bluuebunny/crossref_metadata_2025_split huggingface dataset:
METAbolomics data Balancing with Over-sampling Algorithms (META-BOA): an online resource for addressing class imbalance
Authors: Hashimoto-Roth Emily , Surendra Anuradha , Lavallée-Adam Mathieu , Bennett Steffany A. L. , Čuperlović-Culf Miroslava 
Published: May 2022

AbstractMotivationClass imbalance, or unequal sample sizes between classes, is an increasing concern in machine learning for metabolomic and lipidomic data mining, which can result in overfitting for the over-represented class. Numerous methods have been developed for handling class imbalance, but they are not readily accessible to users with limited computational experience. Moreover, there is no resource that enables users to easily evaluate the effect of different over-sampling algorithms.ResultsMETAbolomics data Balancing with Over-sampling Algorithms (META-BOA) is a web-based application that enables users to select between four different methods for class balancing, followed by data visualization and classification of the sample to observe the augmentation effects. META-BOA outputs a newly balanced dataset, generating additional samples in the minority class, according to the user’s choice of Synthetic Minority Over-sampling Technique (SMOTE), Borderline-SMOTE (BSMOTE), Adaptive Synthetic (ADASYN), or Random Over-Sampling Examples (ROSE). META-BOA further displays both principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE) visualization of data pre- and post-over-sampling. Random forest classification is utilized to compare sample classification in both the original and balanced datasets, enabling users to select the most appropriate method for their analyses.Availability and implementationMETA-BOA is available at https://complimet.ca/meta-boa.Supplementary InformationSupplementary material is available at Bioinformatics online.
ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma
Authors: Bacigalupa Zachary A. , Brown Whitney A. , Krystofiak Evan S. , Wolf Melissa M. , Hongo Rachel A. , Landis Madelyn , Amason Edith K. , Beckermann Kathryn E. , Rathmell Jeffrey C. , Rathmell W. Kimryn 
Published: May 2022

ABSTRACTClear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer driven by VHL loss and aberrant HIF-2α signaling. Acetate metabolism may contribute to this axis by ACSS2-dependent acetylation of HIF-2α and may provide opportunities to intervention. Here we tested the effects of pharmacological and genetic manipulation of ACSS2 on HIF-2α, ccRCC cells, and tumors. ACSS2 inhibition led to HIF-2α degradation and suppressed ccRCC growth in vitro, in vivo, and in primary cell cultures of ccRCC patient tumors. This treatment resulted in reduced glucose and cholesterol metabolism, mitochondrial biogenesis and altered cristae deformation, that are consistent with loss of HIF-2α. Mechanistically, HIF-2α protein levels are regulated through proteolytic degradation and we found, in parallel to VHL, HIF-2α stability was dependent on ACSS2 activity to prevent direct interaction with the E3 ligase MUL1. These findings highlight ACSS2 as a critical upstream regulator of HIF-2α that may be exploited to overcome resistance to HIF-2α inhibitor therapies.STATEMENT OF SIGNIFICANCEWe have unveiled ACSS2 as a critical upstream regulator of HIF-2α in ccRCC. Targeting ACSS2 potently promotes HIF-2α degradation via MUL1 to effectively deplete mitochondrial activity and block ccRCC primary tumor models and growth models resistant to HIF-2α inhibitor therapy.
Characterization of human immunodeficiency virus (HIV-1) envelope glycoprotein variants selected for resistance to a CD4-mimetic compound
Authors: Anang Saumya , Richard Jonathan , Bourassa Catherine , Goyette Guillaume , Chiu Ta-Jung , Chen Hung-Ching , Smith Amos B. , Madani Navid , Finzi Andrés , Sodroski Joseph 
Published: May 2022

ABSTRACTBinding to host cell receptors, CD4 and CCR5/CXCR4, triggers conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer that promote virus entry. CD4 binding allows the gp120 exterior Env to bind CCR5/CXCR4 and induces a pre-hairpin intermediate conformation in the gp41 transmembrane Env. Small-molecule CD4-mimetic compounds (CD4mcs) bind within the conserved Phe-43 cavity of gp120, near the binding site for CD4. CD4mcs inhibit HIV-1 infection by competing with CD4 and by prematurely activating Env, leading to irreversible inactivation. BNM-III-170 is a CD4mc that inhibits the infection of approximately 70% of HIV-1 strains at micromolar concentrations. We selected and analyzed variants of the primary HIV-1AD8 strain resistant to BNM-III-170. Two changes (S375N and I424T) in gp120 residues that flank the Phe-43 cavity each conferred ∼5-fold resistance to BNM- III-170 with minimal fitness cost. A third change (E64G) in Layer 1 of the gp120 inner domain resulted in ∼100-fold resistance to BNM-III-170, ∼2-3-fold resistance to soluble CD4-Ig, and a moderate decrease in viral fitness. The gp120 changes additively or synergistically contributed to BNM-III-170 resistance. The sensitivity of the Env variants to BNM-III-170 inhibition of virus entry correlated with their sensitivity to BNM-III-170- induced Env activation and shedding of gp120. The S375N and I424T changes, but not the E64G change, conferred resistance to BMS-806, a potent HIV-1 entry inhibitor that blocks Env conformational transitions. These studies identify pathways whereby HIV-1 can develop resistance to CD4mcs and BMS-806 conformational blockers, two classes of entry inhibitors that target the conserved gp120 Phe-43 cavity.IMPORTANCECD4-mimetic compounds (CD4mcs) and BMS-806 are small-molecule inhibitors of human immunodeficiency virus (HIV-1) entry into host cells. Although CD4mcs and BMS-806 inhibit HIV-1 entry by different mechanisms, they both target a pocket on the viral envelope glycoprotein (Env) spike that is used for binding to the receptor, CD4, and is highly conserved among HIV-1 strains. Our study identifies changes near this pocket that can confer various levels of resistance to the antiviral effects of both a CD4mc and BMS-806. We relate the antiviral potency of a CD4mc against this panel of HIV-1 variants to the ability of the CD4mc to activate changes in Env conformation and to induce the shedding of the gp120 exterior Env from the spike. These findings will guide efforts to improve the potency and breadth of small-molecule HIV-1 entry inhibitors.
Disruption of long-term psychological distress trajectories during the COVID-19 pandemic: evidence from three British birth cohorts
Authors: Moreno-Agostino Darío , Fisher Helen L. , Goodman Alissa , Hatch Stephani L , Morgan Craig , Richards Marcus , Das-Munshi Jayati , Ploubidis George B. 
Published: May 2022

AbstractImportanceMental health disorders were among the leading global contributors to years lived with disability prior to the COVID-19 pandemic onset, and growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until mid-life and then falls in both sexes, is unknown.ObjectiveTo analyse whether long-term pre-pandemic psychological distress trajectories have altered during the pandemic, and whether these changes have been different across generations and by sex.DesignCross-cohort study with prospective data collection over a 40-year period (earliest time point: 1981; latest time point: February/March 2021).SettingPopulation-based (adult general population), Great Britain.ParticipantsMembers of three nationally representative birth cohorts which comprised all people born in Great Britain in a single week of 1946, 1958, or 1970, and who participated in at least one of the data collection waves conducted after the start of the pandemic (40.6%, 42.8%, 39.4%, respectively).Exposure(s)Time, COVID-19 pandemic.Main Outcome(s) and Measure(s)Psychological distress factor scores, as measured by validated self-reported questionnaires.Results16,389 participants (2,175 from the 1946 birth cohort, 52.8% women; 7,446 from the 1958 birth cohort, 52.4% women; and 6,768 from the 1970 birth cohort, 56.2% women) participated in the study. By September/October 2020, psychological distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts: Standardised Mean Differences (SMD) and 95% confidence intervals (CIs) of -0.02 [-0.07, 0.04], 0.05 [0.02, 0.07], and 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively. Increases in distress were larger among women than men, widening the pre-existing inequalities observed in the pre-pandemic peak and in the most recent pre-pandemic assessment.Conclusions and RelevancePre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems.
Unhealthy lifestyle mediates the adverse effect of childhood traumas on acceleration of aging: analysis of 110,596 UK Biobank participants
Authors: Yang Gan , Cao Xingqi , Li Xueqin , Zhang Jingyun , Ma Chao , Zhang Ning , Lu Qingyun , Crimmins Eileen M. , Gill Thomas M. , Chen Xi , Liu Zuyun 
Published: May 2022

AbstractBackgroundAccelerated aging makes adults more vulnerable to chronic diseases and death. This study evaluates the association of childhood traumas with a phenotypic aging measure that captures mortality and morbidity risk, and the role of unhealthy lifestyle in mediating these associations.MethodsWe assembled data from 110,596 members of the UK Biobank aged 40-69 years who participated in the baseline survey (2006-2010) and online mental health questionnaire (2016). A phenotypic aging measure—Phenotypic Age Acceleration (PhenoAgeAccel) was calculated, with the higher value indicating the acceleration of aging. Body mass index, smoking status, alcohol consumption, physical activity, and diet were combined to construct an unhealthy lifestyle score (range: 0-5). Childhood traumas including physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse were assessed. General linear regression and formal mediation analysis were performed.ResultsEach individual childhood trauma and cumulative childhood traumas were significantly associated with PhenoAgeAccel. For instance, compared with participants who did not experience childhood traumas, those who experienced four (β=0.292, standard error [SE]: 0.091) or five childhood traumas had higher PhenoAgeAccel (β=0.669, SE: 0.169) in fully adjusted models. The formal mediation analysis revealed that unhealthy lifestyle partially mediated the associations of childhood traumas with PhenoAgeAccel (26.1%-42.6%).ConclusionsIn a large sample from UKB, childhood traumas were positively associated with acceleration of aging; and more importantly, unhealthy lifestyle partially mediated these associations. These findings reveal a novel pathway from childhood traumas to late-life health through lifestyle and underscore the potential of more psychological strategies beyond lifestyle interventions to promote healthy aging.
Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform
Authors: Wing Kevin , Grint Daniel J , Mathur Rohini , Gibbs Hamish P , Hickman George , Nightingale Emily , Schultze Anna , Forbes Harriet , Nafilyan Vahé , Bhaskaran Krishnan , Williamson Elizabeth , House Thomas , Pellis Lorenzo , Herrett Emily , Gautam Nileesa , Curtis Helen J , Rentsch Christopher T , Wong Angel YS , MacKenna Brian , Mehrkar Amir , Bacon Seb , Douglas Ian J , Evans Stephen JW , Tomlinson Laurie , Goldacre Ben , Eggo Rosalind M 
Published: May 2022

AbstractEthnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in wave 1 (01/02/2020-31/08/2020) and 2 731 427 in wave 2 (01/09/2020-31/01/2021). Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves (e.g. wave 2, 67+ living with 3 other generations vs 67+ year olds only: White HR 1·61 95% CI 1·38-1·87, South Asian HR 1·76 95% CI 1·48-2·10), with a trend for increased risks of severe COVID-19 with increasing generations in wave 2. Multigenerational living was associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics.FundingThis research was funded in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Crosslinker design determines microtubule network organization by opposing motors
Authors: Henkin Gil , Chew Wei-Xiang , Nédélec François , Surrey Thomas 
Published: May 2022

ABSTRACTDuring cell division, crosslinking motors determine the architecture of the spindle, a dynamic microtubule network that segregates the chromosomes. It is unclear how motors with opposite directionality coordinate to drive both contractile and extensile behaviors in the spindle. Particularly, the impact of different crosslinker designs on network self-organization is not understood, limiting our understanding of self-organizing structures in cells, but also our ability to engineer new active materials. Here, we use experiment and theory to examine active microtubule networks driven by mixtures of motors with opposite directionality and different crosslinker design. We find that although the kinesin-14 HSET causes network contraction when dominant, it can also assist the opposing kinesin-5 KIF11 to generate extensile networks. This bifunctionality results from HSET’s asymmetric design, distinct from symmetric KIF11. These findings expand the set of rules underlying patterning of active microtubule assemblies and allow a better understanding of motor cooperation in the spindle.SIGNIFICANCE STATEMENTDuring cell division, the spindle apparatus segregates duplicated chromosomes for their inheritance by the daughter cells. The spindle is a highly interconnected network of microtubule filaments that are crosslinked by different types of molecular motors. How the different motors cooperate to organize the spindle network is not understood. Here, we show that an asymmetric crosslinker design can confer bifunctionality to a mitotic motor in the presence of other motors. The asymmetric motor supports both extensile and contractile microtubule network behaviors as observed in different parts of the spindle. These findings define new rules controlling the generation of active microtubule networks and allow us to better understand how motors cooperate to organize the correct spindle architecture when a cell divides.
Spt4 drives cellular senescence by activating non-coding RNA transcription in ribosomal RNA gene clusters
Authors: Yokoyama Masaaki , Sasaki Mariko , Kobayashi Takehiko 
Published: May 2022

SUMMARYGenome instability can drive aging in many organisms. The ribosomal RNA gene (rDNA) cluster is one of the most unstable regions in the genome. Replicative lifespan in budding yeast is correlated to rDNA stability, suggesting that the rDNA locus produces an aging signal. To understand the underlying mechanism, we looked for yeast mutants with more stable rDNA and longer lifespan than wild-type cells. We reveal that absence of a transcription elongation factor, Spt4, resulted in an increased rDNA stability, a reduced activity of the regulatory E-pro promoter in the rDNA, and extended replicative lifespan in a SIR2-dependent manner. Spt4-dependent lifespan restriction was abolished in the absence of non-coding RNA transcription at the E-pro locus. The amount of Spt4 increases and its function becomes more important as cells age. These findings suggest that Spt4 is a promising aging factor that accelerates cellular senescence through rDNA instability driven by non-coding RNA transcription
Enhanced Mirror Neuron Network Activity and Effective Connectivity during Live Interaction Among Female Subjects
Authors: Hsu Chun-Ting , Sato Wataru , Kochiyama Takanori , Nakai Ryusuke , Asano Kohei , Abe Nobuhito , Yoshikawa Sakiko 
Published: May 2022

AbstractFacial expressions are indispensable in daily human communication. Previous neuroimaging studies investigating facial expression processing have presented pre-recorded stimuli and lacked live face-to-face interaction. Our paradigm alternated between presentations of real-time model performance and pre-recorded videos of dynamic facial expressions to participants. Simultaneous functional magnetic resonance imaging (fMRI) and facial electromyography activity recordings, as well as post-scan valence and arousal ratings were acquired from 44 female participants. Live facial expressions enhanced the subjective valence and arousal ratings as well as facial muscular responses. Live performances showed greater engagement of the right posterior superior temporal sulcus (pSTS), right inferior frontal gyrus (IFG), right amygdala and right fusiform gyrus, and modulated the effective connectivity within the right mirror neuron system (IFG, pSTS, and right inferior parietal lobule). A support vector machine algorithm could classify multivoxel activation patterns in brain regions involved in dynamic facial expression processing in the mentalizing networks (anterior and posterior cingulate cortex). These results indicate that live social interaction modulates the activity and connectivity of the right mirror neuron system and enhances spontaneous mimicry, further facilitating emotional contagion.HighlightsWe alternately presented real-time and pre-recorded dynamic facial expressions.Live facial expressions enhanced emotion contagion and spontaneous facial mimicry.Live conditions modulated mirror neuron system activity and effective connectivity.The mentalizing network showed distinctive multivoxel patterns in live conditions.The results support the validity of second-person design in social neuroscience.
Paracrine factors of stressed peripheral blood mononuclear cells activate pro-angiogenic and anti-proteolytic processes in whole blood cells and protect the endothelial barrier
Authors: Copic Dragan , Direder Martin , Schossleitner Klaudia , Laggner Maria , Klas Katharina , Bormann Daniel , Ankersmit Hendrik Jan , Mildner Michael 
Published: May 2022

AbstractTissue regenerative properties have been attributed to secreted paracrine factors derived from stem cells and other cell types. Especially, the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) has been shown to possess high tissue-regenerative and pro-angiogenic capacities in a variety of preclinical studies. In the light of future therapeutic intravenous applications of PBMCsec, we investigated possible effects of PBMCsec on circulating white blood cells and endothelial cells lining the vasculature.MethodsTo identify changes in the transcriptional profile of white blood cells treated with PBMCSec, whole blood was drawn from healthy individuals and stimulated with PBMCsec for 8 hours ex vivo before further processing for single cell RNA sequencing (scRNAseq). In addition, we performed in vitro assay to confirm findings arising from the transcriptional profiling.ResultsAddition of PBMCsec to whole blood significantly altered the gene signature of granulocytes (17 genes), T-cells (45 genes), B-cells (72 genes) and most prominently monocytes (322 genes). We detected a strong upregulation of several tissue-regenerative and pro-angiogenic cyto- and chemokines in monocytes, including VEGFA, CXCL1 and CXCL5. Intriguingly, inhibitors of endopeptidase activity, such as SERPINB2, were also strongly induced. Measurement of the trans-endothelial electrical resistance of primary human microvascular endothelial cells revealed a strong barrier-protective effect of PBMCsec after barrier disruption.ConclusionTogether, we show that PBMCsec induces angiogenic and proteolytic processes in the blood and is able to attenuate endothelial barrier damage. These regenerative properties suggest that systemic application of PBMCsec might be a promising novel strategy to restore damaged organs.
CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission
Authors: Li Lei , Liu Haowen , Qian Kang-Ying , Nurrish Stephen , Zeng Xian-Ting , Zeng Wan-Xin , Wang Jiafan , Kaplan Joshua M , Tong Xia-Jing , Hu Zhitao 
Published: May 2022

AbstractChanges in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2’s AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.