bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques
Authors: Williams Wilton B. , Meyerhoff R. Ryan , Edwards RJ , Li Hui , Nicely Nathan I. , Henderson Rory , Zhou Ye , Janowska Katarzyna , Mansouri Katayoun , Manne Kartik , Stalls Victoria , Hsu Allen L. , Borgnia Mario J. , Stewart-Jones Guillaume , Lee Matthew S. , Bronkema Naomi , Perfect John , Moody M. Anthony , Wiehe Kevin , Bradley Todd , Kepler Thomas B. , Alam S. Munir , Parks Robert J. , Foulger Andrew , Bonsignori Mattia , LaBranche Celia C. , Montefiori David C. , Seaman Michael , Santra Sampa , Francica Joseph R. , Lynn Geoffrey M. , Aussedat Baptiste , Walkowicz William E. , Laga Richard , Kelsoe Garnett , Saunders Kevin O. , Fera Daniela , Kwong Peter D. , Seder Robert A. , Bartesaghi Alberto , Shaw George M. , Acharya Priyamvada , Haynes Barton F. 
Published: July 2020

SummaryThe HIV-1 envelope (Env) is comprised by mass of over 50% glycans. A goal of HIV-1 vaccine development is the induction of Env glycan-reactive broadly neutralizing antibodies (bnAbs). The 2G12 bnAb recognizes an Env glycan cluster using a unique variable heavy (VH) domain-swapped conformation that results in fragment antigen-binding (Fab) dimerization. Here we describe Fab-dimerized glycan (FDG)-reactive antibodies without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques that neutralized heterologous HIV-1 isolates. FDG precursors were boosted by vaccination in macaques, and were present in HIV-1-naïve humans with an average estimated frequency of one per 340,000 B cells. These data demonstrate frequent HIV-1 Env glycan-reactive bnAb B cell precursors in macaques and humans and reveal a novel strategy for their induction by vaccination.HighlightsDiscovery of Fab-dimerized HIV-1 glycan-reactive antibodies with a non-domain-swapped architectureFab-dimerized antibodies neutralize heterologous HIV-1 isolates.Antibodies with this architecture can be elicited by vaccination in macaques.Fab-dimerized antibodies are found in HIV-1 naïve humans.
SALL4 controls cell fate in response to DNA base composition
Authors: Pantier Raphaël , Chhatbar Kashyap , Quante Timo , Skourti-Stathaki Konstantina , Cholewa-Waclaw Justyna , Alston Grace , Alexander-Howden Beatrice , Lee Heng Yang , Cook Atlanta G. , Spruijt Cornelia G. , Vermeulen Michiel , Selfridge Jim , Bird Adrian 
Published: July 2020

SummaryMammalian genomes contain long domains with distinct average compositions of A/T versus G/C base pairs. In a screen for proteins that might interpret base composition by binding to AT-rich motifs, we identified the stem cell factor SALL4 which contains multiple zinc-fingers. Mutation of the domain responsible for AT binding drastically reduced SALL4 genome occupancy and prematurely up-regulated genes in proportion to their AT content. Inactivation of this single AT-binding zinc-finger cluster mimicked defects seen inSall4-null cells, including precocious differentiation of embryonic stem cells and embryonic lethality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by down-regulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differentiation. We conclude that base composition is not merely a passive by-product of genome evolution, but constitutes a signal that aids control of cell fate.
High-content Imaging-based Pooled CRISPR Screens in Mammalian Cells
Authors: Yan Xiaowei , Stuurman Nico , Ribeiro Susana A. , Tanenbaum Marvin E. , Horlbeck Max A. , Liem Christina R. , Jost Marco , Weissman Jonathan S. , Vale Ronald D. 
Published: July 2020

ABSTRACTCRISPR (clustered regularly interspaced short palindromic repeats) -based gene inactivation provides a powerful means of linking genes to particular cellular phenotypes. CRISPR-based screening has mostly relied upon using large genomic pools of single guide RNAs (sgRNAs). However, this approach is limited to phenotypes that can be enriched by chemical selection or FACS sorting. Here, we developed a microscopy-based approach, which we name optical enrichment, to computationally select cells displaying a particular CRISPR-induced phenotype, mark them by photo-conversion of an expressed photo-activatable fluorescent protein, and then isolate the fluorescent cells using fluorescence-activated cell sorting (FACS). A plugin was developed for the open source software μManager to automate the phenotypic identification and photo-conversion of cells, allowing ~1.5 million individual cells to be screened in 8 hr. We used this approach to screen 6092 sgRNAs targeting 544 genes for their effects on nuclear size regulation and identified 14 bona fide hits. These results present a highly scalable approach to facilitate imaging-based pooled CRISPR screens.
Language networks in aphasia and health: a 1000 participant Activation Likelihood Estimate analysis
Authors: Stefaniak James D. , Alyahya Reem S. W. , Lambon Ralph Matthew A. 
Published: July 2020

AbstractAphasia recovery post-stroke is classically and most commonly hypothesised to rely on regions that were not involved in language premorbidly, through ‘neurocomputational invasion’ or engagement of ‘quiescent homologues’. Contemporary accounts have suggested, instead, that recovery might be supported by under-utilised areas of the premorbid language network, which are downregulated in health to save neural resources (‘variable neurodisplacement’). Despite the importance of understanding the neural bases of language recovery clinically and theoretically, there is no consensus as to which specific regions are activated more consistently in post-stroke aphasia (PSA) than healthy individuals. Accordingly, we performed an Activation Likelihood Estimation analysis of language functional neuroimaging studies in PSA and linked control data. We obtained coordinate-based functional neuroimaging data for 481 individuals with aphasia following left hemisphere stroke (one third of which was previously unpublished) and for 530 healthy controls. Instead of the language network expanding by activating novel right hemisphere regions ‘de novo’ post-stroke, as would be predicted by neurocomputational invasion/quiescent homologue engagement mechanisms of recovery, we found that multiple regions throughout both hemispheres were consistently activated during language tasks in PSA and controls. Multiple undamaged regions were less consistently activated in PSA than controls, including domain-general regions of medial superior frontal cortex and right fronto-temporal cortex. In the reverse direction, the right anterior insula and inferior frontal gyrus were more consistently activated in PSA than controls, particularly for executively-demanding comprehension tasks. These regions overlap with control networks known to be recruited during difficult tasks in healthy individuals and were more consistently activated by patients during higher than lower demand tasks in this meta-analysis. Overall, these findings run counter to neurocomputational invasion of the language network into new territory or engagement of quiescent homologues. Instead, many parts of the pre-existing language network are less consistently activated in PSA, except for more consistent use of spare capacity within right hemisphere executive-control related regions (cf. variable neurodisplacement). This study provides novel insights into the language network changes that occur post-stroke. Such knowledge is essential if we are to design neurobiologically-informed therapeutic interventions to facilitate language recovery.
CAUTI’s Next Top Model – model dependentKlebsiellabiofilm inhibition by bacteriophages and antimicrobials
Authors: Townsend Eleanor , Moat John , Jameson Eleanor 
Published: July 2020

AbstractKlebsiellainfections, including catheter associated urinary tract infections, are a considerable burden on health care systems. This is due to their difficulty to treat, caused by antimicrobial resistance and their ability to form biofilms. In this study, we investigated the use of aKlebsiellaphage cocktail to reduce biofilm viability. We used two methodologies to investigate this, a standard 96-well plate assay and a more complicated Foley catheter-based model. The phage cocktail was used alone and in combination with clinically relevant antibiotic treatments. Viability was measured by both a resazurin based stain and colony forming unit counts, of cells sloughed off from the biofilm. We showed that phage infection dynamics and host survival vary significantly in different standard laboratory media, presumably due to the expression of different surface receptors and capsule composition by the bacteria effecting phage binding. This underscores the importance of a realistic model for developing phage therapyWe demonstrate that bacteriophage-based treatments are a viable option for preventingKlebsiellacolonisation and biofilm formation on urinary catheters. Phage cocktails were able to significantly reduce the amount of biofilm that formed when they were present during early biofilm formation. The phages used in this study were unable to significantly reduce a pre-formed mature biofilm, despite encoding depolymerases. Phages applied together with antimicrobial treatments, showed synergistic interactions, in some cases the combined treatment was much more effective than antimicrobial treatments alone.We show that phage cocktails have the potential to preventKlebsiellabiofilms in catheters, if used early or as a preventative treatment and will work well alongside standard antibiotics in the treatment of catheter-associated urinary tract infections (CAUTI).
Identification of antimicrobial resistance-associated genes through whole genome sequencing of high and low MIC isolates ofMycoplasma bovis
Authors: Ledger Lisa , Eidt Jason , Cai Hugh Y. 
Published: July 2020

AbstractAntimicrobial resistance (AMR) inMycoplasma bovishas previously been associated with mutations within topoisomerases and ribosomal genes rather than specific resistance-conferring genes. This study used whole genome sequencing (WGS) to identify potential new AMR mechanisms. It was found that a 2019 clinical isolate with high MIC (2019-043682) had a new core genome multilocus sequencing (cgMLST) type (ST10-like) and 91% homology with the published genome ofM. bovisPG45. Closely related to PG45, a 1982 isolate (1982-M6152) shared the same cgMLST type (ST17), 97.2% homology and similar low MIC results. Known and potential AMR-associated genetic events were identified through comparison with the publishedM. bovisPG45 genome. Isolate 2019-043682 had 507 genes with non-synonymous mutations (NSMs) and 67 genes disrupted. Isolate 1982-M6152 had 81 NSMs and 20 disruptions. Based on functional roles and known mechanisms of antimicrobials, a 55 gene subset was assessed for potential AMR mechanisms. Of these, 14 were previously identified from other bacteria as sites of AMR mutation, 41 shared similar functions to them, and 11 contained gene-disrupting mutations. This study indicated thatM. bovismay obtain high AMR characteristics by mutating or disrupting other functional genes, in addition to topoisomerases and ribosomal genes.
Role of PARylation and PTEN Mutation on PARP and PARG Inhibitor Efficacy on Glioblastoma
Authors: Hermanowski Henre , Huebert Barbara , Aldrighetti Christopher , Hurley Jenna K , Quénet Delphine 
Published: July 2020

AbstractGlioblastoma (GBM) is the most aggressive primary adult brain tumor, with a median survival of approximately 15 months. Despite novel therapeutic approaches, median survival has remained largely unchanged since the standard of care therapy for GBM was established nearly 15 years ago. Phosphatase and tensin homolog (PTEN) is a prognostic biomarker of GBM. PTEN mutation is associated with defects in homologous recombination (HR), making it a candidate for targeted therapy by synthetic lethality (SL). The SL concept has been clinically validated in HR-deficient breast and ovarian cancers upon treatment with poly(ADP-ribose) polymerase (PARP 1) inhibitors (PARPi). This inhibitor, as well as poly(ADP-ribose) glycohydrolase (PARG) inhibitors (PARGi), dysregulate PARylation post-translational modification, which plays a major role in DNA repair and genomic stability. To determine whether PARPi/PARGi promotes SL in GBM, this study investigated the effects of PARPi (veliparib and olaparib) and PARGi in GBM cells with wildtype versus mutant PTEN. Sensitivity to these drugs was analyzed in function of PTEN status. Specifically, PTEN-wildtype cells displayed higher levels of DNA damage after PARPi treatment compared to PTEN-mutant cells. However, focusing on DNA double-strand break (DSB) repair, there was no indication of efficient activation of non-homologous end joining (NHEJ) or homologous recombination (HR). These findings highlight the complex relationship between PARylation and PTEN. Thus, our results do not support the SL between PARP/PARG inhibition and PTEN mutations in GBM cells in absence of other DNA damaging agents.
Regulatory effects of theUty/Ddx3ylocus on neighboring chromosome Y genes and autosomal mRNA transcripts in adult mouse non-reproductive cells
Authors: Deschepper Christian F. 
Published: July 2020

ABSTRACTIn addition to sperm-related genes, the male-specific chromosome Y (chrY) contains a class of ubiquitously expressed and evolutionary conserved dosage-sensitive regulator genes that include the neighboringUty, Ddx3yand (in mice)Eif2s3ygenes. However, no study to date has investigated the functional impact of targeted mutations of any of these genes within adult non-reproductive somatic cells. We thus compared adult male mice carrying a gene trap within theirUtygene (UtyGT) to their wild-type (WT) isogenic controls, and performed deep sequencing of RNA and genome-wide profiling of chromatin features in extracts from either cardiac tissue, cardiomyocyte-specific nuclei or purified cardiomyocytes. The apparent impact ofUtyGTon gene transcription concentrated mostly on chrY genes surrounding the locus of insertion,i.e. Uty, Ddx3y, long non-coding RNAs (lncRNAs) contained within their introns andEif2s3y, in addition to possible effects on the autosomalMalat1lncRNA. Notwithstanding,UtyGTalso caused coordinate changes in the abundance of hundreds of mRNA transcripts related to coherent cell functions, including RNA processing and translation. The results altogether indicated that tightly co-regulated chrY genes had nonetheless more widespread effects on the autosomal transcriptome in adult somatic cells, most likely due to mechanisms other than just transcriptional regulation of corresponding protein-coding genes.
Unifying the known and unknown microbial coding sequence space
Authors: Vanni Chiara , Schechter Matthew S. , Acinas Silvia G. , Barberán Albert , Buttigieg Pier Luigi , Casamayor Emilio O. , Delmont Tom O. , Duarte Carlos M. , Eren A. Murat , Finn Robert D. , Kottmann Renzo , Mitchell Alex , Sanchez Pablo , Siren Kimmo , Steinegger Martin , Glöckner Frank Oliver , Fernandez-Guerra Antonio 
Published: July 2020

AbstractGenes of unknown function are among the biggest challenges in molecular biology, especially in microbial systems, where 40%-60% of the predicted genes are unknown. Despite previous attempts, systematic approaches to include the unknown fraction into analytical workflows are still lacking. Here, we propose a conceptual framework and a computational workflow that bridge the known-unknown gap in genomes and metagenomes. We showcase our approach by exploring 415,971,742 genes predicted from 1,749 metagenomes and 28,941 bacterial and archaeal genomes. We quantify the extent of the unknown fraction, its diversity, and its relevance across multiple biomes. Furthermore, we provide a collection of 283,874 lineage-specific genes of unknown function forCand. Patescibacteria, being a significant resource to expand our understanding of their unusual biology. Finally, by identifying a target gene of unknown function for antibiotic resistance, we demonstrate how we can enable the generation of hypotheses that can be used to augment experimental data.
Decoding spoken English phonemes from intracortical electrode arrays in dorsal precentral gyrus
Authors: Wilson Guy H. , Stavisky Sergey D. , Willett Francis R. , Avansino Donald T. , Kelemen Jessica N. , Hochberg Leigh R. , Henderson Jaimie M. , Druckmann Shaul , Shenoy Krishna V. 
Published: July 2020

AbstractObjectiveTo evaluate the potential of intracortical electrode array signals for brain-computer interfaces (BCIs) to restore lost speech, we measured the performance of classifiers trained to discriminate a comprehensive basis set for speech: 39 English phonemes. We classified neural correlates of spoken-out-loud words in the “hand knob” area of precentral gyrus, which we view as a step towards the eventual goal of decoding attempted speech from ventral speech areas in patients who are unable to speak.ApproachNeural and audio data were recorded while two BrainGate2 pilot clinical trial participants, each with two chronically-implanted 96-electrode arrays, spoke 420 different words that broadly sampled English phonemes. Phoneme onsets were identified from audio recordings, and their identities were then classified from neural features consisting of each electrode’s binned action potential counts or high-frequency local field potential power. We also examined two potential confounds specific to decoding overt speech: acoustic contamination of neural signals and systematic differences in labeling different phonemes’ onset times.Main resultsA linear decoder achieved up to 29.3% classification accuracy (chance = 6%) across 39 phonemes, while a recurrent neural network classifier achieved 33.9% accuracy. Parameter sweeps indicated that performance did not saturate when adding more electrodes or more training data, and that accuracy improved when utilizing time-varying structure in the data. Microphonic contamination and phoneme onset differences modestly increased decoding accuracy, but could be mitigated by acoustic artifact subtraction and using a neural speech onset marker, respectively.SignificanceThe ability to decode a comprehensive set of phonemes using intracortical electrode array signals from a nontraditional speech area suggests that placing electrode arrays in ventral speech areas is a promising direction for speech BCIs.
Receptor-independent membrane mediated pathways of serotonin action
Authors: Dey Simli , Surendran Dayana , Enberg Oskar , Gupta Ankur , Fanibunda Sashaina E. , Das Anirban , Maity Barun Kumar , Dey Arpan , Kallianpur Mamata , Scheidt Holger , Walker Gilbert , Vaidya Vidita A. , Huster Daniel , Maiti Sudipta 
Published: July 2020

AbstractSerotonin is a neurotransmitter as well as a somatic signaling molecule, and the serotonergic system is a major target for psychotropic drugs. Serotonin, together with a few related neurotransmitters, has recently been found to exhibit an unexpectedly high lipid membrane affinity1–3. It has been conjectured that extrasynaptic serotonin can diffuse in the lipid membrane to efficiently reach remote receptors (and receptors with buried ligand-binding sites)4, providing a mechanism for the diffuse ‘volume’ neurotransmission that serotonin is capable of5–10. Here we show that membrane binding by serotonin can directly modulate membrane properties and cellular function, independent of its receptor-mediated actions. Atomic force microscopy shows that serotonin binding makes artificial lipid bilayers softer. It induces nucleation of liquid disordered domains inside the raft-like liquid-ordered domains in a ternary bilayer displaying phase separation. Solid-state NMR spectroscopy corroborates this data, revealing a rather homogeneous decrease in the order parameter of the lipid chains in the presence of serotonin. In the RN46A immortalized serotonergic neuronal cell line, extracellular serotonin enhances transferrin receptor endocytosis, an action exerted even in the presence of both broad-spectrum serotonin receptor and transporter inhibitors. Similarly, it increases the binding and internalization of Islet Amyloid Polypeptide (IAPP) oligomers, suggesting a connection between serotonin, which is co-secreted with IAPP by pancreatic beta cells, and the cellular effects of IAPP. Our results uncover a hitherto unknown serotonin-bilayer interaction that can potentiate key cellular processes in a receptor-independent fashion. Therefore, some pathways of serotonergic action may escape potent pharmaceutical agents designed for serotonin transporters or receptors. Conversely, bio-orthogonal serotonin-mimetics may provide a new class of cell-membrane modulators.
Subpolitics and sustainability reporting boundaries. The case of working conditions in global supply chains
Authors: Antonini Carla , Beck Cornelia , Larrinaga Carlos 
Published: July 2020

PurposeThis paper explores the subpolitical role and main characteristics of a specific accounting technique, sustainability reporting boundaries. Its focus is on how the sett2ing of sustainability reporting boundaries affects the definition and distribution of social risks along the supply chain, particularly the risks related to working condition and human rights.Design/methodology/approachThe paper draws on Beck's (1986) exploration of the ways in which techno-economic spheres offer opportunities for the politicisation of new areas. It is argued that the sphere of sustainability reporting offers that opportunity for the politicisation of supply chains. Using the case of Inditex, the historical context of initiatives relating to the ready-made garment (RMG) industry at global, European and industry level as well as media coverage on the entity are analysed; this is correlated with the analysis of boundary setting in relation to sustainability reports, focusing specifically on working conditions.FindingsThe analysis suggests that accounting technologies that set contested boundaries are subpolitical, that is, defined outside traditional political processes. The paper finds that the way social risks are framed along the supply chain renders them invisible and impersonal and that the framing of these risks becomes endless as they are contested by different groups of experts. Setting sustainability reporting boundaries has subpolitical properties in producing and framing those risks, whilst is simultaneously limited by the inherent politicisation of such an exercise. The questionable legitimacy of sustainability reporting boundaries calls for the construction not only of discursive justifications but also of new possibilities for political participation.Research limitations/implicationsThe analysis is limited to working conditions along one organisation's supply chain.Originality/valueThe contribution of this paper is threefold: (1) It studies in-depth how working conditions in global supply chains are portrayed in sustainability reports. (2) It answers the call to study accounting technologies themselves, in this case sustainability reporting boundaries. (3) It extends Beck's work on global ecological dangers to working conditions in global supply chains to explore how sustainability reporting boundaries are subpolitically involved in the definition and distribution of social risks along the supply chain.