bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative effectiveness of first line pembrolizumab vs. chemotherapy in aNSCLC: A Norwegian Population-Based Cohort Study
Authors: Brant Simon Boge , Børø Siri , Jonasson Christian , Helland Åslaug , Thoresen Steinar Østerbø 
Published: October 2024

AbstractThe KEYNOTE-042(1,2) trial showed a benefit of treating patients with non-oncogene addicted advanced NSCLC with PD-L1 tumour proportion score over 50% with Pembrolizumab as monotherapy over platinum doublet chemotherapy. To contextualize these results, we undertake a detailed emulation of the inclusion criteria in Keynote–042 using Norwegian health registry data, and discuss both the clinical context, as well as the general utility of such registry data for pharmacoepidemiologic research in oncology. Within the population of patients with PD-L1 tumour proportion score over 50%, an observational analogue of an intention to treat analysis showed similar results to those of the Keynote-042 study.
Frailty and loneliness among community-dwelling older adults: Examining reciprocal associations within a measurement burst design
Authors: Schultz Anna , Mayerl Hannes , Freidl Wolfgang , Stolz Erwin 
Published: October 2024

AbstractBackgroundPrevious research indicates that frailty and loneliness are interrelated. The aim of this study is to analyze their possible reciprocal relationship while disentangling between- and within-person effects. The separation of these sources of variance is vital for a better understanding of potential causal mechanisms.MethodsWithin the FRequent health Assessment In Later life (FRAIL70+) project, participants aged 70 and over completed two measurement bursts spread one year apart with seven biweekly assessments each. The final sample consisted of 426 individuals at baseline (Mage=77.2;SD=5.4; 64.6% female). A latent curve model with structured residuals was used to examine the potential reciprocal relationship between frailty (37-item deficit accumulation approach) and loneliness (3-item UCLA scale).ResultsNo relevant cross-lagged effects over repeated 2-week periods were found between frailty and loneliness at the within-person level, but increases in frailty co-occurred with increases in loneliness. At the between-person level, higher levels of frailty correlated with higher levels of loneliness in each burst.ConclusionThe findings do not support the assumption that frailty and loneliness share a causal reciprocal relationship over weeks and months. Nonetheless, higher levels of frailty were weakly associated with higher levels of loneliness at the within- and considerably associated at the between-person level, which may indicate a common source of both domains.
NIAGADS: A Comprehensive National Data Repository for Alzheimer’s Disease and Related Dementia Genetics and Genomics Research
Authors: Kuzma Amanda , Valladares Otto , Greenfest-Allen Emily , Nicaretta Heather , Kirsch Maureen , Ren Youli , Katanic Zivadin , White Heather , Wilk Andrew , Bass Lauren , Brettschneider Jascha , Carter Luke , Cifello Jeffrey , Chuang Wei-Hsuan , Clark Kaylyn , Gangadharan Prabhakaran , Haut Jacob , Ho Pei-Chuan , Horng Wenhwai , Iqbal Taha , Jin Yumi , Keskinen Peter , Rose Alexis Lerro , Moon Michelle K , Manuel Joseph , Qu Liming , Robbins Flawless , Saravanan Naveensri , Sha Jin , Tate Sam , Zhao Yi ,   Alzheimer’s Disease Sequencing Project, Cantwell Laura , Gardner Jake , Chou Shin-Yi , Tzeng Jung-Ying , Bush William , Naj Adam , Kuksa Pavel , Lee Wan-Ping , Leung Yuk Yee , Schellenberg Gerard , Wang Li-San 
Published: October 2024

AbstractNIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer’s Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer’s Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud- based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimer’s disease.
B cell immune repertoire sequencing in tobacco cigarette smoking, vaping, and chronic obstructive pulmonary disease in the COPDGene cohort
Authors: Moll Matthew , Xu Zhonghui , Boueiz Adel , Ryu Min Hyung , Silverman Edwin K. , Cho Michael H. , Hersh Craig P. , Sauler Maor , Polverino Francesca , Kinney Gregory L. , Curtis Jeffrey L. , Crotty-Alexander Laura E. , Vollmers Christopher , Castaldi Peter J. 
Published: October 2024

AbstractRationaleCigarette smoking (CS) impairs B cell function and antibody production, increasing infection risk. The impact of e-cigarette use (’vaping’) and combined CS and vaping (’dual-use’) on B cell activity is unclear.ObjectiveTo examine B cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, dual-use, COPD-related outcomes, and demographic factors.MethodsBCR-seq was performed on blood RNA samples from 234 participants in the COPDGene study. We assessed multivariable associations of B cell function measures (immunoglobulin heavy chain (IGH) subclass expression and usage, class-switching, V-segment usage, and clonal expansion) with CS, vaping, dual-use, COPD severity, age, sex, and race. We adjusted for multiple comparisons using the Benjamini-Hochberg method, identifying significant associations at 5% FDR and suggestive associations at 10% FDR.ResultsAmong 234 non-Hispanic white (NHW) and African American (AA) participants, CS and dual-use were significantly positively associated with increased secretory IgA production, with dual-use showing the strongest associations. Dual-use was positively associated with class switching and B cell clonal expansion, indicating increased B cell activation, with similar trends in those only smoking or only vaping. We observed significant associations between race and IgG antibody usage. AA participants had higher IgG subclass proportions and lower IgM usage compared to NHW participants.ConclusionsCS and vaping additively enhance B cell activation, most notably in dual-users. Self-reported race was strongly associated with IgG isotype usage. These findings highlight associations between B cell activation and antibody transcription, suggesting potential differences in immune and vaccine responses linked to CS, vaping, and race.
ML-driven design of 3’ UTRs for mRNA stability
Authors: Morrow Alyssa K. , Thornal Ashley , Flynn Elise Duboscq , Hoelzli Emily , Shan Meimei , Garipler Görkem , Kirchner Rory , Reddy Aniketh Janardhan , Tabchouri Sophia , Gupta Ankit , Michel Jean-Baptiste , Laserson Uri 
Published: October 2024

AbstractUsing mRNA as a therapeutic has received enormous attention in the last few years, but instability of the molecule remains a hurdle to achieving long-lasting therapeutic levels of protein expression. In this study, we describe our approach for designing stable mRNA molecules by combining machine learning-driven sequence design with high-throughput experimental assays. We developed a high-throughput massively parallel reporter assay (MPRA) that, in a single experiment, measures the half-life of tens of thousands of unique mRNA sequences containing designed 3’ UTRs. Over multiple design-build-test iterations, we have accumulated 180,000 unique measurements of mRNA stability covering unique genomic and synthetic 3’ UTRs, representing the largest such dataset of sequences. We trained highly-accurate machine learning models to map from 3’ UTR sequence to mRNA stability, and used them to guide the design of synthetic 3’ UTRs that increase mRNA stability in cell lines. Finally, we validated the function of several ML-designed 3’ UTRs in mouse models, resulting in up to 2-fold more protein production over time and 30–100-fold higher protein output at later time points compared to a commonly used benchmark. These results highlight the potential of ML-driven sequence design for mRNA therapeutics.
A clinical mutation inuvrA, a DNA repair gene, confers survival advantage toMycobacterium tuberculosisin the host
Authors: Naz Saba , Datta Dipanwita , Khan Sidra , Singh Yogendra , Nandicoori Vinay Kumar , Kumar Dhiraj 
Published: October 2024

AbstractDNA repair pathways play an essential role in maintaining the genomic integrity of bacteria, and a perturbation in their biological activity helps bacteria survive under duress. In drug-resistant clinical strains, we identified a Q135K mutation in theuvrAgene, a DNA repair pathway gene. To delineate the role ofuvrAand the Q135K mutation, we generated the gene replacement mutant of UvrA (RvΔuvrA) inMycobacterium tuberculosis H37Rv(Mtb-Rv). While the lack of UvrA function inRvΔuvrAcould be restored upon complementation withuvrA, theuvrA-Q135Kmutant identified in clinical drug-resistant strains failed to do so. This was reflected in higher mutation rates inRvΔuvrAandRvΔuvrA::uvrAQ135A,compared with wild-typeRvorRvΔuvrA::uvrAcomplemented strains in the presence and absence of oxidative stress. Killing kinetics experiments with anti-TB drugs showed increased survival ofRvΔuvrAandRvΔuvrA::uvrAQ135K,strains compared withRvorRvΔuvrA::uvrA. Importantly,RvΔuvrAandRvΔuvrA::uvrAQ135Kshowed enhanced survival in peritoneal macrophages and murine infection model of infection. Together, data suggests that acquiring Q135K mutation benefits the pathogen, which helps enhance the host’s survival adaptability.Author SummaryDNA repair mechanisms in an organism are necessary for correcting the errors generated during replication or when it is damaged/modified due to insults. As a GC organism, Mtb is highly prone to host-mediated attacks on its genome, which, if uncorrected, can impact its genome integrity. The drug-resistant clinical strains ofMtbharbor Q135K mutation inuvrA, the first enzyme in the nucleotide excision repair pathway. With the help of genetic, molecular, and murine challenge experiments, we show that the UvrA-Q135K mutation abrogates the enzyme’s activity, compromising theMtbstrain harboring the mutation in the oxidative and nitrosative stress. On the contrary, the mutation in UvrA imparts survival advantage in activated macrophages and murine infection models. Results presented argue that identified mutation helps in better adaptability in the host, which may include faster acquisition of drug resistance.
Estimating the effective population size across space and time in the Critically Endangered western chimpanzee in Guinea-Bissau: challenges and implications for conservation management
Authors: Ferreira da Silva Maria Joana , Borges Filipa , Gerini Federica , Sá Rui M. , Silva Francisco , Maié Tiago , Hernández-Alonso Germán , Ramos-Madrigal Jazmín , Gopalakrishnan Shyam , Aleixo-Pais Isa , Djaló Mohamed , Fernandes Nelson , Camará Idrissa , Regalla Aissa , Casanova Catarina , Costa Mafalda , Colmonero-Costeira Ivo , Fernandes Carlos Rodríguez , Chikhi Lounès , Minhós Tânia , Bruford Michael W. 
Published: October 2024

AbstractEffective population size (Ne) is a key concept in evolutionary and conservation biology. The western chimpanzee (Pan troglodytes verus) is a Critically Endangered taxon. In Guinea-Bissau, chimpanzees are mainly threatened by habitat loss, hunting and diseases. Guinea-Bissau is considered a key area for its conservation. Genetic tools have not yet been applied to inform management and no estimates ofNehave been obtained. In this study, we use country’s range-wide microsatellite data and five whole-genome sequences to estimate severalNeand infer the recent and ancient demographic history of populations using different methods. We also aim to integrate the differentNeestimates to improve our understanding of the evolutionary history and current demography of this great ape and to discuss strengths and limitations of each estimator and their complementarity in informing conservation decisions. Results from the PSMC method suggest a large ancestralNe, likely due to ancient structure over the whole subspecies distribution until approximately 10-15,000 years ago. After that, a change in connectivity, a real decrease in size or a combination of both occurred, which reduced the then still large ancestral population to a smaller size (MSVAR: ∼10,000 decreasing to 1,000-6,000 individuals), possibly indicating a fragmentation into coastal and inner subpopulations. In the most recent past, contemporaryNeis below or close to 500 (GONE: 116-580, NeEstimator: 107-549), suggesting a high risk of extinction. The populations at coastal Parks may have been small or isolated for several generations whereas the Boé Park one exhibit higher long-termNeestimates and can be considered a stronghold of chimpanzee conservation. Through combining different types of molecular markers and analytical methodologies, we try to overcome the limitations of obtaining high quality DNA sampling from wild threatened populations and estimateNeat different temporal and spatial scales, which is crucial information to make informed conservation decisions at local and regional scales.
Electrical diversity of neurons in sensory cortices
Authors: Calcini Niccolò , Zeldenrust Fleur , Celikel Tansu 
Published: October 2024

AbstractThe classification of neuronal types is a complex task with numerous molecular, anatomical, and functional (electrical) features have been identified as informative in discriminating neuronal populations. The functional characterization of neurons has traditionally been carried out with predefined sets of parameters such as firing rate and action potential generation threshold. Here we provide an objective method to choose what parameters are most informative about a neuron’s functional cell type. Using this method we show that despite the significant molecular and anatomical variability across neurons, functional characterization of neuronal activity identifies 9 and 11 distinct neuronal subpopulations in the upper layers of the somatosensory and visual cortices respectively. This novel classification method will help to unravel the functional (electrophysiological) diversity of cellular classes throughout the nervous system. Further, the thorough comparison between the different classes of cells will provide a solid building block for the study of the sensory cortices.
Nonlinear dependency of the bacterial flagellar motor speed on proton motive force and its consequences for swimming
Authors: Krasnopeeva Ekaterina , Le Nagard Lucas , Poon Wilson , Lo Chien-Jung , Pilizota Teuta 
Published: October 2024

AbstractThe bacterial flagellar motor enables bacteria to swim by rotating helical flagellar filaments that form a bundle at the back of the cell.Escherichia coli’s motor uses the energy stored in the proton motive force (PMF) to generate the torque driving this rotation. Until now, motor speed was thought to be proportional to the PMF, irrespective of the viscous load. Here, we show that the PMF-speed proportionality saturates at high load and high PMF, and, thus, the PMF-speed relationship is nonlinear in the high torque regime. Furthermore, we show that free swimming occurs close to or within this saturated regime, making the observed limiting torque evolutionary relevant.
A chronicPseudomonas aeruginosamouse lung infection modeling the pathophysiology and inflammation of human cystic fibrosis
Authors: Vaillancourt Mylene , Aguilar Diane , Fernandes Sheryl E. , Jorth Peter A. 
Published: October 2024

AbstractInvestigation of chronic cystic fibrosis (CF) lung infections has been limited by a lack of murine models that reproduce obstructive lung pathology, chronicity of bacterial infections, and complex inflammation in human CF lung pathology. Three different approaches have been used separately to address these limitations, including using transgenicScnn1b-Tgmice overexpressing a lung epithelial sodium channel to mimic the mucus-rich and hyperinflammatory CF lung environment, using synthetic CF sputum medium (SCFM) in an acute infection to induce bacterial phenotypes consistent with human CF, or using agar beads to promote chronic infections. Here, we combine these three models to establish a chronicPseudomonas aeruginosalung infection model using SCFM agar beads andScnn1b-Tg mice (SCFM-Tg-mice) to recapitulate nutrients, mucus, and inflammation characteristic of the human CF lung environment. Like people with CF, SCFM-Tg-mice failed to clear bacterial infections. Lung function measurements showed that infected SCFM-Tg-mice had decreased inspiratory capacity and compliance, elevated airway resistance, and significantly reduced FVC and FEV0.1. Using spectral flow cytometry and multiplex cytokine arrays we show that, like people with CF, SCFM-Tg-mice developed inflammation characterized by eosinophil infiltration and Th2 lymphocytic cytokine responses. Chronically infected SCFM-Tg-mice developed an exacerbated mix of innate and Th1, Th2, and Th17-mediated inflammation, causing higher lung cellular damage, and elevated numbers of unusual Siglec F+neutrophils. Thus, SCFM-Tg-mice represents a powerful tool to investigate bacterial pathogenesis and potential treatments for chronic CF lung infections and reveal a potential role for Siglec F+neutrophils in CF inflammation.ImportanceHost-pathogen interaction studies ofPseudomonas aeruginosacystic fibrosis (CF) lung infections have been hampered by limitations of mouse infection models. Here we combine synthetic CF sputum medium (SCFM) agar beads andScnn1b-Tg transgenic mice to model the mucus obstructed airways and complex inflammatory characteristic of the human cystic fibrosis lung environment. In this model, which we name SCFM-Tg-mice, we use SCFM to cause changes in bacterial gene expression consistent with sputum collected from people with CF and theScnn1b-Tgmice produce excessive airway mucus like people with CF. We show that SCMF-Tg-mice infected withP. aeruginosahave defects in lung function and increased inflammation that is consistent with human CF lung infections. This model can be adapted for other bacterial species and can be used to test hypotheses about bacterial pathogenesis and potential treatments in a CF human-like system.
Reward and punishment contingency shifting reveals distinct roles for VTA dopamine and GABA neurons in behavioral flexibility
Authors: Lefner Merridee J , Moghaddam Bita 
Published: October 2024

AbstractIn dynamic environments where stimuli predicting rewarding or aversive outcomes unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and GABA neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. We measured VTA dopamine and GABA population activity while male and female rats learned to associate three discrete auditory cues to three distinct outcomes: reward, punishment, or no outcome within the same session. After learning, the reward and punishment cue-outcome contingencies were reversed, and subsequently rereversed. As expected, the dopamine population rapidly adapted to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. In contrast, the GABA population increased activity to all sensory events regardless of valence, including the neutral cue. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity within and across sessions. The observed valence-specific dissociations in the directionality and temporal progression of VTA dopamine and GABA calcium activity indicates that these populations are independently recruited and serve distinct roles during appetitive and aversive associative learning and contingency reversal.
Early-Life Behavior Phenotypes and Cortisol Responses to Common Lab Stressors in a Cichlid Fish
Authors: Alvey Alyssa P. , Stern Eliyah R. , Lee June , Parrish Abigail G. , Solomon-Lane Tessa K. 
Published: October 2024

AbstractThe stress response is highly conserved across species, and increased glucocorticoid release (cortisol in fishes) is a key element. In the highly social cichlid fish, Burton’s Mouthbrooder (Astatotilapia burtoni), stress axis activity is associated with juvenile social behavior and status, and it mediates early-life social effects, yet little is known about early-life stress physiology. We measured water-borne cortisol, a non-invasive method, in juveniles less than 1-week old. We first tested whether juveniles habituate to the beaker confinement necessary for sample collection. Repeated exposure to a beaker did not affect cortisol compared to handled and unhandled controls. In a separate cohort, we next measured behavior in an open field exploration and social cue investigation, followed by a test of whether common lab stressors elevated cortisol. Controls were undisturbed in a collection beaker (90 min). For the stressor treatments, we collected three sequential samples (30 min each) to try and quantify stress response peak and recovery; however, we found no effect of time. Stressors included handling, brief net confinement, and brief gentle movement. These stressors led to a significant increase in cortisol, with the highest levels resulting from confinement. The behavior tests revealed a bold-shy axis across both tests, describing the behavior of most individuals. A distinct group of socially-motivated juveniles showed a dramatic switch, staying in the territory during the open field but leaving to investigate the social cue. We found no associations between behavior and cortisol response. This work provides insight into early-life behavior and stress axis development and function.HighlightsAstatotilapia burtoniunder 1-week old did not habituate to beaker confinementYoung juveniles displayed bold/shy or socially-motivated behavior phenotypesCortisol increased in response to lab stressors: handling, confinement, and movementIndividual variation in cortisol establishes an expected hormone range for this ageJuvenile cortisol did not correlate with behavior or differ by behavior phenotype
Unitarity effects in elastic scattering at the LHC
Authors: Maneyro M. , Luna E. G. S. , Peláez M. 
Published: October 2024

We study the high-energy behavior of the elastic scattering amplitude using two distinct unitarization schemes: the eikonal and the U-matrix. Our analysis begins with a formalism involving solely Pomerons, incorporating pion-loop insertions in the Pomeron trajectory representing the nearest singularity generated by t-channel unitarity. Subsequently, we explore a scenario that includes the presence of an Odderon. In our analyses, we explore the tension between the TOTEM and the ATLAS measurements for σtot and dσ/dt at 7, 8, and 13 TeV and the subsequent implications for the properties of both the Pomeron and Odderon. Our results show that the Odderon phase factor ξO=−1 is favored in both unitarization schemes, supporting an Odderon with a phase opposite to that of other crossing-odd components of the scattering amplitude. More interestingly, this specific phase factor stands as the sole one that aligns with results consistent with a nonzero Odderon coupling.

Published by the American Physical Society
2024