bluuebunny/crossref_metadata_2025_split huggingface dataset:
Active antithrombin glycoforms are selectively physiosorbed on plasma extracellular vesicles
Authors: Radeghieri Annalisa , Alacqua Silvia , Zendrini Andrea , Previcini Vanessa , Todaro Francesca , Martini Giuliana , Ricotta Doris , Bergese Paolo 
Published: July 2021

AbstractAntithrombin (AT) is a glycoprotein produced by the liver and a principal antagonist of active clotting proteases. A deficit in AT function leads to AT qualitative deficiency, challenging to diagnose. Here we report that active AT may travel physiosorbed on the surface of plasma extracellular vesicles (EVs), contributing to form the “EV-protein corona”. The corona is enriched in specific AT glycoforms, thus suggesting glycosylation to play a key role in AT partitioning between EVs and plasma. Differences in AT glycoform composition of the corona of EVs separated from plasma of healthy and AT qualitative deficiency-affected subjects were also noticed. This suggests deconstructing the plasma into its nanostructured components, as extracellular vesicles, could help to unravel pathophysiological mechanisms otherwise undiscovered.
Transposable element activity in the transcriptomic analysis of mouse pancreatic tumors
Authors: Lerat Emmanuelle , Burlet Nelly , Navratil Vincent , Noûs Camilles 
Published: July 2021

AbstractTransposable elements (TEs) are middle-repeated DNA sequences that can move along chromosomes using internal coding and regulatory regions. By their ability to move and because they are repeated, TEs can promote mutations. Especially they can alter the expression pattern of neighboring genes and have been shown to be involved in the mammalian regulatory network evolution. Human and mouse share more than 95% of their genomes and are affected by comparable diseases, which makes the mouse a perfect model in cancer research. However not much investigation concerning the mouse TE content has been made on this topics. In human cancer condition, a global activation of TEs can been observed which may ask the question of their impact on neighboring gene functioning. In this work, we used RNA sequences of highly aggressive pancreatic tumors from mouse to analyze the gene and TE deregulation happening in this condition compared to pancreas from healthy animals. Our results show that several TE families are deregulated and that the presence of TEs is associated with the expression divergence of genes in the tumor condition. These results illustrate the potential role of TEs in the global deregulation at work in the cancer cells.
A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers
Authors: Zhou Lin , Zheng Siqi , Rosas Bringas Fernando R. , Bakker Bjorn , Simon Judith E. , Bakker Petra L. , Kazemier Hinke G. , Schubert Michael , Roorda Maurits , van Vugt Marcel , Chang Michael , Foijer Floris 
Published: July 2021

AbstractMaternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the SCF ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work might provide a new angle of how to exploit MELK overexpression in cancers and might thus lead to novel intervention strategies.
Classification of Free-Living Body Posture with ECG Patch Accelerometers: Application to the Multicenter AIDS Cohort Study
Authors: Etzkorn Lacey H. , Heravi Amir S. , Wu Katherine C. , Post Wendy S. , Urbanek Jacek , Crainiceanu Ciprian 
Published: July 2021

SummaryAs health studies increasingly monitor free-living heart performance via ECG patches with accelerometers, researchers will seek to investigate cardio-electrical responses to physical activity and sedentary behavior, increasing demand for fast, scalable methods to process accelerometer data. We provide the first published analysis of tri-axial accelerometry data from Zio XT patch and introduce an extension of posture classification algorithms for use with ECG patches worn in the free-living environment. Our novel extensions to posture classification include (1) estimation of an upright posture for each individual without the reference measurements used by existing posture classification algorithms; (2) correction for device removal and re-positioning using novel spherical change-point detection; and (3) classification of upright and recumbent periods using a clustering and voting process rather than a simple inclination threshold used in other algorithms. Methods were built using data from 14 participants from the Multicenter AIDS Cohort Study (MACS), and applied to 1, 250 MACS participants. As no posture labels exist in the free-living environment, we evaluate the algorithm against labelled data from the Towson Accelerometer Study and against data labelled by hand from the MACS study.
Global and Gene-specific Transcriptional Responses to Acute Stress
Authors: Fischl Harry , Brown Thomas , Angel Andrew , Mellor Jane 
Published: July 2021

ABSTRACTNucleosomes may regulate transcription by controlling access to promoters by transcription factors and RNA polymerase II (Pol2). Potentially active genes display nucleosome depleted regions flanked by positioned -1 and +1 nucleosomes. On yeast genes, the transcription start site (TSS) is on the upstream face of the +1 nucleosome, but whether precise +1 nucleosome positioning controls Pol2 access to the TSS remains unclear. Here, using acute nutrient starvation to rapidly reprogramme the genome, we show highly dynamic upstream or downstream shifts in the position of +1 nucleosomes, coincident with levels of transcriptionally engaged Pol2 at 58% of genes. Transcript level changes broadly reflect Pol2 occupancy changes with a delay but can be further influenced by Pub1 or Puf3 dependent changes in transcript degradation rates. The response to acute stress has a second component as we also observed genome-wide changes in Pol2 distribution on genes, independent of changes in Pol2 occupancy, with Pol2 accumulating upstream of a +170 nt stalling site. Mathematical modelling supports a global increase in promoter-proximal early transcription termination as a major component of the global stress response. Thus, we uncover a two-component transcriptional response to stress, one focused on the +1 nucleosome, the second on Pol2 itself.A two-component responses to acute stress involving a gene-specific response and a global responseDynamic shifting of +1 nucleosome position with transcriptional activation or repression.Global targeting of Pol2 leading to early transcription termination on acute stress
A study of the correlation between phenotypic antimicrobial susceptibility testing methods and the associated genotypes determined by whole genome sequencing for a collection of Escherichia coli of bovine origin
Authors: Maunsell Thomas J , Nguyen Scott , Garach Farid El , Miossec Christine , Cuinet Emmanuel , Woehrlé Frédérique , Fanning Séamus , Niedziela Dagmara A. 
Published: July 2021

AbstractAntimicrobial resistance (AMR) has increased at an alarming pace in the recent years. Molecular-based methods such as whole genome sequencing (WGS) offer a potential alternative to the conventional labour-intensive methods traditionally used to characterise AMR phenotypes. The aim of this study was to investigate whether WGS could be used as a predictor of AMR in Escherichia coli isolates of bovine origin.Genomes of 143 E. coli cultured from cattle presenting with diarrhoea or mastitis were sequenced on an Illumina MiSeq platform. AMR genes were identified using the ResFinder and AMRFinder databases. Antimicrobial susceptibility testing by disk diffusion was performed on a panel of 10 antibiotics, covering 7 antimicrobial classes. Minimum inhibitory concentration (MIC) measurements were made using the Sensititre plate with 6 antibiotics, covering 5 antimicrobial classes. Correlation between genotype and phenotype was assessed statistically by means of a two-by-two table analysis and Cohen’s kappa (κ) test.The overall κ correlation between WGS and disk diffusion was 0.81, indicating a near perfect agreement, and the average positive predicted value was 77.4 %. Correlation for individual antimicrobial compounds varied, with five yielding near perfect agreement (κ = 0.81–1.00; amoxicillin, florfenicol, gentamicin, tetracycline and trimethoprim-sulfamethoxazole), one showing substantial agreement (κ = 0.65; nalidixic acid), and four showing moderate agreement (κ = 0.41– 0.60). The overall κ correlation between WGS and MIC was 0.55 indicating moderate agreement, and the average positive predicted value was 68.6 %. Three antibiotics yielded near perfect agreement (gentamicin, tetracycline and trimethoprim-sulfamethoxazole) and a further three showed fair agreement (κ = 0.21–0.40).WGS is a useful tool that can be used for the prediction of AMR phenotypes, and correlates well with disk diffusion results. MIC measurements may be necessary for antimicrobial compounds with a high proportion of intermediately resistant isolates recorded, such as cephalothin.HighlightsCulture based antimicrobial susceptibility testing is used to identify therapeutics in the treatment of clinical veterinary isolatesWhole genome sequencing is increasingly adopted for surveillance, epidemiological traceback investigations, and detection of antimicrobial resistance genesLittle is known in correlations between antimicrobial resistance genotypes and disk diffusion antimicrobial susceptibility testingThis study finds that whole genome sequencing is a useful predictor for antimicrobial susceptibility however, minimum inhibitory concentration measurements may still be needed for intermediately resistant isolates
Genetic instability from a single S-phase after whole genome duplication
Authors: Gemble Simon , Wardenaar René , Keuper Kristina , Srivastava Nishit , Nano Maddalena , Macé Anne-Sophie , Tijhuis Andréa E. , Bernhard Sara Vanessa , Spierings Diana C.J. , Simon Anthony , Goundiam Oumou , Hochegger Helfrid , Piel Matthieu , Foijer Floris , Storchová Zuzana , Basto Renata 
Published: July 2021

ABSTRACTDiploid and stable karyotypes are associated with health and fitness in animals. In contrast, whole genome duplications (WGDs) - doubling full chromosome content - are linked to genetic instability (GIN) and frequently found in human cancers 1–3. It has been established that WGDs fuel chromosome instability through abnormal mitosis 4–8, however, the immediate consequences of tetraploidy in the first interphase are not known. This is an essential question because single WGD events such as cytokinesis failure can promote tumorigenesis 9. Here, we found that newly born tetraploid human cells undergo high rates of DNA damage during DNA replication in the first S-phase. Using DNA combing and single cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we found that these defects result from the lack of protein mass scaling up at the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the GIN landscape that favors tumorigenesis after tetraploidization.
The context of experienced sensory discrepancies shapes multisensory integration and recalibration differently
Authors: Park Hame , Kayser Christoph 
Published: July 2021

AbstractWhether two sensory cues interact during perceptual judgments depends on their immediate properties, but as suggested by Bayesian models, also on the observer’s a priori belief that these originate from a common source. While in many experiments this a priori belief is considered fixed, in real life it must adapt to the momentary context or environment. To understand the adaptive nature of human multisensory perception we investigated the context-sensitivity of spatial judgements in a ventriloquism paradigm. We exposed observers to audio-visual stimuli whose discrepancy either varied over a wider (± 46°) or a narrower range (± 26°) and hypothesized that exposure to a wider range of discrepancies would facilitate multisensory binding by increasing participants a priori belief about a common source for a given discrepancy. Our data support this hypothesis by revealing an enhanced integration (ventriloquism) bias in the wider context, which was echoed in Bayesian causal inference models fit to participants’ data, which assigned a stronger a priori integration tendency during the wider context. Interestingly, the immediate ventriloquism aftereffect, a multisensory response bias obtained following a multisensory test trial, was not affected by the contextual manipulation, although participant’s confidence in their spatial judgments differed between contexts for both integration and recalibration trials. These results highlight the context-sensitivity of multisensory binding and suggest that the immediate ventriloquism aftereffect is not a purely sensory-level consequence of the multisensory integration process.
Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia
Authors: Tirtakusuma Ricky , Szoltysek Katarzyna , Milne Paul , Grinev Vasily V , Ptasinska Anetta , Meyer Claus , Nakjang Sirintra , Hehir-Kwa Jayne Y , Williamson Daniel , Cauchy Pierre , Assi Salam A , Imperato Maria R , Vogiatzi Fotini , Lin Shan , Wunderlich Mark , Stutterheim Janine , Komkov Alexander , Zerkalenkova Elena , Evans Paul , McNeill Hesta , Elder Alex , Martinez-Soria Natalia , Fordham Sarah E , Shi Yuzhe , Russell Lisa J , Pal Deepali , Smith Alex , Kingsbury Zoya , Becq Jennifer , Eckert Cornelia , Haas Oskar A , Carey Peter , Bailey Simon , Skinner Roderick , Miakova Natalia , Collin Matthew , Bigley Venetia , Haniffa Muzlifah , Marschalek Rolf , Harrison Christine J , Cargo Catherine A , Schewe Denis , Olshanskaya Yulia , Thirman Michael J , Cockerill Peter N , Mulloy James C , Blair Helen J , Vormoor Josef , Allan James M , Bonifer Constanze , Heidenreich Olaf , Bomken Simon 
Published: July 2021

AbstractThe fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation.Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.
Phenotypic determinism and stochasticity in antibody repertoires of clonally expanded plasma cells
Authors: Neumeier Daniel , Yermanos Alexander , Agrafiotis Andreas , Csepregi Lucia , Chowdhury Tasnia , Ehling Roy A , Kuhn Raphael , Roberto Raphaël Brisset-Di , Di Tacchio Mariangela , Antonialli Renan , Starkie Dale , Lightwood Daniel J , Oxenius Annette , Reddy Sai T 
Published: July 2021

ABSTRACTThe capacity of humoral B cell-mediated immunity to effectively respond to and protect against pathogenic infections is largely driven by the presence of a diverse repertoire of polyclonal antibodies in the serum, which are produced by plasma cells (PCs).1,2 Recent studies have started to reveal the balance between deterministic mechanisms and stochasticity of antibody repertoires on a genotypic level (i.e., clonal diversity, somatic hypermutation, germline gene usage).3–8 However, it remains unclear if clonal selection and expansion of PCs follows any deterministic rules or is stochastic with regards to phenotypic antibody properties (i.e., antigen-binding, affinity, epitope specificity). Here we report on the in-depth genotypic and phenotypic characterization of clonally expanded PC antibody repertoires following protein immunization. We find that there is only a strong correlation with antigen-specificity among the most expanded clones (top ~ 10), whereas among the rest of the clonal repertoire antigen-specificity is stochastic. Furthermore, we report both on a polyclonal repertoire and clonal lineage level that antibody-antigen binding affinity does not correlate with clonal expansion or somatic hypermutation. Lastly, we provide evidence for convergence towards dominant epitopes despite clonal sequence diversity among the most expanded clones. Our results highlight the extent to which clonal expansion can be ascribed to antigen binding, affinity and epitope specificity and they have implications for the assessment of effective vaccines.Graphical abstract
Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss
Authors: Wu Tong , Zhu Jian , Strickland Amy , Ko Kwang Woo , Sasaki Yo , Dingwall Caitlin , Yamada Yurie , Figley Matthew D , Mao Xianrong , Neiner Alicia , Bloom Joseph , DiAntonio Aaron , Milbrandt Jeffrey 
Published: July 2021

SUMMARYSARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might also activate SARM1. Here we show that the nicotinamide analogue 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration and neuronal death. Systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to peripheral nerve induces SARM1-dependent axon degeneration. We also identify a related pyridine derivative, 2-aminopyridine, as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and furthermore, suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.
Cellular and genetic drivers of RNA editing variation in the human brain
Authors: Cuddleston Ryn , Li Junhao , Fan Xuanjia , Kozenkov Alexey , Lalli Matthew , Khalique Shahrukh , Dracheva Stella , Mukamel Eran A. , Breen Michael S. 
Published: July 2021

ABSTRACTPosttranscriptional adenosine-to-inosine modifications amplify the functionality of RNA molecules in the brain, yet the cellular and genetic regulation of RNA editing is poorly described. We quantified base-specific RNA editing across three major cell populations from the human prefrontal cortex: glutamatergic neurons, medial ganglionic eminence GABAergic neurons, and oligodendrocytes. We found more selective editing and RNA hyper-editing in neurons relative to oligodendrocytes. The pattern of RNA editing was highly cell type-specific, with 189,229 cell type-associated sites. The cellular specificity for thousands of sites was confirmed by single nucleus RNA-sequencing. Importantly, cell type-associated sites were enriched in GTEx RNA-sequencing data, edited ∼twentyfold higher than all other sites, and variation in RNA editing was predominantly explained by neuronal proportions in bulk brain tissue. Finally, we discovered 661,791 cis-editing quantitative trait loci across thirteen brain regions, including hundreds with cell type-associated features. These data reveal an expansive repertoire of highly regulated RNA editing sites across human brain cell types and provide a resolved atlas linking cell types to editing variation and genetic regulatory effects.
Modeling lung cell development using human pluripotent stem cells
Authors: Ngan Shuk Yee , Quach Henry , Dierolf Joshua , Laselva Onofrio , Lee Jin-A , Huang Elena , Mangos Maria , Xia Sunny , Bear Christine E. , Wong Amy P. 
Published: July 2021

ABSTRACTHuman pluripotent stem cells (hPSC) differentiations can capture developmental phenotypes and processes. They are useful for studying fundamental biological mechanisms driving tissue morphogenesis and cell lineage development. Here, we show temporal development of lung cell lineages using hPSC that recapitulate developmental milestones observed in primary tissue, the generation of renewable fetal lung epithelial spheroids, and the functional utility of the lung models at different differentiation stages for cystic fibrosis disease modeling. We first show the presence of hPSC-derived lung progenitor cells reminiscent of early trimester lung development and containing basal stem cells that generate renewable airway spheroids. Maturation and polarization in air liquid interface (ALI) generates additional epithelial cell lineages found in adult airways, including pulmonary neuroendocrine, brush, mature basal, ciliated and secretory cell types. Finally, pseudotime and RNA velocity analyses of the integrated datasets from fetal and ALI stages reveal both previously identified and new cell lineage relationships. Overall, hPSC differentiation can capture aspects of human lung development and potentially provide important insight into congenital causes of diseases.
Rescue of stalled clathrin-mediated endocytosis by asymmetric Arp2/3-mediated actin assembly
Authors: Jin Meiyan , Shirazinejad Cyna , Wang Bowen , Yan Amy , Schöneberg Johannes , Upadhyayula Srigokul , Xu Ke , Drubin David G. 
Published: July 2021

AbstractActin assembly facilitates vesicle formation in several trafficking pathways. Clathrin-mediated endocytosis (CME) shows elevated actin assembly dependence under high membrane tension. Why actin assembly at CME sites occurs heterogeneously even within the same cell, and how assembly forces are harnessed, are not fully understood. Here, endocytic dynamics, actin presence, and geometry of CME proteins from three different functional modules, were analyzed using three-dimensional (3D) super-resolution microscopy, live-cell imaging, and machine-learning-based computation. When hundreds of CME events were compared, sites with actin assembly showed a distinct signature, a delay between completion of coat expansion and vesicle scission, indicating that actin assembly occurs preferentially at stalled CME sites. N-WASP is recruited to one side of CME sites where it is positioned to stimulate asymmetric actin assembly. We propose that asymmetric actin assembly rescues stalled CME sites by pulling vesicles into the cell much like a bottle opener pulls off a bottle cap.