bluuebunny/crossref_metadata_2025_split huggingface dataset:
Valence-partitioned learning signals drive choice behavior and phenomenal subjective experience in humans
Authors: Sands L. Paul , Jiang Angela , Jones Rachel E. , Trattner Jonathan D. , Kishida Kenneth T. 
Published: March 2023

SUMMARYHow the human brain generates conscious phenomenal experience is a fundamental problem. In particular, it is unknown how variable and dynamic changes in subjective affect are driven by interactions with objective phenomena. We hypothesize a neurocomputational mechanism that generates valence-specific learning signals associated with ‘what it is like’ to be rewarded or punished. Our hypothesized model maintains a partition between appetitive and aversive information while generating independent and parallel reward and punishment learning signals. This valence-partitioned reinforcement learning (VPRL) model and its associated learning signals are shown to predict dynamic changes in 1) human choice behavior, 2) phenomenal subjective experience, and 3) BOLD-imaging responses that implicate a network of regions that process appetitive and aversive information that converge on the ventral striatum and ventromedial prefrontal cortex during moments of introspection. Our results demonstrate the utility of valence-partitioned reinforcement learning as a neurocomputational basis for investigating mechanisms that may drive conscious experience.HighlightsTD-Reinforcement Learning (RL) theory interprets punishments relative to rewards.Environmentally, appetitive and aversive events are statistically independent.Valence-partitioned RL (VPRL) processes reward and punishment independently.We show VPRL better accounts for human choice behavior and associated BOLD activity.VPRL signals predict dynamic changes in human subjective experience.
A biophysical framework for double-drugging kinases
Authors: Kim C. , Ludewig H. , Hadzipasic A. , Kutter S. , Nguyen V. , Kern D. 
Published: March 2023

AbstractOrthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as “double-drugging”, has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not been undertaken. Here, we provide a quantitative framework for double-drugging of kinases employing isothermal titration calorimetry, Förster resonance energy transfer, coupled-enzyme assays, and X-ray crystallography. We discern positive and negative cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with different combinations of orthosteric and allosteric modulators. We find that a conformational equilibrium shift is the main principle governing this cooperative effect. Notably, for both kinases, we find a synergistic decrease of the required orthosteric and allosteric drug dosages when used in combination to inhibit kinase activities to clinically relevant inhibition levels. X-ray crystal structures of the doubledrugged kinase complexes reveal the molecular principles underlying the cooperative nature of double-drugging AurA and Abl with orthosteric and allosteric inhibitors. Finally, we observe the first fully-closed conformation of Abl when bound to a pair of positively cooperative orthosteric and allosteric modulators, shedding light onto the puzzling abnormality of previously solved closed Abl structures. Collectively, our data provide mechanistic and structural insights into rational design and evaluation of doubledrugging strategies.
Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis
Authors: Armstrong Claire , Passanisi Victor J. , Ashraf Humza M. , Spencer Sabrina L. 
Published: March 2023

SummaryFaithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this change in histone biosynthesis as DNA replication begins. Here, we use single-cell timelapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the Restriction Point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert.
T6SS-mediated competitive exclusion amongPantoea agglomeransassociated with plants
Authors: Ripcke Kai , Picazo Devani Romero , Vichare Shreya , Unterweger Daniel , Dagan Tal , Hülter Nils F. 
Published: March 2023

AbstractEstablishment of symbiotic interactions with a host habitat depends on colonization success of the microbiome members. One route to success is increasing competitiveness against genotypes having similar adaptations. Many bacteria deploy the type VI secretion system (T6SS) to deliver toxic effector proteins into the cytoplasm of competing cells, whereas the attacking cells are protected from self-intoxication by immunity proteins. While the evolution of antagonistic interactions between species competing for similar niches is expected, the interactions between closely related strains having a similar core genetic makeup, remains understudied. Here we show that the strength of T6SS-mediated competition between closely relatedP. agglomeransstrains is not associated with phylogenetic relatedness and rather depends on their effector and immunity genes repertoire. Annotating the T6SS components in elevenP. agglomeransisolates from wheat seeds, we observed a heterogeneous composition of effector and immunity determinants. Competition experiments further showed profound differences in the strain survival following reciprocal T6SS-mediated interactions. Reconstructing the evolution of T6SS loci across plant-associatedP. agglomeransisolates indicates intra-chromosomal recombination as the main driver of effector and immunity gene diversification. Our results provide empirical data on intraspecific interactions during microbiota assembly likely to be at play during colonization of germinating plant seeds.
AttenuatedMycobacterium tuberculosisVaccine Protection in a Low Dose Murine Challenge Model
Authors: Vidal Samuel J. , Sellers Daniel , Yu Jingyou , Wakabayashi Shoko , Sixsmith Jaimie , Aid Malika , Barrett Julia , Stevens Sage F. , Liu Xiaowen , Li Wenjun , Plumlee Courtney R. , Urdahl Kevin B. , Martinot Amanda J. , Barouch Dan H. 
Published: March 2023

AbstractBacillus Calmette–Guérin (BCG) remains the only clinically approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next generation TB vaccines have typically used a murine aerosol challenge model that employs a high supraphysiologic challenge dose. Here we show that the protective efficacy of a live attenuatedMycobacterium tuberculosis(Mtb) vaccine candidate ΔLprG markedly exceeds that of BCG in a low dose murine aerosol challenge model. BCG vaccination reduced bacterial loads but failed to prevent establishment or dissemination of infection in this model. In contrast, ΔLprG prevented detectable infection in 61% of mice and resulted in striking anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low dose challenge model, which revealed serum IL-17A, IL-6, CXCL2, CCL2, IFN-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides strikingly increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low dose murine challenge model.
CRISPR-ChIP delineates a Menin-dependent oncogenic DOT1L complex in MLL- leukaemia
Authors: Gilan Omer , Bell Charles C. , Talarmain Laure , Neville Daniel , Knezevic Kathy , Ferguson Daniel , Boudes Marion , Chan Yih-Chih , Davidovich Chen , Lam Enid Y.N. , Dawson Mark A. 
Published: March 2023

SummaryThe regulation of all chromatin-templated processes involves the selective recruitment of chromatin factors to facilitate DNA repair, replication, and transcription. Chromatin immunoprecipitation (ChIP) is a critical experimental method used to provide spatiotemporal evidence for the coordination of these chromatin-based events including the dynamic regulation of chromatin modifications at cis-regulatory elements. However, obtaining a global appreciation of all the factors that influence a specific chromatin event has remained challenging. Here, as a proof of concept we demonstrate the utility of coupling unbiased functional genomics with ChIP to identify the factors associated with active transcription. Specifically, we use this method to identify the major chromatin factors associated with the catalysis of two evolutionarily conserved histone modifications; H3K4me3 present at the transcriptional start site and H3K79me2 present through the gene body of actively transcribed genes. With CRISPR-ChIP, we identify all the non-redundant COMPASS complex members required for H3K4me3 and demonstrate that RNA polymerase II is dispensable for the maintenance of H3K4me3. As H3K79me2 has a putative oncogenic function in leukaemia cells driven by MLL-translocations, using CRISPR-ChIP we reveal a functional partitioning of H3K79 methylation into two distinct regulatory units. An oncogenic DOT1L complex, where the malignant driver directs the catalytic activity of DOT1L at MLL-Fusion target genes and a separate endogenous DOT1L complex, where catalytic activity is directed by MLLT10. This functional demarcation provides an explanation for the observed synergy with Menin and DOT1L inhibitors and why Menin inhibition surprisingly controls methylation of H3K79 at a critical subset of genes that sustain MLL-fusion leukaemia. Overall, CRISPR-ChIP provides a powerful tool for the unbiased interrogation of the mechanisms underpinning chromatin regulation.
Ozone mediates tumor-selective cell death caused by air plasma-activated medium independently of NOx
Authors: Suzuki-Karasaki Manami , Ochiai Yushi , Innami Shizuka , Okajima Hiroshi , Suzuki-Karasaki Miki , Nakayama Hideki , Suzuki-Karasaki Yoshihiro 
Published: March 2023

AbstractCold atmospheric plasma and plasma-treated liquids (PTLs) are emerging promising tools for tumor-targeted cancer treatment, as they preferentially injure tumor cells more than non-malignant cells. Oxidative stress is critical to the antitumor effect, but the oxidant mediating the effect is debatable. Previously, we reported that air plasma-activated medium (APAM) has tumor-selective cytotoxicity in vitro and in vivo. Moreover, an unusual mitochondrial positioning named monopolar perinuclear mitochondrial clustering (MPMC) and nuclear damage proceeds to cell death. We noticed that air plasma generation was accompanied by ozone (O3) formation, leading to suppose the possible role of O3in the effect of APAM. In this study, we produced an O3-dissolved medium (ODM) and comparatively analyzed its biological effect with APAM. Both agents had comparable amounts of dissolved O3(dO3), while APAM, but not ODM, contained nitrite and nitrate. Like APAM, ODM could induce apoptosis, nonapoptotic cell death, tubulin remodeling, MPMC, and nuclear shrinkage. Catalase mitigated all these events. The increases in various intracellular and mitochondrial reactive oxygen species (ROS) and lipid peroxides proceeded to cell death, and catalase also prevented them. Conversely, suppressing cellular H2O2removal systems augmented mitochondrial ROS production and cell death. In contrast, like APAM, ODM minimally increased ROS production and MPMC in non-malignant cells. These results indicate that dO3is a critical mediator of the actions of APAM, including tumor-selective induction of MPMC and cell death. Our findings suggest ODM could be a more chemically-defined alternative to PTLs in cancer treatment.
The streptococcal phase-variable Type I Restriction-Modification system SsuCC20p dictates the methylome ofStreptococcus suisand impacts virulence
Authors: Roodsant Thomas J. , van der Putten Boas , Brizuela Jaime , Coolen Jordy P.M. , Baltussen Tim J.H. , Schipper Kim , Pannekoek Yvonne , Van der Ark Kees C.H. , Schultsz Constance 
Published: March 2023

AbstractPhase-variable Type I Restriction Modification (RM) systems are epigenetic regulatory systems that have been identified in numerous human bacterial pathogens. We previously showed that an emerging zoonotic lineage ofStreptococcus suisacquired a phase-variable Type I RM system named SsuCC20p. The SsuCC20p locus was present in the genome of disease-associated isolates from multiple streptococcal species. This indicates that it is not restricted toS. suisand can be acquired through horizontal gene transfer. We demonstrate that SsuCC20p phase-variability relies on a recombinase present within the locus.In vitro, only SsuCC20p is responsible for the genome methylation profiles that were detected in the representative zoonoticS. suisisolate 861160. In addition, we show that, contrary to previous observations,hsdSgenes located downstream of thehsdMgene and the recombinase gene, can contribute to the SsuCC20p genome methylation profile. SsuCC20p locked mutants expressing a singlehsdSeach showed unique genome methylation profiles. The differential genome methylation of the distinct locked mutants caused phase dependent differences in global gene expression in a growth condition dependent manner. We observed significant differences in virulence betweenhsdSlocked mutants in a zebrafish larvae infection model. These data indicate that the streptococcal phase-variable Type I RM system SsuCC20p can impact bacterial virulence via epigenetic regulation of gene expression and potentially contributes to the zoonotic potential ofS. suis.ImportancePhase-variation contributes to the virulence of bacterial pathogens as it allows a single strain to produce phenotypic diverse subpopulations. Phase-variable Restriction Modification (RM) systems are systems that allow for such phase-variation via epigenetic regulation of gene expression levels. The phase-variable RM system SsuCC20p was found in multiple streptococcal species and was acquired by an emerging zoonotic lineage ofStreptococcus suis. We show that the phase-variability of SsuCC20p is dependent on a recombinase encoded within the SsuCC20p locus. We characterized the genome methylation profiles of the different phases of SsuCC20p and showed that the differential genome methylation within the phases causes differences in gene expression levels and virulence. Altogether, we show that the acquisition of a phase-variable RM system impacts virulence and can potentially contribute to the zoonotic potential ofS. suis. Bacterial pathogens can increase their virulence through acquisition of mobile elements containing epigenetic regulatory systems such as RM systems.
The ELEMI healthcare professional Study
Authors: Delanerolle Gayathri , Li Yunshan , Cavalini Heitor , Barnard-Kelly Katharine , Elliot Katheryn , Raymont Vanessa , Pluchino Nicola , Flores Idaliz , Elneil Sohier , Majumder Kingshuk , Welsh Amy Boyd , Sillem Martin , Hull M. Louise , O’Hara Rebecca , Rathod Shanaya , Shetty Ashish , Shi Jian Qing , Hapangama Dharani K , Phiri Peter 
Published: March 2023

AbstractIntroductionEndometriosis impacts 1 in 10 women and can be a debilitating disease. Late diagnosis is a major challenge with Endometriosis, contributing further to the exacerbation of symptoms and suboptimal clinical management. Regardless of the commonality of the condition, public awareness and research around endometriosis is severely lacking.MethodsTo explore the knowledge base about Endometriosis we developed a digital cross-sectional study. We used the Qualtrics XM platform and developed a questionnaire. The primary objective of the study was to report the understanding of Endometriosis among healthcare professionals in a mental healthcare setting in the UK.ResultsWe gathered the responses of 144 healthcare professionals, although only 68 participants responded to all questions. Approximately 96% of participants agreed that there is a need for a comprehensive clinical strategy where mental health care services could assist women very early in the pathway. Around 63.1% confirmed awareness of endometriosis although the χ2(p-value=0.158) test showed that the perceived clinical knowledge was not necessarily associated with their profession. Over 92% of participants confirmed that it would be useful to conduct mental health-based research among endometriosis patients.DiscussionIt is clear than patients with endometriosis would greatly benefit from a streamlined clinical pathway. It would also have financial benefits to the NHS, including less visits to A&E. The absence of comprehensive knowledge and understanding amongst healthcare professional on endometriosis leads to delayed diagnosis and treatment, exacerbating their psychological and physiological symptoms.ConclusionsOur study shows the importance of funding mental health research to further add to the body of knowledge in order to develop evidence based clinical practices that are equally acceptable to women with endometriosis. This will have benefits for both the patients, healthcare professional, and also the NHS. It will enable for better treatment pathways and symptom management, aiding the development for improved healthcare policies.
Poor Oral Health Is Associated with Worse Brain Imaging Profiles
Authors: Rivier Cyprien A. , Renedo Daniela , de Havenon Adam , Gill Thomas M. , Payabvash Sam , Sheth Kevin N. , Falcone Guido J. 
Published: March 2023

ABSTRACTImportancePoor oral health is a modifiable risk factor that is associated with a variety of health outcomes. However, the relationship between oral and brain health is not well understood.ObjectiveTo test the hypothesis that poor oral health is associated with worse neuroimaging brain health profiles in persons without stroke or dementia.DesignWe conducted a 2-stage cross-sectional neuroimaging study using data from the UK Biobank (UKB). First, we tested for association between self-reported poor oral health and MRI neuroimaging markers of brain health. Second, we used Mendelian Randomization (MR) analyses to test for association between genetically-determined poor oral health and the same neuroimaging markers.SettingOngoing population study in the United Kingdom. The UKB enrolled participants between 2006 and 2010. Data analysis was performed from September 1, 2022, to January 10, 2023.Participants40,175 persons aged 40 to 70 enrolled between 2006 to 2010 who underwent a dedicated research brain MRI between 2012 and 2013.ExposuresDuring MRI assessment, poor oral health was defined as the presence of dentures or loose teeth. As instruments for the MR analysis, we used 116 independent DNA sequence variants known to significantly increase the composite risk of decayed, missing, or filled teeth and dentures.Main Outcomes and MeasuresAs neuroimaging markers of brain health, we assessed the volume of white matter hyperintensities (WMH), as well as aggregate measures of fractional anisotropy (FA) and mean diffusivity (MD), two metrics indicative of white matter tract disintegrity obtained through diffusion tensor imaging. These measurements were evaluated across 48 distinct brain regions, with FA and MD values for each region also considered as individual outcomes for the MR method.ResultsAmong study participants, 5,470 (14%) had poor oral health. We found that poor oral health was associated with a 9% increase in WMH volume (beta = 0.09, standard deviation (SD) = 0.014, p P< 0.001), a 10% change in the aggregate FA score (beta = 0.10, SD = 0.013, P < 0.001), and a 5% change in the aggregate MD score (beta = 0.05, SD = 0.013, P < 0.001). Genetically-determined poor oral health was associated with a 30% increase in WMH volume (beta = 0.30, SD = 0.06, P < 0.001), a 43% change in aggregate FA score (beta = 0.42, SD = 0.06, P < 0.001), and an 10% change in aggregate MD score (beta = 0.10, SD = 0.03, P = 0.01).Conclusions and RelevanceAmong middle age Britons without stroke or dementia enrolled in a large population study, poor oral health was associated with worse neuroimaging brain health profiles. Genetic analyses confirmed these associations, supporting a potential causal association. Because the neuroimaging markers evaluated in the current study are established risk factors for stroke and dementia, our results suggest that oral health may be a promising target for interventions focused on improving brain health.
The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype
Authors: Field Jared T. , Chapman Donald , Hai Yan , Ghavami Saeid , West Adrian R. , Ozerklig Berkay , Saleem Ayesha , Kline Julia , Mendelson Asher A. , Kindrachuk Jason , Triggs-Raine Barbara , Gordon Joseph W. 
Published: March 2023

AbstractMitochondrial quality control is critical in muscle to ensure both contractile and metabolic function. Nix is a BCL-2 family member, mitophagy receptor, and has been implicated in muscle atrophy. Human GWAS suggests altered Nix expression could predispose to manifestations of mitochondrial disease. To interrogate Nix function, we generated a muscle-specific knockout model. Nix knockout mice displayed a ragged-red fibre phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, Nix knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibres. Kinome- and gene expression analyses revealed that Nix knockout impairs NFAT and canonical myostatin signaling, with alterations in muscle fibre-type composition and evidence of regeneration. Mechanistic experiments demonstrated that Nix modulates mitophagy, along with ER-phagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for Nix coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.
Variational Log-Gaussian Point-Process Methods for Grid Cells
Authors: Rule Michael Everett , Chaudhuri-Vayalambrone Prannoy , Krstulovic Marino , Bauza Marius , Krupic Julija , O’Leary Timothy 
Published: March 2023

AbstractWe present practical solutions to applying Gaussian-process methods to calculate spatial statistics for grid cells in large environments. Gaussian processes are a data efficient approach to inferring neural tuning as a function of time, space, and other variables. We discuss how to design appropriate kernels for grid cells, and show that a variational Bayesian approach to log-Gaussian Poisson models can be calculated quickly. This class of models has closed-form expressions for the evidence lower-bound, and can be estimated rapidly for certain parameterizations of the posterior covariance. We provide an implementation that operates in a low-rank spatial frequency subspace for further acceleration, and demonstrate these methods on experimental data.