bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping chromatin interactions at melanoma susceptibility loci and cell-type specific dataset integration uncovers distant gene targets ofcis-regulation
Authors: Thakur Rohit , Xu Mai , Sowards Hayley , Yon Joshuah , Jessop Lea , Myers Timothy , Zhang Tongwu , Chari Raj , Long Erping , Rehling Thomas , Hennessey Rebecca , Funderburk Karen , Yin Jinhu , Machiela Mitchell J. , Johnson Matthew E. , Wells Andrew D. , Chesi Alessandra , Grant Struan F.A. , Iles Mark M. , Landi Maria Teresa , Law Matthew H. ,   Melanoma Meta-Analysis Consortium, Choi Jiyeon , Brown Kevin M. 
Published: November 2024

ABSTRACTGenome-wide association studies (GWAS) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping cell-type specific chromatin interactions. We performed a melanoma GWAS region-focused capture-HiC assay in human primary melanocytes to identify physical interactions between fine-mapped risk variants and potential causal melanoma susceptibility genes. Overall, chromatin interaction data alone nominated potential causal genes for 61 of the 68 melanoma risk signals, identifying many candidates beyond those reported by previous studies. We further integrated these data with cell-type specific epigenomic (chromatin state, accessibility), gene expression (eQTL/TWAS), DNA methylation (meQTL/MWAS), and massively parallel reporter assay (MPRA) data to prioritize potentiallycis-regulatory variants and their respective candidate gene targets. From the set of fine-mapped variants across these loci, we identified 140 prioritized candidate causal variants linked to 195 candidate genes at 42 risk signals. In addition, we developed an integrative scoring system to facilitate candidate gene prioritization, integrating melanocyte and melanoma datasets. Notably, at several GWAS risk signals we observed long-range chromatin connections (500 kb to >1 Mb) with distant candidate target genes. We validated several suchcis-regulatory interactions using CRISPR inhibition, providing evidence for known cancer driver genesMDM4andCBL, as well as the SRY-box transcription factorSOX4, as likely melanoma risk genes.
Comorbidities associated with chronic kidney disease among young people living with HIV in Uganda. A nested case control study
Authors: Nasuuna Esther M , Tomlinson Laurie A , Kalyesubula Robert , Castelnuovo Barbara , Nanyeenya Nicholus , Dziva Chikwari Chido , Weiss Helen A 
Published: November 2024

AbstractIntroductionChronic kidney disease (CKD) is often complicated by disorders in multiple body systems, associated with higher mortality and morbidity. Young people living with HIV (YPLHIV) have an increased risk of multisystem chronic comorbidities. However, there are few data describing comorbidities associated with CKD among YPLHIV.MethodsWe conducted a case-control study in seven ART clinics in Kampala, Uganda. Cases were YPLHIV (aged 10-24 years) diagnosed with CKD and controls were those without CKD. We collected data on demographic and clinical factors: blood pressure, fasting glucose levels, anaemia, electrolytes, parathyroid hormone, and cognitive impairment. We summarized the demographic and clinical factors and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals for associations between CKD comorbidities, adjusted for age, sex and viral suppression.ResultsA total of 292 participants (96 cases and 196 controls) were recruited. Cases were mostly male (59.4% vs 36.5%), and younger (88.5% vs 46.4% aged <17 years) compared to controls. CKD was associated with having a detectable HIV viral load (OR=3.73; 95% CI 1.53-9.12) and proteinuria (aOR=4.19; 95% CI 2.28-7.72). CKD was also associated with low haematocrit, hypochloraemia, hyperphosphatemia, and high mean corpuscular volume. There was no evidence of an association of CKD with hypertension, anaemia, or stunting.ConclusionThe pattern of comorbidities among YPLHIV with CKD is uncertain and difficulties may relate to difficulty determining true kidney function and normal ranges in this population. Further studies are needed to discern the pattern of CKD complications to improve management efforts and clinical outcomes.
Matching Clinical Profiles with Interventions to Optimize Daily Stepping in People with Stroke
Authors: McCartney Kiersten M. , Pohlig Ryan T. , Miller Allison , Thompson Elizabeth D. , Reisman Darcy 
Published: November 2024

ABSTRACTBackgroundIndividualizing interventions is imperative to optimize physical activity in people with chronic stroke. This secondary analysis grouped individuals with chronic stroke into clinical profiles based on baseline characteristics and examined if these clinical profiles preferentially benefitted from a specific rehabilitation intervention to improve daily step-activity.MethodsParticipants had non-cerebellar strokes ≥6 months prior to enrollment, were 21-85 years old, had walking speeds of 0.3-1.0 m/s, and took <8,000 steps-per-day. Participants were randomized to 1 of 3 interventions: high-intensity treadmill training (FAST), a step-activity behavioral intervention (SAM), or a combined intervention (FAST+SAM). The primary outcome was the interaction of latent class (clinical profile) and intervention group (FAST, SAM, FAST+SAM) on a change in steps-per-day. Key clinical characteristics to identify the latent classes included walking speed, walking endurance, balance self-efficacy, cognition, and area deprivation.ResultsOf the 190 participants with complete pre- and post-intervention data (mean [SD] age, 64 [12] years; 93 females [48.9%]), 3 distinct profiles of people with chronic stroke were identified. Within our sample, class 1 had the lowest walking capacity (speed and endurance), lowest balance self-efficacy, and highest area deprivation, and had the greatest change in step-activity when enrolled in the SAM (mean[95%CI], 1624 [426 – 2821]) or FAST+SAM (1150 [723 – 1577]) intervention. Class 2 had walking capacity, baseline steps-per-day, and self-efficacy values between Class 1 and 3, and had the greatest change in step-activity when enrolled in the SAM (2002 [1193–2811]) intervention. Class 3 had the highest walking capacity, highest self-efficacy, and lowest area deprivation and the greatest change in step-activity when enrolled in the FAST+SAM (1532 [915–2150]) intervention.ConclusionsPeople with chronic stroke require different interventions to optimize a change in step-activity. Clinicians can use clinically relevant measures to personalize intervention selection to augment step-activity in people with chronic stroke.Trial RegistrationNCT02835313;https://clinicaltrials.gov/ct2/show/NCT02835313
Prevent with Pleasure: A systematic review of HIV public communication campaigns incorporating a pleasure-based approach
Authors: Muschialli Luke , Ford Jessie V. , Gonsalves Lianne , Pralat Robert 
Published: November 2024

AbstractPrevious research suggests integrating pleasure into HIV prevention programming improves health outcomes. There are no existing reviews on how exactly pleasure is used within HIV public communications campaigns (PCCs). This manuscript investigates: (1) how HIV PCCs operationalise pleasure; and (2) the efficacy of pleasure-based HIV PCCs. EMBASE, Web of Science Core Collection and PsycINFO were searched for articles that present pleasure-based HIV PCCs on 13/12/2023 (PROSPERO ID: CRD42023487275) with no language restrictions. A narrative synthesis on pleasure operationalisation centred around three inductively coded categories:Enjoyment,Emotional ConnectionandEmpowerment. Another narrative synthesis summarised efficacy data around six categories of HIV-related outcomes. 19,238 articles were retrieved, with 47 articles included in analysis, describing 29 campaigns. 65.5% of interventions operationalisedEmpowerment, 48.3%Enjoyment, and 31.0%Emotional Connection, with narrative synthesis highlighting the diverse ways this was achieved across target communities. An analysis of efficacy identified heterogeneous outcome reporting with inconsistent results across studies, but important outcomes, such as stigma reduction and condom use, were positively associated with intervention exposure across all interventions. We highlight a range of mechanisms through which pleasure can be operationalised, which should inform future intervention development, even if the extant literature weakly supports the efficacy of such interventions.
Whole-Slide ECM Imaging Reveals Dense Fibrous Matrix as a High-Risk Factor for Recurrence in Stage II Colon Cancer
Authors: Ravensbergen C.J. , Colaco V.S. , Putter H. , Crobach A.S.L.P. , Boonstra J. , Lindeman J.H.F. , Tollenaar R.A.E.M. , Mesker W.E. 
Published: November 2024

AbstractIntroductionThe extracellular matrix (ECM) supports tumor progression by influencing tumor cell migration and invasion. This study examines the link between peritumoral ECM morphology and five-year recurrence risk in TNM Stage II colon cancer, using quantitative whole-slide ECM imaging. We hypothesize that loose ECM regions are associated with increased recurrence risk due to enhanced tumor budding (TB) or poorly differentiated clusters (PDC).MethodsIn a case-control study of 100 TNM Stage II colon cancer patients (25 with recurrence and 75 controls matched by lymph node sampling and tumor extent), Picrosirius red-stained sections were imaged to quantify ten ECM parameters across 798 regions of interest (ROIs). Conditional logistic regression assessed associations between ECM morphologies, TB, PDCs, and recurrence.ResultsUnsupervised clustering identified three ECM morphologies: dense fibrous, loose sparse, and complex tortuous. Dense fibrous ECM correlated strongly with recurrence (aOR 9.43, 95% CI 3.29-29.30,p< 0.001), while loose sparse and complex tortuous ECMs were associated with reduced recurrence risk (aOR 0.33, 95% CI 0.11-0.91,p= 0.040, and aOR 0.14, 95% CI 0.02-0.53,p= 0.012, respectively). TB was highest in loose sparse ECM (mean 9.3), and PDCs were highest in dense fibrous ECM (mean 5.5).DiscussionOur findings suggest that ECM morphology, particularly dense fibrous ECM, predicts recurrence in Stage II colon cancer, highlighting ECM profiling as a promising tool for patient stratification beyond traditional staging.
Deciphering the function of Com_YlbF domain-containing proteins in Staphylococcus aureus
Authors: Corredor-Rozo Zayda , Marquez-Ortiz Ricaurte , Velandia-Romero Myriam L. , Abril-Riaño Deisy , Madroñero Johana , Prada Luisa F. , Vanegas-Gomez Natasha , García Begoña , Echeverz Maite , Calderón-Peláez María Angélica , Chaparro-Olaya Jacqueline , Morales Liliana , Nieto-Clavijo Carlos , Escobar-Perez Javier 
Published: November 2024

AbstractThe com_ylbF domain-containing proteins that inhibit sporulation, competition, and biofilm formation by affecting the activity of Ribonuclease RNase-Y inBacillus subtilis. Similar Com_YlbF proteins are found inStaphylococcus aureus, but their function is yet to be determined. This study investigates the role of com_ylbF domain-containing proteins (Qrp/YheA, YmcA, and YlbF) inS. aureusby evaluating the impact ofqrp/yheA,ymcA,andylbFgene deletion on biofilm formation, PIA/PNAG production, and hemolytic capacity. It was found that deletion of the threeqrp/yheA,ymcA,andylbFgenes inS. aureusproduced a decrease in biofilm formation, a slight decrease in PIA/PNAG production, and a decrease in its hemolytic capacity. Global transcriptional analysis in the mutant strain showed dysregulation of several genes associated with pathogenesis, notably a decreased expression of theagrAgene (quorum sensing system), thedelta,alpha,andgammahemolysins, as well as thesdrCgenes,eap/map(adhesion proteins). It also showed-an attenuation of virulence, manifesting as enhanced survival amongGalleria mellonellalarvae, and BALB/c mice, possibly associated due to disrupted RNase-Y activity when theqrp/yheA,ymcA,andylbFare deleted. In conclusion, this work supports the hypothesis that this new family of proteins containing a com_ylbF domain is involved in the regulation of genes related to biofilm formation, hemolysis, and virulence inS. aureusthrough a change in RNase-Y activity.
TSSK homologue regulates the expression ofprotamineandmosquito testes specificgenes inAnopheles stephensi
Authors: Meghwanshi Keshav Kumar , Choudhary Chhavi , Rohilla Pooja , Dixit Rajnikant , Saxena Vishal Kumar , Shukla Jayendra Nath 
Published: November 2024

AbstractThe testis-specific serine/threonine-protein kinase (tssk) gene is known to play an important role in spermiogenesis in mammals. This study identifiestsskhomologues,As_tssk3andAea_tssk1inAnopheles stephensiandAedes aegypti, respectively. BothAs_tssk3andAea_tssk1were found to express in a male-specific manner throughout the development. Efficient knockdown in the expression ofAs_tssk3gene was observed upon feedingAn. stephensilarvae with target dsRNA.As_tssk3knockdown led to a reduced sperm reservoir in male adults. Additionally, the knockdown ofAs_tssk3resulted in the reduced expression of two male specifically expressed genes,protamine & mosquito testes specific(mts-a sperm-specific marker) homologues ofAn. stephensi.In-silicointeraction analysis suggests that As_TSSK3 protein interacts with the Nucleosome Assembly Protein1 like-4 (NAP1like-4), a putative transcription factor. We hypothesize that As_TSSK3 regulates the transcription ofprotamineandmtsgenes via NAP, as both NAP andprotaminehave previously been shown to function in the establishment and maintenance of chromatin dynamics, in independent studies. The study presented here is the first report of characterisation oftsskhomologues in any mosquito species. The knockout studies and phosphorylation assays would provide more insights to explore the mechanism by whichAs_tssk3regulatesprotamineandmtsgenes inAnopheles stephensi.HighlightsThis study identifies thetsskhomologues inAe. aegyptiandAn. stephensiand showed their male-specific expression in both the mosquito species.dsRNA mediated knockdown ofAs_TSSK3resulted into the males with a reduced size of sperm reservoir.dsRNA mediated knockdown ofAs_TSSK3led to the reduction in the expression ofAs_protandAs_mts, homologues of protamine and mosquito testis specific, genes inAn. stephensi.In-silico studies suggest that As_TSSK3 regulates the expression ofAs_protandAs_mtsgenes via NAP.
Sla2 is a core interaction hub for Clathrin Light Chain and the Pan1/End3/Sla1 Complex
Authors: Draper-Barr George , Defelipe Lucas A. , Ruiz-Carrillo David , Gustavsson Emil , Landau Meytal , García-Alai Maria 
Published: November 2024

AbstractThe interaction network of Sla2, a vital adaptor protein in the endocytic mid-coat, undergoes constant rearrangement incorporating or replacing interacting proteins over time. Sla2 serves as a scaffold linking the membrane to the actin cytoskeleton, with this role modulated by Clathrin Light Chain (CLC), which inhibits Sla2’s function under certain conditions. We show that Sla2 has two independent binding sites for CLC: one previously described in homologs of Fungi (Sla2) and Metazoa (Hip1R), and a second found only in Fungi. We present the structural model of the Sla2 actin-binding domains in the context of regulatory structural domains by electron cryo-microscopy. We provide an interaction map of Sla2 and the regulatory proteins Sla1 and Pan1, predicted by AI modelling and confirmed by molecular biophysics techniques. Pan1 competes with CLC for the conserved binding site on Sla2. These results enhance the mapping of crucial interactions at endocytic checkpoints and highlight the divergence between Metazoa and Fungi in this vital process.TeaserSla2 forms complexes with three regulatory proteins in the endocytic pit, two of which compete for the same site
Quantification of Cyclin-CDK dissociation constants in living cells using fluorescence cross-correlation spectroscopy with green and near-infrared fluorescent proteins
Authors: Toyama Aika , Goto Yuhei , Yamauchi Yuhei , Sugiyama Hironori , Kondo Yohei , Mochizuki Atsushi , Aoki Kazuhiro 
Published: November 2024

AbstractThe cell cycle is a highly coordinated process governed by cyclin-bound cyclin-dependent kinases (CDKs). While the interaction between cyclin and CDK are well-documented, the dissociation constants (Kd) between specific cyclin-CDK pairs within living cells remain poorly understood. Fluorescence cross-correlation spectroscopy (FCCS) enables the quantification of the Kd, but challenges remain in selecting an optimal pair of fluorescent molecules for FCCS in a living cell. In this study, we demonstrate that mNeonGreen and phycocyanobilin-bound miRFP670 represent a suitable pair for FCCS in living cells from the viewpoint of high photostability and low bleed-through. This fluorescent protein pair enables us to measure the Kdvalues of the cyclin-dependent kinase Cdc2 and B-type cyclin Cdc13 in fission yeast cells. Moreover, we conducted a comprehensive analysis of the Kdvalues for 36 cyclin-CDK complexes, formed by 9 distinct cyclins and 4 CDKs, in mammalian cells, including unconventional cyclin-CDK pairs. These findings provide insights into the redundancy of cyclin-CDK binding in cell cycle progression, with potential implications for understanding cell cycle regulation in both fission yeast and higher eukaryotes.
Multi-view BLUP: a promising solution for post-omics data integrative prediction
Authors: Wu Bingjie , Xiong Huijuan , Zhuo Lin , Xiao Yingjie , Yan Jianbing , Yang Wenyu 
Published: November 2024

ABSTRACTPhenotype prediction is a promising strategy for accelerating molecular plant breeding. Data from multiple sources (called multi-view data) can provide complementary information to characterize a biological object from various aspects. By integrating multi-view information into phenotype prediction, a multi-view best linear unbiased prediction (MVBLUP) method was proposed in this paper. By assigning different weights to measure the importance of different views of data and using a differential evolution algorithm with an early stopping mechanism to adjust the weight vector adaptively, a multi-view kinship matrix was obtained first and then incorporated into the BLUP model for phenotype prediction. To validate the efficiency of MVBLUP, we conducted numerical experiments on four multi-view datasets.Compared to the average performance of the single-view method, the prediction accuracy of the MVBLUP method has improved by a range of 0.038 to 0.201.The results demonstrate that the MVBLUP model is an effective method of integrating multi-view data.
Hallmarks of glucocorticoid receptor condensates involvement in transcription regulation
Authors: Benítez Belén , Stortz Martin , De Rossi María Cecilia , Presman Diego M. , Levi Valeria 
Published: November 2024

AbstractSeveral proteins necessary for mRNA production concentrate in intranuclear condensates, which are proposed to affect transcriptional output. The glucocorticoid receptor (GR) is a ligand-activated transcription factor that regulates the expression of hundreds of genes relevant to many physiological and pathological processes. As with all members of the steroid receptor family, GR forms condensates of unknown function. Here, we examine whether GR condensates are involved in transcription regulation using Airyscan super-resolution microscopy and nano-antibodies targeting initiation and elongating states of RNA polymerase II (Pol2). We observed subpopulations of GR condensates colocalizing with initiating and, surprisingly, elongating Pol2 foci. The analysis of GR mutants with different transcriptional outputs suggests a correlation between condensate formation capability and transcription initiation. Moreover, the number of GR molecules within initiation and elongation condensates appears to be linked to transcriptional activity. Taken together, our data suggests an involvement of GR condensates in transcription initiation and elongation.
Visual physiology of Australian stingless bees
Authors: Penmetcha Bhavana , Ryan Laura A , Ogawa Yuri , Hart Nathan S , Narendra Ajay 
Published: November 2024

AbstractStingless bees engage in a range of visually guided behaviours that require relatively high spatial resolution and contrast sensitivity. Although the eyes of honeybees, bumblebees, carpenter bees, and sweat bees have been studied extensively, there is limited knowledge of stingless bees. Here, we studied two sympatric Australian species,Tetragonula carbonariaandAustroplebeia australis, which are important crop pollinators. The biggerA. australishad more and larger ommatidial facets compared toT. carbonaria. Using pattern electrophysiology, we showed thatA. australishad higher contrast sensitivity (13.07) compared toT. carbonaria(5.99), but their spatial resolving power did not differ (0.53 cycles deg-1). We discuss these differences in visual physiology in the context of the distinct foraging behaviours of the two species.
Structural insights into the opening mechanism of C1C2 channelrhodopsin
Authors: Mulder Matthias , Hwang Songhwan , Broser Matthias , Brünle Steffen , Skopintsev Petr , Schattenberg Caspar , Schnick Christina , Hartmann Sina , Church Jonathan , Schapiro Igor , Dworkowski Florian , Weinert Tobias , Hegemann Peter , Sun Han , Standfuss Jörg 
Published: November 2024

AbstractChannelrhodopsins, light-gated cation channels, enable precise control of neural cell depolarization or hyperpolarization with light in the field of optogenetics. This study integrates time-resolved serial crystallography and atomistic molecular dynamics (MD) simulations to resolve the structural changes during C1C2 channelrhodopsin activation. Our observations reveal that within the crystal environment, C1C2 predominantly remains in a light-activated state with characteristics of the M390intermediate. Here, rearrangement of retinal within its binding pocket partially opens the central gate towards the extracellular vestibule. These structural changes initiate channel opening but were insufficient to allow K+flow. Adjusting protonation states to represent the subsequent N520intermediate in our MD simulations induced further conformational changes, including rearrangements of transmembrane helices 2 and 7, that opened the putative ion- translocation pathway. This allows spontaneous but low cation but not anion conduction, that matches experiments. Our findings provide critical structural insights into key intermediates of the channel opening mechanism, enhancing our understanding of ion conduction and selectivity in channelrhodopsins at an atomistic level.
Characterising Protein Search Drift using exhaustive protein search and Alphafold2
Authors: Buchan Daniel WA 
Published: November 2024

AbstractIn this paper we present the first exhaustive analysis of iterative protein search drift and show how such results may impact downstream modelling. Assembling and extracting evolutionary information from families of related proteins is a core challenge in the studey of molecular evolution. For instance, iterative protein search is a common first step in a wide variety of bioinformatics tools and pipelines. And the output of such searches often form the inputs for modelling tools such as Alphafold2. Here we characterise profile drift; the tendency for some searches to become contaminated with sequences outside of the intended evolutionary family. We observe that drift occurs in nearly 15% of searches and can be observed to have measurable impacts on downstream predictive tasks such as structure prediction.