bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TFIIH Complex is Required to Establish and Maintain Mitotic Chromosome Structure
Authors: Haase Julian , Chen Richard , Bonner Mary Kate , Jenkins Lisa M. Miller , Kelly Alexander E. 
Published: November 2021

AbstractCondensins compact chromosomes to promote their equal segregation during mitosis, but the mechanism of condensin engagement with and action on chromatin is incompletely understood. Here, we show that the general transcription factor TFIIH complex is continuously required to establish and maintain a compacted chromosome structure in transcriptionally silent Xenopus egg extracts. Inhibiting the DNA-dependent ATPase activity of the TFIIH complex subunit XPB rapidly and reversibly induces a complete loss of chromosome structure and prevents the enrichment of condensins I and II, but not topoisomerase II, on chromatin. In addition, inhibiting TFIIH prevents condensation of both mouse and Xenopus nuclei in Xenopus egg extracts, which suggests a fundamental mechanism of TFIIH action. Reducing nucleosome density through partial histone depletion restores chromosome structure and condensin enrichment in the absence of TFIIH activity. We propose that the TFIIH complex promotes mitotic chromosome condensation by dynamically altering chromatin structure to facilitate condensin loading and condensin-dependent loop extrusion.
Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
Authors: Lyons Scott P. , Greiner Elora C. , Cressey Lauren E. , Adamo Mark E. , Kettenbach Arminja N. 
Published: November 2021

AbstractThe family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration. For PP2A, PP4, and PP6, holoenzyme formation is in part regulated by carboxyl (C)-terminal methyl-esterification (often referred to as “methylation”). Here, we use mass spectrometry-based proteomics, methylation-ablating mutations, and genome editing to elucidate the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly. We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells and that deletion of the C-terminal leucine faithfully recapitulates loss of methylation. We observe that loss of PP2A methylation consistently reduced B55, B56, and B72 regulatory subunit binding in cancer and non-transformed cell lines. However, Striatin subunit binding is only affected in non-transformed cells. For PP4, we find that PP4R1 and PP4R3β bind in a methylation-dependent manner. Intriguingly, loss of methylation does not affect PP6 holoenzymes. Our analyses demonstrate in an unbiased, comprehensive, and isoform-specific manner the crucial regulatory function of endogenous PPP methylation in transformed and non-transformed cell lines
COVID-19 vaccinations: perceptions and behaviours in people with primary ciliary dyskinesia
Authors: Pedersen Eva SL , Mallet Christina M , Lam Yin Ting , Bellu Sara , Cizeau Isabelle , Copeland Fiona , Fernandez Trini Lopez , Manion Michelle , Harris Amanda , Lucas Jane S , Santamaria Francesca ,   COVID-PCD patient advisory group, Goutaki Myrofora , Kuehni Claudia E 
Published: November 2021

AbstractPrimary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at high risk of severe COVID-19 and vaccination against SARS-CoV-2 is therefore important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behavior after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A questionnaire was e-mailed to participants in May 2021 that asked about COVID-19 vaccinations. 423 participants from 31 countries replied (median age: 30 years; 261 (62%) female). Vaccination uptake and willingness was high with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reasons for hesitancy were fear of side effects (reported by 88%). Mild side effects were common but no participant reported severe side effects. Half of participants changed their social contact behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific public information and involvement of representatives is important for high vaccine uptake.
Sources of variation in the spectral slope of the sleep EEG
Authors: Kozhemiako N , Mylonas D , Pan JQ , Prerau MJ , Redline S , Purcell SM 
Published: November 2021

AbstractBuilding on previous work linking changes in the electroencephalogram (EEG) spectral slope to arousal level, Lendner et al. (2021) reported that wake, non rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep exhibit progressively steeper 30-45 Hz slopes, interpreted in terms of increasing cortical inhibition. Here we sought to replicate Lendner et al.’s scalp EEG findings (based on 20 individuals) in a larger sample of 11,630 individuals from multiple cohorts in the National Sleep Research Resource (NSRR). In a final analytic sample of N = 10,255 distinct recordings, there was unambiguous statistical support for the hypothesis that, within individuals, the mean spectral slope grows steeper going from wake to NREM to REM sleep. We found that the choice of mastoid referencing scheme modulated the extent to which electromyogenic or electrocardiographic artifacts were likely to bias 30-45 Hz slope estimates, as well as other sources of technical, device-specific bias. Nonetheless, within individuals, slope estimates were relatively stable over time. Both cross-sectionally and longitudinal, slopes tended to become shallower with increasing age, particularly for REM sleep; males tended to show flatter slopes than females across all states. Although conceptually distinct, spectral slope did not predict sleep state substantially better than other summaries of the high frequency EEG power spectrum (>20 Hz, in this context) including beta band power, however. Finally, to more fully describe sources of variation in the spectral slope and its relationship to other sleep parameters, we quantified state-dependent differences in the variances (both within and between individuals) of spectral slope, power and interhemispheric coherence, as well as their covariances. In contrast to the common conception of the REM EEG as relatively wake-like (i.e. ‘paradoxical’ sleep), REM and wake were the most divergent states for multiple metrics, with NREM exhibiting intermediate profiles. Under a simplified modelling framework, changes in spectral slope could not, by themselves, fully account for the observed differences between states, if assuming a strict power law model. Although the spectral slope is an appealing, theoretically inspired parameterization of the sleep EEG, here we underscore some practical considerations that should be borne in mind when applying it in diverse datasets. Future work will be needed to fully characterize state-dependent changes in the aperiodic portions of the EEG power spectra, which appear to be consistent with, albeit not fully explained by, changes in the spectral slope.
Parametric control of flexible timing through low-dimensional neural manifolds
Authors: Beiran Manuel , Meirhaeghe Nicolas , Sohn Hansem , Jazayeri Mehrdad , Ostojic Srdjan 
Published: November 2021

AbstractBiological brains possess an unparalleled ability to adapt behavioral responses to changing stimuli and environments. How neural processes enable this capacity is a fundamental open question. Previous works have identified two candidate mechanisms: a low-dimensional organization of neural activity and a modulation by contextual inputs. We hypothesized that combining the two might facilitate generalization and adaptation in complex tasks. We tested this hypothesis in the framework of flexible timing tasks where dynamics play a key role. Examining trained recurrent neural networks, we found that confining the dynamics to a low-dimensional subspace allowed tonic inputs to parametrically control the overall input-output transform, enabling generalization to novel inputs and adaptation to changing conditions. Reverse-engineering and theoretical analyses demonstrated that this parametric control relies on a mechanism where tonic inputs modulate the dynamics along non-linear manifolds in activity space while preserving their geometry. Comparisons with data from behaving monkeys confirmed the behavioral and neural signatures of this mechanism.
Natural variation in gene expression and Zika virus susceptibility revealed by villages of neural progenitor cells
Authors: Wells Michael F. , Nemesh James , Ghosh Sulagna , Mitchell Jana M. , Mello Curtis J. , Meyer Daniel , Raghunathan Kavya , Tegtmeyer Matthew , Hawes Derek , Neumann Anna , Worringer Kathleen A. , Raymond Joseph J. , Kommineni Sravya , Chan Karrie , Ho Daniel , Peterson Brant K. , Piccioni Federica , Nehme Ralda , Eggan Kevin , McCarroll Steven A. 
Published: November 2021

SUMMARYVariation in the human genome contributes to abundant diversity in human traits and vulnerabilities, but the underlying molecular and cellular mechanisms are not yet known, and will need scalable approaches to accelerate their recognition. Here, we advanced and applied an experimental platform that analyzes genetic, molecular, and phenotypic heterogeneity across cells from very many human donors cultured in a single, shared in vitro environment, with algorithms (Dropulation and Census-seq) for assigning phenotypes to individual donors. We used natural genetic variation and synthetic (CRISPR-Cas9) genetic perturbations to analyze the vulnerability of neural progenitor cells to infection with Zika virus. These analyses identified a common variant in the antiviral IFITM3 gene that regulated IFITM3 expression and explained most inter-individual variation in NPCs’ susceptibility to Zika virus infectivity. These and other approaches could provide scalable ways to recognize the impact of genes and genetic variation on cellular phenotypes.HIGHLIGHTSMeasuring cellular phenotypes in iPSCs and hPSC-derived NPCs from many donorsEffects of donor sex, cell source, genetic and other variables on hPSC RNA expressionNatural genetic variation and synthetic perturbation screens both identify IFITM3 in NPC susceptibility to Zika virusA common genetic variant in IFITM3 explains most inter-individual variation in NPC susceptibility to Zika virus
mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer
Authors: Kumari Anju , Gesumaria Lisa , Liu Yan-Jin , Hughitt V. Keith , Zhang Xiaohu , Ceribelli Michele , Wilson Kelli M. , Klumpp-Thomas Carleen , Chen Lu , McKnight Crystal , Itkin Zina , Thomas Craig J. , Mock Beverly A. , Schrump David S. , Chen Haobin 
Published: November 2021

AbstractPurposeSCLC is a recalcitrant malignancy with limited treatment options. BET inhibitors have shown promising preclinical activity in SCLC, but their broad sensitivity spectrum limits their clinical prospects in this malignancy. Drug combination could be a solution.Experimental designWe performed high-throughput drug combination screens in SCLC cell lines to identify potential therapeutics synergizing with BET inhibitors. Validation was performed in SCLC cell lines and patient-derived xenograft models. Genome-wide RNA sequencing of xenograft tumors was performed to determine the mechanism underlying the synergy of the drug combination.ResultsInhibitors of the PI-3K-AKT-mTOR pathway were the top candidates from the screens. Among the therapeutics targeting this pathway, mTOR inhibitors showed the highest degree of synergy with BET inhibitors in vitro. Furthermore, the combination of these two classes of drugs showed superior antitumor efficacy and tolerability in vivo. Using both in vitro and in vivo SCLC models, we demonstrate that BET inhibitors activate the intrinsic apoptotic cascade, and mTOR inhibitors further enhance these apoptotic effects. Mechanistically, BET inhibitors activate the TSC2-mTOR-p70S6K1 signaling cascade by upregulating RSK3, an upstream kinase of TSC2. Activation of p70S6K1 leads to BAD phosphorylation and cell survival. mTOR inhibition blocks this survival signaling cascade and potentiates the antitumor effects of BET inhibitors.ConclusionsOur results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC, and mTOR inhibition can overcome this resistance and enhance apoptosis. These findings provide a rationale to evaluate the combination of mTOR and BET inhibitors in patients with SCLC.
Gene recruitments and dismissals in argonaut octopus genome provide insights to pelagic lifestyle adaptation and shell-like eggcase reacquisition
Authors: Yoshida Masa-aki , Hirota Kazuki , Imoto Junichi , Okuno Miki , Tanaka Hiroyuki , Kajitani Rei , Toyoda Atsushi , Itoh Takehiko , Ikeo Kazuho , Sasaki Takenori , Setiamarga Davin H. E. 
Published: November 2021

AbstractThe paper nautilus,Argonauta argo, also known as the greater argonaut, is a species of octopods distinctly characterized by its pelagic lifestyle and by the presence of a spiral-shaped shell-like eggcase in females. The eggcase functions by protecting the eggs laid inside it, and by building and keeping air intakes for buoyancy. To reveal the genomic background of the species’ adaptation to pelagic lifestyle and the acquisition of its shell-like eggcase, we sequenced the draft genome sequence of the species. The genome size was 1.1 Gb, which is the smallest among the cephalopods known to date, with the top 215 scaffolds (average length 5,064,479 bp) covering 81% (1.09 Gb) of the total assembly. A total of 26,433 protein-coding genes were predicted from 16,802 assembled scaffolds. From these, we identified nearly intact HOX, Parahox, Wnt clusters and some gene clusters probably related to the pelagic lifestyle, such asreflectin, tyrosinase, andopsin. For example,opsinmight have undergone an extensive duplication in order to adapt to the pelagic lifestyle, as opposed to other octopuses, which are mostly the benthic. Our gene models also discovered several genes homologous to those related to calcified shell formation in Conchiferan Mollusks, such as Pif-like, SOD, and TRX. Interestingly, comparative genomics analysis revealed that the homologous genes for such genes were also found in the genome of the octopus, which does not have a shell, as well as the basal cephalopodsNautilus. Therefore, the draft genome sequence ofA. argowe presented here had not only helped us to gain further insights into the genetic background of the dynamic recruitment and dismissal of genes for the formation of an important, converging extended phenotypic structure such as the shell and the shell-like eggcase, but also the evolution of lifestyles in Cephalopods and the octopods, from benthic to pelagic.
Mice infected with Mycobacterium tuberculosis are resistant to secondary infection with SARS-CoV-2
Authors: Mejia Oscar Rosas , Gloag Erin S. , Li Jianying , Ruane-Foster Marisa , Claeys Tiffany A. , Farkas Daniela , Farkas Laszlo , Xin Gang , Robinson Richard T. 
Published: November 2021

ABSTRACTMycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb. In both model systems, Mtb-infected mice were resistant to secondary CoV2 infection and its pathological consequences, and CoV2 infection did not affect Mtb burdens. Single cell RNA sequencing of coinfected and monoinfected lungs demonstrated the resistance of Mtb-infected mice is associated with expansion of T and B cell subsets upon viral challenge. Collectively, these data demonstrate that Mtb infection conditions the lung environment in a manner that is not conducive to CoV2 survival.AUTHOR SUMMARYMycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are distinct organisms which both cause lung disease. We report the surprising observation that Mtb-infected mice are resistant to secondary infection with CoV2, with no impact on Mtb burden and resistance associating with lung T and B cell expansion.
Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
Authors: Heo Dongeun , Ling Jonathan P. , Molina-Castro Gian C. , Langseth Abraham J. , Waisman Ari , Nave Klaus-Armin , Möbius Wiebke , Wong Philip C. , Bergles Dwight E. 
Published: November 2021

AbstractGeneration of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA binding protein TDP-43 occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation ofTardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43 deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult CNS induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.
LuxT is a Global Regulator of Low-Cell Density Behaviors Including Type III Secretion, Siderophore Production, and Aerolysin Production inVibrio harveyi
Authors: Eickhoff Michaela J. , Fei Chenyi , Cong Jian-Ping , Bassler Bonnie L. 
Published: November 2021

AbstractQuorum sensing (QS) is a chemical communication process in which bacteria produce, release, and detect extracellular signaling molecules called autoinducers. Via combined transcriptional and post-transcriptional regulatory mechanisms, QS allows bacteria to collectively alter gene expression on a population-wide scale. Recently, the TetR-family transcriptional regulator LuxT was shown to controlV. harveyi qrr1, encoding the Qrr1 small RNA that functions at the core of the QS regulatory cascade. Here, we use RNA-Sequencing to reveal that, beyond control ofqrr1, LuxT is a global regulator of 414V. harveyigenes including those involved in type III secretion, siderophore production, and aerolysin toxin biosynthesis. Importantly, LuxT directly repressesswrZ,encoding a GntR-family transcriptional regulator, and LuxT control of type III secretion, siderophore, and aerolysin genes occurs by two mechanisms, one that is SwrZ-dependent and one that is SwrZ-independent. All of these target genes specify QS-controlled behaviors that are enacted whenV. harveyiis at low cell density. Thus, LuxT and SwrZ function in parallel with QS to drive particular low cell density behaviors. Phylogenetic analyses reveal thatluxTis highly conserved amongVibrionaceae,butswrZis less well conserved. In a test case, we find that inAliivibrio fischeri,LuxT also repressesswrZ. SwrZ is a repressor ofA. fischerisiderophore production genes. Thus, LuxT repression ofswrZdrives activation ofA. fischerisiderophore gene expression. Our results indicate that LuxT is a major regulator amongVibrionaceae,and, in the species that also possessswrZ, LuxT functions with SwrZ to control gene expression.ImportanceBacteria precisely tune gene expression patterns to successfully react to changes that occur in the environment. Defining the mechanisms that enable bacteria to thrive in diverse and fluctuating habitats, including in host organisms, is crucial for a deep understanding of the microbial world and also for development of effective applications to promote or to combat particular bacteria. In this study, we show that a regulator called LuxT controls over 400 genes in the marine bacteriumVibrio harveyiand, moreover, that LuxT is highly conserved amongVibrionaceaespecies, ubiquitous marine bacteria that often cause disease. We characterize the mechanisms by which LuxT controls genes involved in virulence and nutrient acquisition. We show that LuxT functions in parallel with a set of regulators of the bacterial cell-to-cell communication process called quorum sensing to promoteV. harveyibehaviors at low cell density.
Potent antibody immunity to SARS-CoV-2 variants elicited by a third dose of inactivated vaccine
Authors: Ju Bin , Zhou Bing , Song Shuo , Fan Qing , Ge Xiangyang , Wang Haiyan , Cheng Lin , Guo Huimin , Shu Dan , Liu Lei , Zhang Zheng 
Published: November 2021

SummarySARS-CoV-2 variants are still prevalent worldwide and continue to pose a challenge to the effectiveness of current vaccines. It remains unknown whether a third dose of inactivated vaccine elicits immune potential against SARS-CoV-2 variants. Here, we showed a significant decline in plasma neutralization against SARS-CoV-2 at seven months after a second dose of the inactivated vaccine in a large-scale cohort. However, we also found that a third vaccination with an inactivated vaccine largely increased plasma neutralization against variants including Beta, Delta, and Lambda. More importantly, the high-affinity anti-RBD memory B cells were also generated by the third vaccination, suggesting a more potent and longer protection. These findings highlighted the importance and effectiveness of a third dose of inactivated vaccine in conferring higher protection against the emerging variants in populations.