bluuebunny/crossref_metadata_2025_split huggingface dataset:
Site-variable allocation ratios in randomized controlled trials: implications for sample size, recruitment efficiency, and statistical analysis
Authors: Roshanov Pavel S. 
Published: November 2024

ABSTRACTIntroductionIn multicentre randomized trials, some sites face logistical constraints that specifically affect their ability to recruit into one arm of the trial more than other arms. Often these are greater limits on their ability to deliver one of the study interventions. This paper proposes the use of allocation ratios that differ by site to increase recruitment capacity in asymmetrically constrained sites.MethodsSimulations of randomized trials assessed the impact of several allocation ratios (1:1 to 1:5)—and variation of ratios across sites—on sample size and recruitment capacity, and evaluated several adjustment approaches for time-to-event, binary, and continuous outcomes to prevent bias from site-variable allocation ratios.ResultsDeviating from 1:1 allocation increases recruitment capacity within sites facing asymmetric constraints faster than it increases sample size requirements. For instance, a 1:3 ratio increased sample size by 35% but doubled the hypothetical recruitment capacity with fewer sites. The bias in treatment effect estimates that occurs when the baseline risk or outcome mean differ between sites allocated with different ratios was readily prevented with simple covariate adjustment or stratification by site or allocation ratio.ConclusionsSite-variable allocation ratios may relieve recruitment bottlenecks caused by asymmetric constraints in trial procedures that affect some of the sites in a trial. Accounting for the variation in allocation ratios during analysis is necessary to ensure unbiased treatment effect estimates. This strategy is particularly relevant for trials with low marginal costs for participant recruitment and follow-up, such as many large pragmatic trials embedded in routine care.
The Causal Nexus of Immune Cells and Vitiligo: A Genetic Perspective
Authors: Lin Ziyi , Wu Zhimin , Duan Xingwu 
Published: November 2024

AbstractObjectiveThis study aims to explore the causal relationship between 731 immune cell traits and vitiligo using Mendelian randomization.MethodsWe used a two-sample Mendelian randomization (MR) analysis, employing genetic variations extracted from genome-wide association studies (GWAS) as instrumental variables (IVs). Data sources included immune phenotype data from 3,757 European individuals and data from FinnGen, comprising a total of 385,538 samples (292 cases and 385,509 controls). The study used the inverse-variance weighted (IVW) method as the primary analysis method and conducted various robustness tests through median-based weighted analysis, mode-based weighted analysis, and the MR-Egger method to control for false positive results in multiple hypothesis testing.ResultsOur study found that the pathogenesis of vitiligo may significantly reduce the levels of the following immune cells: TD CD4+ %T cells (b=-0.458, 95% CI=0.17-0.76, PFDR=0.015, P=0.000), CD25 on CD39+ CD4+ cells (b=-0.155, 95% CI=0.78-0.94, PFDR=0.166, P=0.769), and CD4 on HLA DR+ CD4+ cells (b=-0.431, 95% CI=0.50-0.85, PFDR=0.166, P=0.001). Additionally, the causal effect estimate of vitiligo on CCR2 on monocyte is 0.75 (b=-0.290, 95% CI=0.64-0.88, PFDR=0.114, P=0.828), and a negative association was also found on FSC-A on NK cells (b=-0.481, 95% CI=0.47-0.82, PFDR=0.142, P=0.197). On the other hand, our study suggests that the occurrence of vitiligo may increase the levels of CD28 on CD28+ CD45RA+ CD8br cells (b=0.311, 95% CI=1.13-1.65, PFDR=0.166, P=0.393).ConclusionThe results of this study reveal causal links between vitiligo and multiple immune cell traits, highlighting the important role of the immune system in the pathogenesis of vitiligo. These findings provide new research directions for controlling vitiligo through immune regulation and may pave the way for early intervention and treatment strategies.
Incidence and Progression Patterns of Chronic Pain Disparities Revealed by Analyzing the All of Us Research Program Data
Authors: Baldwin Edwin , Zhou Jin , Luo Wenting , Hooten W. Michael , Fan Jungwei W. , Li Haiquan 
Published: November 2024

AbstractDisparities in the progression of ten chronic overlapping pain conditions (COPC) and four comorbid mental disorders among traditionally underrepresented populations have rarely been reported in the literature. In this study, we conducted retrospective cohort analyses using All of Us Research Program data from 1981 to 2022 to address this issue. Separate cohorts were created to assess the disparities by sex, race, and ethnicity. Logistic regression models, controlling for demographic variables, were employed to identify significant disparity factors associated with the progression from one COPC or mental condition to another. Among 122 frequent disease pairs, we identified demographic disparities in nine progression pathways. For example, we found an increased likelihood of subsequent depression after irritable bowel syndrome in Hispanics versus non-Hispanic individuals (OR:3.13, p<10−10). To our knowledge, this is the first study to unveil demographic disparities in COPC progression. These findings underscore the importance of examining health disparities among individuals affected by multiple chronic pain conditions.Author SummaryUnderstanding the disparities in chronic overlapping pain conditions (COPC) can aid patients and clinicians in managing and optimizing therapy. Although disparities have been extensively reported for individual COPCs, progression disparity between conditions has been rarely studied. This study addresses this gap by identifying multiple disparities related to sex, race, and ethnicity in COPC progression, providing valuable insights for patients and clinicians to help prevent the exacerbation of other COPCs.
Circulating Levels of HMGB-1 and NPM/B23 proteins and Clinical Significance in Debut NSCLC patients
Authors: Hui Tan , Liu Lu , Yi Ying , Valenzuela Carmen , Zhao Qiang , Zhang Zhiwei , Li Wen , Perea Silvio E. , Perera Yasser 
Published: November 2024

AbstractAlarmins are endogenous molecules that alert the immune system to circumvent the invading antigens in the host. They are basically sensed by specific cellular receptors, leading to recruitment and activation of dendritic cells to mount innate and adaptive immune responses. However, a dual role of alarmins as mediators in either antitumor immunity or tumor progression has been also reported. Here, we investigated the status of the HMGB-1 alarmin and the alarmin-like NPM/B23 in 162 debut NSCLC patients and 60 age-matched healthy individuals as control. NSCLC patients exhibited lower median values of circulating HMGB-1 compared to control (30.04versus37.30 ng/ml, p=0.02), but higher levels of HMGB-1 were positively correlated with tumor size > 2.0 cm (p=0.004) irrespectively of tumor histology. Otherwise, circulating NPM/B23 levels were significantly increased in NSCLC patients respect to control (812versus551 pg/ml, p=0.00027). Likewise, patients with tumors > 2 cm exhibited higher levels NPM/B23. Strong association was observed between HMGB-1 and NPM/B23 in serum of NSCLC patients (r=0.679 p=0.0001) compared to healthy individuals who exhibited a weaker correlation (r=0.278 p=0.031). However, the strongest correlation between both alarmins was observed in patients with STAS and tumors ≤ 2 cm (r=0.900 p=0.0001). Co-expression of HMGB-1 and NPM/B23 was also observed in tumor tissues although to a lesser extent. Our data unveil that concomitant circulating HMGB-1 and NPM/B23 could serve as a putative alarmin-based biomarker of NSCLC disease progression.
Genealogy based trait association with LOCATER boosts power at loci with allelic heterogeneity
Authors: Wang Xinxin , Christ Ryan , Young Erica , Kang Chul Joo , Das Indraniel , Belter Edward A. , Laakso Markku , Aslett Louis J.M. , Steinsaltz David , Stitziel Nathan O. , Hall Ira M. 
Published: November 2024

ABSTRACTA key methodological challenge for genome wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work we developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus specific haplotype tree. Here, we developed a genome-wide LOCATER analysis pipeline and applied it to a genome sequencing study of 6,795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identified 351 significant trait associations at 47 genomic loci and found that LOCATER boosted single marker test (SMT) association power at 5 loci by combining independent signals from distinct alleles. LOCATER successfully recovered known quantitative trait loci not found by SMT, includingLIPG, recovered known allelic heterogeneity at theAPOE/C1/C4/C2gene cluster, and suggested one novel association. We find that confounders have a more pronounced effect on genealogy-based methods than SMT; we propose a new randomization approach and a general method for genomic control to eliminate their effects. This study demonstrates that genealogy-based methods such as LOCATER excel when multiple causal variants are present and suggests that their application to larger and more diverse cohorts will be fruitful.
Design and Methods of the “Understanding pre-exposure prophylaxis modalities for HIV prevention in European communities” (PROTECT) Survey
Authors: Kolstee Johann , Wang Haoyi , Zimmermann Hanne , Schroeder Melanie , Appiah Ama , Brown Carolyn , Milinkovic Ana , Jonas Kai J. 
Published: November 2024

ABSTRACTBackgroundDespite the increasing availability of oral PrEP in Europe, gaps remain in the coverage of HIV prevention strategies at a population level. Long-acting injectable PrEP (LA PrEP) has the potential to help provide greater HIV prevention coverage to increasing proportions of men who have sex with men (MSM) and trans people, communities still disproportionately affected by HIV.MethodsAn online cross-sectional survey was conducted across 20 European countries from October 2023 to April 2024. The survey was translated into 22 local and migrant languages. The main aim of the survey was to understand which MSM and trans* people in Europe are interested and intend to use LA-PrEP if it becomes available.ResultsA total of 15,458 MSM and trans* individuals participated in the survey. Participants were recruited mainly from gay dating apps and through a social media campaign. Overall, the sample was sexually active (96.4%), engaged in condomless anal intercourse in the past 6 months (83.4%), had more than 10 partners in the past 6 months (57.6%) and was PrEP naïve (51.4%).ConclusionsMSM and trans people in Europe can be engaged effectively to participate in research about LA PrEP.
Weberviruses are gut-associated phages that infectKlebsiellaspp
Authors: Dawson Samuel J. T. , Shibu Preetha , Garnett Sara , Newberry Fiona , Brook Thomas C. , Tijani Tobi , Kujawska Magdalena , Hall Lindsay J. , McCartney Anne L. , Negus David , Hoyles Lesley 
Published: November 2024

ABSTRACTWeberviruses are bacteriophages (phages) that have been shown to infect and lyse members of the genusKlebsiella. Due to their antimicrobial properties, phages and their products have emerged as a potential therapeutic option to help tackle increasing rates of antimicrobial resistance amongstKlebsiellaspp. Weberviruses are an attractive option due to their high burst sizes, long shelf life and associated depolymerase enzymes. In this study we isolated and characterized seven new weberviruses and compared their genomes with those of their closest relatives to further our understanding of the genusWebervirus. We show that the seven phages isolated in this study can lyse a range of clinical multidrug-resistantKlebsiellastrains, includingK. variicola. Gene-sharing network-based analysis using vConTACT2 and incorporating all publicly available webervirus genomes (n=67) confirmed the seven phages as members of the genusWebervirusand that weberviruses are affiliated with the familyDrexlerviridae. Using the online resource PhageClouds, we demonstrated that weberviruses can be readily detected in metagenome-derived phage datasets from a diverse range of geographical locations. Using a curated database of 67 isolated phage genomes and 60 metagenome-assembled genomes (n=127 total), we found that weberviruses are primarily associated with samples originating from the gut, with human faeces (61/127, 48 %), sewage (39/127, 31 %) and wastewater (14/127, 11 %) being the most frequent sources of these phages.
Type IV pili-associated secretion of a biofilm matrix protein fromClostridium perfringensthat forms intermolecular isopeptide bonds
Authors: Kivimaki Sarah E. , Dempsey Samantha , Camper Collette , Tani Julia M. , Hicklin Ian K. , Blaby-Haas Crysten E. , Brown Anne M. , Melville Stephen B. 
Published: November 2024

AbstractClostridium perfringensis a Gram-positive anaerobic spore-forming bacterial pathogen of humans and animals.C. perfringensalso produces type IV pili (T4P) and has two complete sets of T4P-associated genes, one of which has been shown to produce surface pili needed for cell adherence. One hypothesis about the role of the other set of T4P genes is that they could comprise a system analogous to the type II secretion systems (TTSS) found in Gram-negative bacteria, which is used to export folded proteins from the periplasm through the outer membrane to the extracellular environment. Gram-positive bacteria have a similar secretion barrier in the thick peptidoglycan (PG) layer, which blocks secretion of folded proteins >25 kD. To determine if the T4P-associated genes comprise a Gram-positive TTSS, the secretome of mutants lacking type IV pilins were examined and a single protein, a von Willebrand A domain containing protein BsaC (CPE0517) was identified as being dependent on PilA3 for secretion. BsaC is in an operon with a signal peptidase and two putative biofilm matrix proteins with homology toBacillus subtilisTasA. One of these proteins, BsaA, was shown by another group to produce high mol wt oligomers. We analyzed BsaA monomer interactions withde novomodeling, which projected that the monomers formed isopeptide bonds as part of a donor strand exchange process. Mutations in residues predicted to form the isopeptide bonds led to loss of oligomerization, supporting the predicted bond formation process. Phylogenetic analysis showed the BsaA family of proteins are widespread among bacteria and archaea but only a subset are predicted to form isopeptide bonds.ImportanceFor bacteria to secrete folded proteins to the environment, they have to overcome the physical barriers of an outer membrane in Gram-negative bacteria and the thick peptidoglycan layer in Gram-positive bacteria. One mechanism to do this is the use of a Type II secretion system in Gram-negative bacteria, which has a similar structure as type IV pili and is modeled to act as a piston that pumps folded proteins through the outer membrane to the environment.Clostridium perfringens, like all or most all of the clostridia, has type IV pili and, in fact, has two sets of pilus-associated genes. Here we present evidence thatC. perfringensuses one set of pilus genes to secrete a biofilm associated protein and may be responsible for secreting the main biofilm protein BsaA. We show that BsaA monomers are, unlike most other biofilm matrix proteins, linked by intermolecular isopeptide bonds, enhancing the physical strength of BsaA fibers.
Corticonigral projections recruit substantia nigra pars lateralis dopaminergic neurons for auditory threat memories
Authors: Sansalone Lorenzo , Evans Rebekah C. , Twedell Emily , Zhang Renshu , Khaliq Zayd M. 
Published: November 2024

AbstractDopaminergic neurons (DANs) in the lateral substantia nigra project to the tail of striatum (TS), which is involved in threat conditioning. Auditory cortex also contributes to threatening behaviors, but whether it directly interacts with midbrain DANs and how these interactions might influence threat conditioning remain unclear. Here, functional mapping revealed robust excitatory input from auditory and temporal association cortexes to substantia nigra pars lateralis (SNL) DANs, but not to pars compacta (SNc) DANs. SNL DANs exhibited unique firing patterns, with irregular pacemaking and higher maximal firing, reflecting different channel complements than SNc DANs. Behaviorally, inhibiting cortex to SNL projections impaired memory retrieval during auditory threat conditioning. Thus, we demonstrate robust corticonigral projections to SNL DANs, contrasting with previous observations of sparse cortical input to substantia nigra DANs. These findings distinguish SNL DANs from other nigral populations, highlighting their role in threatening behaviors and expanding knowledge of cortex to midbrain interactions.
Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol
Authors: Zhou Xin , van der Stoel Miesje M. , Kaptan Shreyas , Li Haoran , Li Shiqian , Hölttä Maarit , Vihinen Helena , Jokitalo Eija , Thiele Christoph , Pietiläinen Olli , Morioka Shin , Sasaki Junko , Sasaki Takehiko , Vattulainen Ilpo , Ikonen Elina 
Published: November 2024

AbstractSac1 is a conserved phosphoinositide phosphatase, whose loss-of-function compromises cell and organism viability. Here, we employed acute auxin-inducible Sac1 degradation to identify its immediate downstream effectors in human cells. Most of Sac1 was degraded in ∼1 h, paralleled by increased PI(4)P and decreased cholesterol in the trans-Golgi network (TGN) during the following hour, and superseded by Golgi fragmentation, impaired glycosylation, and selective degradation of TGN proteins by ∼4 h. The TGN disintegration resulted from its acute deacidification caused by disassembly of the Golgi V-ATPase. Mechanistically, Sac1 mediated TGN membrane composition maintained an assembly promoting conformation of the V0a2 subunit. Key phenotypes of acute Sac1 degradation were recapitulated in human differentiated trophoblasts, causing processing defects of chorionic gonadotropin, in line with loss-of-function intolerance of the humanSACML1gene. Collectively, our findings reveal that the assembly of the Golgi V-ATPase is controlled by the TGN membrane via Sac1 fuelled lipid exchange.
F2,6BP restores mitochondrial genome integrity in Huntington’s Disease
Authors: Chakraborty Anirban , Mandal Santi M. , Mankevich Mikita , Sreenivasmurthy Sravan Gopalkrishnashetty , Hegde Muralidhar L. , Krishnan Balaji , Ghosh Gourisankar , Hazra Tapas 
Published: November 2024

AbstractSeveral reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington’s disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3’-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3’-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients’ brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.
A modiolar-pillar gradient in auditory-nerve dendritic length: a novel post-synaptic contribution to dynamic range?
Authors: Kostrikov Serhii , Hjortkjaer Jens , Dau Torsten , Corfas Gabriel , Liberman Leslie D. , Liberman M. Charles 
Published: November 2024

AbstractAuditory-nerve fibers (ANFs) from a given cochlear region can vary in threshold sensitivity by up to 60 dB, corresponding to a 1000-fold difference in stimulus level, although each fiber innervates a single inner hair cell (IHC) via a single synapse. ANFs with high-thresholds also have low spontaneous rates (SRs) and synapse on the side of the IHC closer to the modiolus, whereas the low-threshold, high-SR fibers synapse on the side closer to the pillar cells. Prior biophysical work has identified modiolar-pillar differences in both pre- and post-synaptic properties, but a comprehensive explanation for the wide range of sensitivities remains elusive. Here, in guinea pigs, we used immunostaining for several neuronal markers, including Caspr, a key protein in nodes of Ranvier, to reveal a novel modiolar-pillar gradient in the location of the first ANF heminodes, presumed to be the site of the spike generator, just outside the sensory epithelium. Along the cochlea, from apex to base, the unmyelinated terminal dendrites of modiolar ANFs were 2 - 4 times longer than those of pillar ANFs. This modiolar-pillar gradient in dendritic length, coupled with the 2 - 4 fold smaller caliber of modiolar dendrites seen in prior single-fiber labeling studies, suggests there could be a large difference in the number of length constants between the synapse and the spike initiation zone for low- vs high-SR fibers. The resultant differences in attenuation of post-synaptic potentials propagating along these unmyelinated dendrites could be a key contributor to the observed range of threshold sensitivities among ANFs.
Pharmacological depletion of microglia protects against alcohol-induced corticolimbic neurodegeneration during intoxication in male rats
Authors: Carlson Erika R. , Melbourne Jennifer K. , Nixon Kimberly 
Published: November 2024

AbstractExcessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causative role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia >90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.