships due to the integration of underlying variation in the nitrogen resources supporting the food web. Baseline integrated trophic position estimates using glutamic acid (Glu) and phenylalanine (Phe) allow for disentanglement of baseline variations in underlying δ15N sources supporting the ecosystem and trophic shifts resulting from changes in ecological relationships. Through this application we further confirmed dominant ecosystem support by microphytobenthos derived resources, although to a lesser extent than previously estimated. In addition to phytoplankton derived particulate organic matter and microphytobenthos supported from nutrients from the overlying water column there appears to be an additional resource supporting the benthic community. From the stable isotope mixing models, a subset of species appears to focus on microphytobenthos supported off recycled (porewater) N and/or detrital organic matter mainly driven by increased phenylalanine δ15N values. This additional resource within microphytobenthos may play a role in subsidizing the exceptional benthic productivity observed within the Wadden Sea ecosystem and reflect division in microphytobenthos support along green (herbivory) and brown (recycled/detrital) food web pathways.
Human skeletal muscle ageing atlas
Authors: Kedlian Veronika R. , Wang Yaning , Liu Tianliang , Chen Xiaoping , Bolt Liam , Shen Zhuojian , Fasouli Eirini S. , Prigmore Elena , Kleshchevnikov Vitalii , Li Tong , Lawrence John E , Huang Ni , Guo Qin , Yang Lu , Polański Krzysztof , Dabrowska Monika , Tudor Catherine , Li Xiaobo , Bayraktar Omer , Patel Minal , Meyer Kerstin B. , Kumasaka Natsuhiko , Mahbubani Krishnaa T. , Xiang Andy Peng , Saeb-Parsy Kourosh , Teichmann Sarah A , Zhang Hongbo 
Published: May 2022

AbstractSkeletal muscle ageing increases the incidence of age-associated frailty and sarcopenia in the elderly worldwide, leading to increased morbidity and mortality. However, our understanding of the cellular and molecular mechanisms of muscle ageing is still far from complete. Here, we generate a single-cell and single-nucleus transcriptomic atlas of skeletal muscle ageing from 15 donors across the adult human lifespan, accompanied by myofiber typing using imaging. Our atlas reveals ageing mechanisms acting across different compartments of the muscle, including muscle stem cells (MuSCs), myofibers and the muscle microenvironment. Firstly, we uncover two mechanisms driving MuSC ageing, namely a decrease in ribosome biogenesis and an increase in inflammation. Secondly, we identify a set of nuclei populations explaining the preferential degeneration of the fast-twitch myofibers and suggest two mechanisms acting to compensate for their loss. Importantly, we identify a neuromuscular junction accessory population, which helps myofiber to compensate for aged-related denervation. Thirdly, we reveal multiple microenvironment cell types contributing to the inflammatory milieu of ageing muscle by producing cytokines and chemokines to attract immune cells. Finally, we provide a comparable mouse muscle ageing atlas and further investigate conserved and specific ageing hallmarks across species. In summary, we present a comprehensive human skeletal muscle ageing resource by combining different data modalities, which significantly expands our understanding of muscle biology and ageing.
Sympathetic neurons secrete retrogradely transported TrkA on extracellular vesicles
Authors: Mason Ashley J , Keeler Austin B , Kabir Farah , Winckler Bettina , Deppmann Christopher 
Published: May 2022

AbstractNeuronal derived extracellular vesicles (EVs) have been well described in the central nervous system; however, studies in the peripheral nervous system have largely focused on EVs derived from supporting cell types such as endothelial cells or glia. Here we isolate EVs derived from sympathetic neurons and characterize them using immunoblot assays, nanoparticle tracking analysis and cryo-electron microscopy. Sizing of sympathetic EVs reveal a predominant peak between 45-75 nm as well as a range of larger sizes (90 nm to >350 nm), possibly due to multiple biogenic origins. We identified TrkA, a receptor for nerve growth factor (NGF), as a cargo for sympathetic EVs. Furthermore, TrkA on EVs was phosphorylated, indicating activated TrkA receptor. TrkA binds NGF at the axonal tip and is endocytosed and transported to the soma in signaling endosomes. We therefore examined if TrkA originating in the axon tip was subsequently able to be packaged into EVs and secreted by the somatodendritic domain of neurons. Using a compartmentalized culture system, we found that TrkA derived from endosomes originating in the distal axon can be detected on EVs secreted from the somatodendritic domain. In addition, inhibition of classic TrkA downstream pathways, specifically in somatodendritic compartments greatly decreases TrkA packaging into EVs. Our results suggest a novel trafficking route for TrkA: it can travel long distances to the cell body, be packaged into EVs and secreted. Secretion of TrkA via EVs appears to be regulated by its own downstream effector cascades, raising intriguing future questions about novel functionalities associated with TrkApositiveEVs.
Context-dependent 3D genome regulation by cohesin and related factors
Authors: Nakato Ryuichiro , Sakata Toyonori , Wang Jiankang , Nagai Luis Augusto Eijy , Oba Gina Miku , Bando Masashige , Shirahige Katsuhiko 
Published: May 2022

ABSTRACTCohesin plays vital roles in chromatin folding and gene expression regulation, cooperating with such factors as cohesin loaders, unloaders, acetyltransferase, and the insulation factor CTCF. Although various models of regulation have been proposed (e.g., loop extrusion), how cohesin and related factors collectively or individually regulate the hierarchical chromatin structure and gene expression remains unclear. In this study, we have depleted cohesin and related factors and then conducted a comprehensive evaluation of the resulting 3D genome, transcriptome and epigenome data. We observed substantial variation in depletion effects among factors at topologically associating domain (TAD) boundaries and on interTAD interactions, which were partly related to epigenomic status. Gene expression changes were highly correlated with direct cohesin binding and gain of TAD boundaries than with the loss of boundaries. Our results suggested that cohesin positively regulates gene expression, whereas other mechanisms (e.g., cohesin turnover and acetylation) add to the diversity of this pattern of dysregulation. Moreover, cohesin was broadly enriched in active compartment A, but not in compartment B, which were retained even after CTCF depletion. Our rich dataset and the subsequent data-driven analysis support the context-specific regulation of chromatin folding by cohesin and related factors.