bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Carotid Web Angioarchitecture in Stratification of Stroke Risk
Authors: Negash Bruck , Wiggan Daniel D. , Grin Eric A. , Sangwon Karl L. , Chung Charlotte , Gutstadt Eleanor , Sharashidze Vera , Raz Eytan , Shapiro Maksim , Ishida Koto , Torres Jose L , Zhang Cen , Nakatsuka Michelle A , Rostanski Sara K , Rethana Melissa J. , Kvernland Alexandra , Sanger Matthew , Lillemoe Kaitlyn , Allen Alexander , Kelly Sean , Baranoski Jacob , Rutledge Caleb , Riina Howard A. , Nelson Peter Kim , Nossek Erez
Published: November 2024

Objective

To validate the carotid web (CW) risk stratification assessment described in our previous work with a larger cohort of patients with incidentally found asymptomatic CWs.

Methods

A retrospective analysis of our electronic medical record database identified all patients with a diagnosis of CW from 2017-2024 at our institution. We included symptomatic patients and those with asymptomatic carotid webs, meaning patients with incidentally found webs and no history of stroke or transient ischemic attack (TIA). Patient charts were reviewed for demographics, imaging, comorbidities, hospital course, and incidence of stroke after diagnosis of an asymptomatic carotid web. All angles were measured as described in our previous work on a sagittal reconstruction of CTA imaging of the neck in which the common carotid artery (CCA), external carotid artery (ECA), and ICA could be well visualized, along with the CW itself. A standard logistic regression was performed to evaluate the association between the number of high-risk angles and stroke risk.

Results

26 asymptomatic and nine symptomatic patients were identified. Patients were categorized as having 0, 1, or 2+ high-risk angle values. Patients with more high-risk angles had a markedly higher risk of stroke (OR = 5.91, 95% CI: [4.25, 8.24]). The probability of stroke increased with the number of high-risk angles: patients with 2+ high-risk angles (83.4%) had the highest stroke probability compared to those with 0 (2.8%) or 1 (27.7%) high-risk angles. In the asymptomatic cohort, mean angles all fell below the high-risk threshold values. In the symptomatic cohort, mean angles were above the high-risk threshold values, whereas the mean CPT (53.6°) angle fell below the cut-off value for designation as a high-risk angle.

Conclusions

Given the successful stratification of CWs into high and low-risk groups in this study, the utilization of geometric CW parameters may play a crucial role in improvement of patient selection for intervention in patients with an incidental diagnosis of CW.
TRPV4 channel contributes to aortic root stiffening and atherosclerotic lesion development
Authors: Rahaman Suneha G. , Dutta Bidisha , Rahaman Shaik O.
Published: November 2024

Cardiovascular disease is the number one cause of death in the developed world and atherosclerosis, a chronic arterial disease, is the most dominant underlying pathology. Epidemiologic and experimental studies suggest that arterial stiffness is a risk factor for atherosclerosis. However, there has been surprisingly limited development in mechanistic understanding of the generation of arterial stiffness and little progress in understanding the mechanisms by which matrix stiffening drives the development of atherosclerosis.

Various proinflammatory and fibrotic activities of macrophages and fibroblasts, such as migration, inflammatory gene expression, and myofibroblast activation, are influenced by matrix stiffness. This influence suggests that aorta stiffening may regulate atherosclerosis via a cellular stiffness sensor. Our research indicates that mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels control inflammation and fibrosis in other organs and regulate macrophage and fibroblast activation, implicating TRPV4 as a potential stiffness sensor in atherosclerosis. This suggests a cycle where inflammation, fibrosis, and tissue stiffening reinforce each other, with macrophages playing a key role. Here, we identify a cellular stiffness sensor linking matrix stiffness and atherosclerosis using human aortic tissues, a murine atherosclerosis model, and atomic force microscopy (AFM) analysis. This novel finding suggests that targeting TRPV4 could be a selective strategy to prevent or suppress atherogenesis.
Follicular Bcl6 reactivity is associated with a unique immune landscape and spatial transcriptome in COVID-19
Authors: Brenna Cloe , Bernat Bramon Mora , Ioannidou Kalliopi , Burgermeister Simon , Bodelet Julien , Siebmanns Mia , Georgakis Spiros , Orfanakis Michail , Sédille Nazanin , Feinstein Matthew J , Lomasney Jon W , Chen Oliver Y. , Pantaleo Giuseppe , Berezowska Sabina , Leval Laurence De , Gottardo Raphael , Petrovas Constantinos
Published: November 2024

The regulation of follicular (F) and germinal center (GC) immune reactivity in human lymph nodes (LNs), particularly during the early stages of viral infections, remains poorly understood. We have analyzed lung-draining lymph nodes (LD-LNs) from COVID-19 autopsies using multiplex imaging and spatial transcriptomics to examine the immune landscape and with respect to the aging. We identified three subgroups of Reactive Follicles (RFs) based on Bcl6 prevalence, RF-Bcl6no/low, RF-Bcl6int and RF-Bcl6high. RF-Bcl6high tissues express a distinct B/TFH immune landscape associated with increased prevalence of proliferating B- and TFH-cell subsets. Comparison between LD-LNs and matched subdiaphragmatic LNs revealed a disconnected Bcl6 reactivity between the two anatomical sites. LD-LNs Bcl6 reactivity was associated with a distinct spatial transcriptomic profile. TH1-associated genes/pathways (e.g. CXCR3, STAT5, TNF signaling) were significantly upregulated in RF-Bcl6no/low tissues while the RF-Bcl6high tissues exhibited significant upregulation of GC-promoting genes/pathways (e.g. CXCL13, B cell receptor signaling). Despite the similar prevalence, the in-situ transcriptome profiling indicates a higher monocyte/macrophage functionality in “Aged” compared to “Young” follicles from donors with comparable Bcl6 reactivity. Our findings reveal a heterogeneous F/GC landscape in COVID-19 LD-LNs and highlight specific molecular targets and pathways that could regulate human F/GC immune dynamics during early viral infections.
Evaluating the Survival and Removal ofEscherichia colifrom Surfaces Made with Traditional and Sustainable Cement-Based Materials in Field-Relevant Conditions
Authors: Anderson Claire E. , Hernandez Jason , Hanif Suhi , Owens Lauren , Crider Yoshika , Billington Sarah L. , Lepech Michael , Boehm Alexandria B. , Benjamin-Chung Jade
Published: November 2024

Soil household floors are common in low- and middle-income countries (LMICs) and can serve as reservoirs of enteric pathogens. Cement-based floors may interrupt pathogen transmission, but little is known about pathogen survival or removal from cement-based surfaces. This study investigated the survival ofEscherichia coli(E. coli), an indicator of fecal contamination, on cement-based surfaces and evaluated its reduction through common household activities (mopping, sweeping, and walking). We comparedE. colifate on three mixes: 1) Ordinary Portland Cement (OPC) concrete (used in the United States), 2) OPC mortar (used in Bangladesh), and 3) OPC mortar with fly ash (a sustainable alternative to the Bangladesh mix). Additionally, we compared outcomes on cement-based surfaces with and without soil and at two temperatures representing the dry and wet seasons in Bangladesh. After 4 hours on the cement-based surfaces,E. colidecayed more than 1.1 log10(C/Co) under all conditions tested, which is significantly faster than in bulk soils. The higher temperature increased the decay rate constant (p = 5.56*10−8) while soil presence decreased it (p = 2.80*10−6). Sweeping and mopping resulted in high levels of removal for all mixes, with a mean removal of 71% and 78%, respectively, versus 22% for walking. The concrete and mortar mix designs did not impactE. colisurvival or removal (p > 0.20). Cement-based floors made with a fly ash mix performed similarly to traditional cement-based floors, supporting its potential use as a more sustainable intervention to reduce fecal contamination in rural LMIC household settings.

Importance

Cement-based surfaces may serve as a health intervention to reduce the fecal-oral transmission of pathogens in household settings, but there is a critical lack of evidence about the fate of indicator organisms on these surfaces, especially in field-relevant conditions. This study provides some of the first insights intoE. colisurvival on cement-based surfaces and the effectiveness of daily activities for removingE. coli. Additionally, this study explores the fate ofE. colion cement-based surfaces made with fly ash (which contributes fewer CO2emissions) versus traditional cement mixes. We found thatE. colihad similar survival and removal across all mix designs, demonstrating that fly ash mixes are feasible for use in household settings (e.g., in floors). The findings enhance understanding of fecal-oral transmission pathways and support the use of fly ash mixes in cement-based flooring in future epidemiologic studies assessing effects on enteric disease burdens.
Automated cell detection for immediate early gene-expressing neurons using inhomogeneous background subtraction in fluorescent images
Authors: Osanai Hisayuki , Arai Miari , Kitamura Takashi , Ogawa Sachie K.
Published: November 2024

Although many methods for automated fluorescent-labeled cell detection have been proposed, not all of them assume a highly inhomogeneous background arising from complex biological structures. Here, we propose an automated cell detection algorithm that accounts for and subtracts the inhomogeneous background by avoiding high-intensity pixels in the blur filtering calculation. Cells were detected by intensity thresholding in the background-subtracted image, and the algorithm’s performance was tested on NeuN- and c-Fos-stained images in the mouse prefrontal cortex and hippocampal dentate gyrus. In addition, applications in c-Fos positive cell counting and the quantification for the expression level in double-labeled cells were demonstrated. Our method of automated detection after background assumption (ADABA) offers the advantage of high-throughput and unbiased analysis in regions with complex biological structures that produce inhomogeneous background.

Highlights

- We proposed a method to assume and subtract inhomogeneous background pattern.(79/85)

- Cells were automatically detected in the background-subtracted image.(71/85)

- The automated detection results corresponded with the manual detection.(73/85)

- Detection of IEG positive cells and overlapping with neural marker were demonstrated.(85/85)
RID-Rihaczek Phase Synchrony Method Applied to Resting-State EEG: Simultaneous prediction of visuospatial tracking, verbal communication, executive function, neuro-cognitive health, and intelligence
Authors: Miyatsu Toshiya , Mahyari Arash , Rogala Jacek , Broderick Timothy , Pirolli Peter
Published: November 2024

Brain activity at a resting state and functional connectivity represent individuals’ neural configurations that can be used to predict various performance and trait measures. Yet, most of the previous empirical demonstrations of this phenomena are limited to using resting-state neuroimaging to predict a single task performance/trait measure, and a few studies that predicted multiple task performance/traits measures employed conceptually similar tasks to produce converging evidence for their topic of investigation. In the current paper, we applied RID-Rihazcek phase synchrony, a nonlinear time-frequency-based method for neural computation, to resting-state EEG data and simultaneously predicted a wide variety of measures: standard shooting task performance and novel verbal communication-based team shooting task performance in a simulator, visuo-spatial tracking task performance (Neurotracker), executive function (verbal fluency task), fluid and crystalized Intelligence (Multidimensional Aptitude Battery II: MAB-II), and neurocognitive functioning (Automated Neuropsychological Assessment Metrics-4: ANAM-4) with the averageR2= .60. Our findings show great promise for RID-Rihazcek phase synchrony and resting-state EEG in general to be used in aptitude assessment.
Hormonal contraceptive intake during adolescence and cortical brain measures in the ABCD Study
Authors: Heller Carina , Dhamala Elvisha , Bottenhorn Katherine L. , Herting Megan M. , Bossé Brian , De La Rosa Jennifer S. , Farland Leslie V. , Allen Alicia M. , Barth Claudia , Petersen Nicole
Published: November 2024

Adolescence is a critical period in human development, marked by rapid changes in brain structure and function, influenced, in part, by sex steroids. During adolescence, females may initiate the use of hormonal contraception, which suppresses ovarian production of estradiol and progesterone. Here, we examined the impact of hormonal contraceptive use on adolescent brain structures using magnetic resonance imaging data from 1,234 individuals from the ABCD Study (average age = 14 years). We investigated differences in cortical thickness, surface area, and volume in hormonal contraceptive-users compared to non-users. Statistically significant differences were observed in several regions, and differences in cortical thickness of the paracentral gyrus survived familywise error correction. Estradiol, testosterone and DHEA levels negatively correlated with cortical thickness, surface area, and volume across both hormonal contraceptive-users and non-users only at an uncorrected threshold. These findings highlight the need to further study longitudinal effects of hormonal contraceptives and endogenous hormone changes on brain development in the ABCD Study and related datasets as these data become available.
Cerebellar-Prefrontal Connectivity Predicts Negative Symptom Severity Across the Psychosis Spectrum
Authors: Yarrell Sean A. , Blyth Sophia H. , Rogers Baxter P. , Huang Anna , Moussa-Tooks Alexandra B. , Woodward Neil D. , Heckers Stephan , Brady Roscoe O. , Ward Heather Burrell
Published: November 2024

Background

Negative symptom severity predicts functional outcome and quality life in people with psychosis. However, negative symptoms are poorly responsive to antipsychotic medication and existing literature has not converged on their neurobiological basis. Previous work in small schizophrenia samples has observed that lower cerebellar-prefrontal connectivity is associated with higher negative symptom severity and demonstrated in a separate neuromodulation experiment that increasing cerebellar-prefrontal connectivity reduced negative symptom severity. We sought to expand this finding to test associations between cerebellar-prefrontal connectivity with negative symptom severity and cognitive performance in a large, transdiagnostic sample of individuals with psychotic disorders.

Methods

In this study, 260 individuals with psychotic disorders underwent resting-state MRI and clinical characterization. Negative symptom severity was measured using the Positive and Negative Symptoms Scale, and cognitive performance was assessed with the Screen for Cognitive Impairment in Psychiatry. Using a previously identified cerebellar region as a seed, we performed seed to whole brain analyses and regressed connectivity against negative symptom severity, using age and sex as covariates.

Results

Consistent with prior work, we identified relationships between higher cerebellar-prefrontal connectivity and lower negative symptom severity (r=-0.17, p=.007). Higher cerebellar-prefrontal connectivity was also associated with better delayed verbal learning (r=.13, p=.034).

Conclusions

Our results provide further evidence supporting the relationship between cerebellar-prefrontal connectivity and negative symptom severity and cognitive performance. Larger, randomized, sham-controlled neuromodulation studies should test if increasing cerebellar-prefrontal connectivity leads to reductions in negative symptoms in psychosis.
MOSAIC: A Pipeline for MicrobiOme Studies Analytical Integration and Correction
Authors: Fu Chenlian , Lu Jiuyao , Zhao Ni , Ling Wodan
Published: November 2024

Large-scale and consortium microbiome studies have enabled identification of reliable population-level biomedical signals, wherein integration is essential to eliminate unwanted variations between batches or studies and retain biological signals. Many strategies, each with distinct advantages and limitations, have been adapted or developed for microbiome data. The optimal strategy for a given study needs to be determined on a data-specific, case-by-case basis. Here, we develop the first-of-its-kind MicrobiOme Studies Analytical Integration and Correction (MOSAIC) pipeline to enable a convenient, fair, and comprehensive comparison of integration strategies. It includes modules for pre-processing, integration, and evaluation of artifact removal and signal preservation, using metrics relevant to common microbiome analyses, including alpha and beta diversities, disease prediction, and differential abundance analysis. We applied MOSAIC to extensive real-world and simulated data and found that though no single strategy excels in all aspects, yet certain strategies, the ComBat and ConQuR families, perform better overall.
Complex optogenetic spatial patterning with split recombinase
Authors: Kinstlinger Ian S. , Neu Erin M. , Mowry Shea K. , Tous Cristina , Kotton Darrell N. , Wong Wilson W.
Published: November 2024

Light is a powerful and flexible input into engineered biological systems and is particularly well-suited for spatially controlling genetic circuits. While many light-responsive molecular effectors have been developed, there remains a gap in the feasibility of using them to spatially define cell fate. We addressed this problem by employing recombinase as a sensitive light-switchable circuit element which can permanently program cell fate in response to transient illumination. We show that by combining recombinase switches with hardware for precise spatial illumination, large scale heterogeneous populations of cells can be generatedin situwith high resolution. We envision that this approach will enable new types of multicellular synthetic circuit engineering where the role of initial cell patterning can be directly studied with both high throughput and tight control.
Biochemical, structural, and single-molecule characterization of LIG1 active site mutants demonstrate role of F635 and F872 residues for faithful ligation
Authors: Kalaycioğlu Mustafa , Gulkis Mitchell , Lee Kar Men , Chatterjee Surajit , Balu Kanal , Tang Qun , Ratcliffe Jacob E. , Castro Erick , Almahdor Danah , Çağlayan Melike
Published: November 2024

Human DNA ligase 1 (LIG1) finalizes DNA repair pathways by an ultimate ligation step and discriminates against nicks containing unusual ends, yet the contribution of the conserved active site residues for faithful end joining remains unknown. Here, using biochemistry, X-ray crystallography, and single-molecule approaches, we comprehensively characterized LIG1 mutants carrying Ala(A) and Leu(L) substitutions at the active site residues Phe(F)635 and Phe(F)872. Our results showed an abolished ligation of nick DNA substrates with all 12 non-canonical mismatches, while the mutagenic nick sealing of oxidatively damaged ends by wild-type enzyme is significantly reduced by F635A/L and F872A/L substitutions. Furthermore, sugar discrimination against a single ribonucleotide at 3’- or 5’-end of nick DNA is distinctly affected depending on architecture of 3’-terminus:template base pairing. Finally, our LIG1 structures demonstrated the importance of DNA end alignment governed by the distance to nick site through F635 and F872 residues, and single-molecule measurements showed similar nick DNA binding modes for LIG1 wild-type and active site mutants in real-time. Overall, our study provides a mechanistic insight into the mechanism by which conserved F635 and F872 residues contribute to ligation efficiency of nick repair intermediates that mimic DNA polymerase-mediated mismatch, damaged, or ribonucleotide insertion products and how LIG1 ensures faithful end joining at the final step of DNA repair to maintain genome integrity.
DNA StairLoop: Achieving High Error-correcting and Parallel-processing Capabilities in DNA-based Data Storage
Authors: Yan Zihui , Qu Guanjin , Chen Xin , Zheng Gang , Wu Huaming
Published: November 2024

DNA-based data storage is a promising solution to the challenges of large-scale data storage. However, the low throughput of the mainstream inkjet-based DNA synthesis method has hindered its widespread adoption. In contrast, high-throughput electrochemical synthesis provides higher throughput but with more nucleotide insertion, deletion, and substitution errors. Here, we propose an innovative coding scheme with high error correction capabilities, called DNA StairLoop. This coding scheme features a staircase interleaver and allows for component codes such as the convolutional code and the ow-density Parity-check code, allowing for flexible adaptation of the coding scheme. Both the row and the column decoders are soft input and soft output, enabling further improvement in data recovery accuracy through iterative decoding. The staircase interleaver facilitates extensive parallel decoding capabilities while effectively preserving parallelism across a multitude of nodes. In the in vitro experiment, DNA StairLoop successfully recovered the raw information in a staircase block with a nucleotide error rate of more than 8%. The simulations revealed that the DNA StairLoop can correct 10% nucleotide errors. Moreover, in parallel computing processing, the decoding time of our code continues to decrease dramatically.
Reliability of large language model knowledge across brand and generic cancer drug names
Authors: Gallifant Jack , Chen Shan , Jain Sandeep K. , Moreira Pedro , Topaloglu Umit , Aerts Hugo JWL , Warner Jeremy L. , Cava William G. La , Bitterman Danielle S.
Published: November 2024

Purpose

To evaluate the performance and consistency of large language models (LLMs) across brand and generic oncology drug names in various clinical tasks, addressing concerns about potential fluctuations in LLM performance due to subtle phrasing differences that could impact patient care.

Methods

This study evaluated three LLMs (GPT-3.5-turbo-0125, GPT-4-turbo, and GPT-4o) using drug names from the HemOnc ontology. The assessment included 367 generic-to-brand and 2,516 brand-to-generic pairs, 1,000 drug-drug interaction synthetic patient cases, and 2,438 immune-related adverse event (irAE) cases. LLMs were tested on drug name recognition, word association, drug-drug interaction (DDI) detection, and irAE diagnosis using both brand and generic drug names.

Results

LLMs demonstrated high accuracy in matching brand and generic names (GPT-4o: 97.38% for brand, 94.71% for generic, p < 0.0001). However, they showed significant inconsistencies in word association tasks. GPT-3.5-turbo-0125 exhibited biases favoring brand names for effectiveness (OR 1.43, p < 0.05) and being side-effect-free (OR 1.76, p < 0.05). DDI detection accuracy was poor across all models (<26%), with no significant differences between brand and generic names. Sentiment analysis revealed significant differences, particularly in GPT-3.5-turbo-0125 (brand mean 0.6703, generic mean 0.9482, p < 0.0001). Consistency in irAE diagnosis varied across models.

Conclusions and Relevance

Despite high proficiency in name-matching, LLMs exhibit inconsistencies when processing brand versus generic drug names in more complex tasks. These findings highlight the need for increased awareness, improved robustness assessment methods, and the development of more consistent systems for handling nomenclature variations in clinical applications of LLMs.

Context Summary

Key objective

This study aimed to assess the consistency of large language models (LLMs) in handling brand and generic oncology drug names across various tasks, including drug-drug interaction detection and adverse event identification.

Knowledge generated

LLMs demonstrated high accuracy in matching brand and generic names but showed significant inconsistencies in more complex tasks. Notable, models exhibited significant differences in attributing brand versus generic names to positive terms and sentiment.
Decoding the biology of ethnic differences in asthma
Authors: Ni Duan , Nanan Ralph
Published: November 2024

Ethnicity seems to be a risk factor for asthma and its exacerbation, but no general consensus has been reached so far. Ethnic diversity and differences have long been overlooked and most studies in these regards are observational, lacking in-depth mechanistic insights.

Harnessing comprehensive transcriptomic data at organ system and single cell levels, we comparatively analyzed the signalling landscapes of African American/Black (AA) and other ethnicities. In healthy individuals, most AA PBMC subsets exhibited elevated IL2-STAT5 signals, which is critically implicated in asthma pathogenesis. This extended to various compartments (bronchial and airway epithelium, circulating CD4+T cells and blood) in asthma, where AA upregulated IL2-STAT5 pathway relative to other ethnicities. Mechanistically, the increased IL2-STAT5 signalling correlated with enhanced T cell migration and recruitment. Together, they might contribute to the greater predisposition towards asthma exacerbation in AA.

This first-of-its-kind study sheds some in-depth insights into the biology of ethnic differences in asthma. Our findings, if further validated, will be valuable for future asthma research and clinical practice like therapeutic development and treatment guidance, highlighting the need for ethnicity diversity and inclusions in these areas.
Sex-specific risk of smoking for abdominal aortic aneurysm and exploration of potential mechanism: meta-analysis and prospective cohort study
Authors: Welsh Paul , Pouncey Anna-Louise , Powell Janet T
Published: November 2024

Background

Smoking is the strongest modifiable risk factor for abdominal aortic aneurysm (AAA). This study aims to confirm whether smoking is a stronger risk factor in women than men and identify contributory reasons, including inflammation, for any sex-specific difference observed.

Methods

Systematic review and meta-analysis, conducted according to PRISMA guidance (Prospero registration (CRD2024586609)). Data sources were Medline, Embase, and CENTRAL. Population-based studies reporting risk of AAA, adjusted for age and cardiovascular risk factors, for women versus men, were included. These were complemented by data from the UK Biobank (UKB) cohort, which also were assessed for sex-specific effects of smoking on incident atherosclerotic cardiovascular disease (ASCVD). Results: Meta-analysis of 6 studies (including UKB), 2001-2024) showed that the relative risk ratio of current versus never-smokers for incident AAA in women versus men was 1.78 [95%CI 1.32, 2.38]. Comparison of the sex-specific relative risks of current smoking and number of cigarettes/day were similar in the UKB cohort and these risks were much higher for AAA than for ASCVD, but the risks of pack-years were similar. Sex-specific risks of current smoking for AAA were not significantly modified by inflammatory markers (including C-reactive protein, alkaline phosphatase and white blood cell count), lung function or physical activity. Stopping smoking reduced the risk of AAA by almost half in both sexes. Conclusions: The risk of developing AAA by current smokers is almost twice as high in women versus men. Inflammation was not a major modifier and other reasons for the disparity must be sought.
A protocol for high-dose quadrivalent influenza vaccine effectiveness in the community and long-term care facilities using electronic health records
Authors: Soares Patrícia , Gomez Verónica , Gaio Vânia , Santos João Almeida , Rodrigues Ana Paula , Machado Ausenda
Published: November 2024

Since the 2022-2023 season in Portugal, a high-dose quadrivalent influenza vaccine is freely available for individuals living in long-term care facilities (LTCF). In 2024-2025, vaccination was extended to community-dwelling individuals aged ≥85 years. Given the scarcity of reported high-dose influenza vaccine effectiveness (IVE) estimates for this population, this study aims to estimate the high-dose relative and absolute IVE.

A retrospective cohort study using data from electronic health records databases (EHR) will be implemented, using two cohorts, one of individuals vaccinated with influenza vaccine (to estimate relative IVE) and another of individuals eligible for the high-dose quadrivalent influenza vaccine (to estimate absolute IVE). We will consider two subgroups for both cohorts: individuals living in LTCF and community-dwelling individuals aged ≥85. We will use a fixed cohort approach, defining the eligible population by age at the vaccination campaign(s) start and living status. The outcomes are based on the primary cause of hospital admission. The reference population database will be defined by linking EHR on vaccination, comorbidities, and hospitalisations using a unique identifier through a deterministic data linkage procedure, and influenza vaccination status will be assessed retrospectively. We will use Cox proportional hazards regression models to estimate the hazard ratio (HR), considering as event the first hospitalisation due to influenza-like-illness and as exposure the vaccination status. IVE will be estimated as one minus the confounder-adjusted HR of vaccinated with the high-dose quadrivalent influenza vaccine vs vaccinated with standard dose (to estimate relative IVE) or unvaccinated (to estimate absolute IVE).

While challenges such as EHR constraints and potential reporting bias pose limitations, using routinely collected data has successfully estimated COVID-19 VE and enables precise monitoring of VE with higher representativeness. The results of this study will inform the Health Ministry on the future influenza vaccine programme in Portugal.
A comprehensive representation of selection at loci with multiple alleles that allows complex forms of genotypic fitness
Authors: Vellnow Nikolas , Gossmann Toni I. , Waxman David
Published: November 2024

Genetic diversity is central to the process of evolution. Both natural selection and random genetic drift are influenced by the level of genetic diversity of a population; selection acts on diversity while drift samples from it. At a given locus in a diploid population, each individual carries only two alleles, but the population as a whole can possess a much larger number of alleles, with the upper limit constrained by twice the population size. This allows for many possible types of homozygotes and heterozygotes. Moreover, there are biologically important loci, for example those related to the MHC complex, the ABO blood types, and cystic fibrosis, that exhibit a large number of alleles. Despite this, much of population genetic theory, and data analysis, are limited to considering biallelic loci. However, to the present, what is lacking is a flexible expression for the force of selection that allows an arbitrary number of alleles (and hence an arbitrary number of heterozygotes), along with a variety of forms of fitness. In this work, we remedy this absence by giving an analytical representation of the force of selection that emphasises the very different roles played by the diversity of the population, and the fitnesses of different genotypes. The result presented facilitates our understanding and applies in a variety of different situations involving multiple alleles. This includes situations where fitnesses are: additive, multiplicative, randomly fluctuating, frequency-dependent, and it allows fitnesses which involve explicit gene interactions, such as heterozygote advantage.

Significance statement

Genetic diversity is a cornerstone of evolutionary processes, influencing both natural selection and genetic drift. While many biologically significant loci, like those associated with the MHC complex, ABO blood types, and cystic fibrosis, contain a large number of alleles, population genetics often simplifies analysis to biallelic loci. This study provides a new, flexible framework to quantify the force of selection in populations with an arbitrary number of alleles. This approach broadens our understanding of complex genetic scenarios, including those involving additive, multiplicative, and frequency-dependent fitness, as well as heterozygote advantage. This advancement enables more nuanced modeling of real-world evolutionary dynamics across diverse biological contexts.
Long-Read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons
Authors: Xu Jishu , Hörner Michaela , Atienza Elena Buena , Manibarathi Kalaivani , Nagel Maike , Hauser Stefan , Admard Jakob , Casadei Nicolas , Ossowski Stephan , Schüle Rebecca
Published: November 2024

Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing, and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of human fibroblasts, induced pluripotent stem cells, and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15,072 transcripts in stem cell-derived cortical neurons, 13,048 in fibroblasts, and 12,759 in induced pluripotent stem cells. Our analyses uncovered 35,519 differential transcript expression events and 5,135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Notably, differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such asAPP, KIF2A, andBSCL2, associated with Alzheimer’s disease, neuronal migration disorders, and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript- level variations that often remain hidden in traditional differential gene expression analyses.

Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.
Cellular moonlighting function of Hsp20 directs morphological and pathogenic development inUstilago maydis
Authors: Mitra Aroni , Kar Ankita , Bhakta Koustav , Roy Anisha , Mukherjee Dibya , Ghosh Abhrajyoti , Ghosh Anupama
Published: November 2024

Ustilago maydisHsp20 is involved in the pathogenicity of the fungus. In this study we have investigated the molecular basis of contribution of Hsp20 toU. maydispathogenicity. Through biochemical studies we have demonstrated environment-dependent oligomeric plasticity associated with Hsp20. Hsp20 was also found to form higher order oligomers that undergo phase separation in vitro. Within cells Hsp20 was found to form distinct punctate structures that we believe play a pivotal role in its function. These punctate structures were demonstrated to sequester proteins such as actin and septin within it. Absence of Hsp20 was found to significantly affect key cellular processes like endocytosis, budding, cell polarity determination and mating inU. maydiscells. The deletion mutant failed to sporulate and complete pathogenic life cycle. This study presents a comprehensive understanding of the pathogenic development ofU. maydisin reference to the moonlighting function of Hsp20 within the cell.
Adducins regulate morphology and fate of neural progenitors during neocortical neurogenesis
Authors: Ossola Chiara , Cokorac Nikola , Faletti Stefania , Capra Emanuele , Bertani Ilaria , Ambrosini Chiara , Faga Giovanni , Kalebic Nereo
Published: November 2024

The evolutionary expansion of the mammalian neocortex is mediated by an increase in the proliferative capacity of neural progenitor cells. However, the molecular machinery controlling the proliferation of apical and basal progenitors during neocortical development is still poorly understood. Here we show that the three actin-associated morpho-regulatory adducins (ADD1-3), underlie abundance of basal progenitors in developing mouse and ferret neocortexin vivoand in human cortical organoids. Over expression of adducins in embryonic mouse neocortex increases the number of protrusions of basal progenitors, leading to an increase in their proliferative capacity and neuronal output. Conversely, knock-out of ADD1 in human cortical organoids, which also leads to down-regulation of other adducins, results in reduced proliferation of progenitors and aberrant neurogenesis. Hence, we show that adducins underlie proliferation and fate of neural progenitors, which are key cellular features underlying progression of mammalian neurogenesis.
An environment-responsive SCLA-type GRAS protein controls reproductive strategy inMarchantia polymorpha
Authors: Hoey David J. , Carella Philip , Yang Weibing , Schornack Sebastian
Published: November 2024

By controlling their reproductive strategies, plants strike a balance between generating genetic diversity or maintaining stability, promoting long-term survival in a range of environmental conditions. The liverwortMarchantia polymorphapropagates clonally through vegetative gemmae or via sexually generated spores, but our understanding of the genetic pathways underpinning reproductive decision-making is limited. GRAS transcriptional regulators are highly conserved proteins across land plants, with diverse functionality in stress and development. Here, we discover a central role for the SCLA-type transcription regulator MpGRAS7in both stress signalling and reproduction in Marchantia. MpGRAS7is highly expressed in gemma cups and gametangiophores and is activated in response to Far Red (FR) light and abscisic acid (ABA) environmental cues. Genetic dissection further suggests MpGRAS7is required to maintain gemma dormancy, gemma cup frequency, and FR-induced gametangiophore development. The sequence conservation and expression patterns of MpGRAS7orthologs in flowering plants hints towards the broader function of SCLA-type GRAS proteins in stress-regulated developmental transitions in plants.
The landscape of structural variation in aye-ayes (Daubentonia madagascariensis)
Authors: Versoza Cyril J. , Jensen Jeffrey D. , Pfeifer Susanne P.
Published: November 2024

Aye-ayes (Daubentonia madagascariensis) are one of the 25 most critically endangered primate species in the world. Endemic to Madagascar, their small and highly fragmented populations make them particularly vulnerable to both genetic disease and anthropogenic environmental changes. Over the past decade, conservation genomic efforts have largely focused on inferring and monitoring population structure based on single nucleotide variants to identify and protect critical areas of genetic diversity. However, the recent release of a highly contiguous genome assembly allows, for the first time, for the study of structural genomic variation (deletions, duplications, insertions, and inversions) which are likely to impact a substantial proportion of the species’ genome. Based on whole-genome, short-read sequencing data from 14 individuals, >1,000 high-confidence autosomal structural variants were detected, affecting ∼240 kb of the aye-aye genome. The majority of these variants (>85%) were deletions shorter than 200 bp, consistent with the notion that longer structural mutations are often associated with strongly deleterious fitness effects. For example, two deletions longer than 850 bp located within disease-linked genes were predicted to impose substantial fitness deficits owing to a resulting frameshift and gene fusion, respectively; whereas several other major effect variants outside of coding regions are likely to impact gene regulatory landscapes. Taken together, this first glimpse into the landscape of structural variation in aye-ayes will enable future opportunities to advance our understanding of the traits impacting the fitness of this endangered species, as well as allow for enhanced evolutionary comparisons across the full primate clade.
Ccp1 depletion disrupts network integration of hippocampal parvalbumin interneurons
Authors: Le Bail Romain , Lakaye Bernard , Espuny-Camacho Ira , Janke Carsten , Magiera Maria M. , Engel Dominique , Silva Carla G. , Nguyen Laurent
Published: November 2024

Post-translational modifications (PTMs) of microtubules (MTs) endow them with specific properties that are essential for key cellular functions, such as axonal transport. Polyglutamylation, a PTM that accumulates in long-lived MTs, has been linked to neurodegeneration in the cerebellum when in excess. While hyperglutamylation of MTs leads to neurodegeneration and disrupts the function of specific neuronal subtypes like Purkinje cells, cortical neurons, and hippocampal excitatory neurons, little is known about its impact on inhibitory interneurons and their functional integration into local networks. In this study, we generated a conditional knockout mouse model to deplete cytosolic carboxypeptidase 1 (Ccp1) in GABAergic neurons, a key MT deglutamylase expressed by hippocampal interneurons. Our findings reveal that the loss of Ccp1 has a profound effect on hippocampal parvalbumin (PV)-expressing interneurons, impairing their axonal transport and reducing their perisomatic inhibition of pyramidal cells (PCs) in the CA2 region of the hippocampus.

Research Topics

Molecular Neuroscience, Cell Biology

Highlights

Different subtypes of hippocampal interneurons express unique sets of (de)glutamylases and show varying levels of protein posttranslational glutamylation.

Parvalbumin interneurons become hyperglutamylated when Ccp1 activity is lost.

The loss of Ccp1 disrupts axonal transport in interneurons and is associated with decreased perisomatic inhibition of hippocampal pyramidal cells in the CA2 region.
Development of a New N-Terminomic Method to Study the Pathodegradome of theStaphylococcus aureusV8 Protease in Human Neutrophils
Authors: Mustor Emilee M. , Frey Andrew M. , Jobson Mary-Elizabeth , Chaput Dale , Shaw Lindsey Neil
Published: November 2024

Staphylococcus aureusis a notorious human pathogen that relies on an array of virulence factors to engender infection and evade the host-immune system. Among these are the secreted proteases, which promote pathogenesis by degrading host proteins and modulating host-defenses. Human neutrophils play a pivotal role in these defenses, acting as the first responders against invading bacteria. While manyS. aureuseffectors of virulence have been shown to target leukocytes, there is limited knowledge on how the extracellular proteases modulate neutrophil fate. Typically, protease substrates have been identified in isolated settings using one at a time approaches; with neutrophil targets few and far between. Herein, we have developed a novel N-terminomic methodology termed TAGS-CR that can facilitate global substrate characterization in streamlined manner. We thus present the application of TAGS-CR to unravelling the human neutrophil pathodegradome of theS. aureusV8 protease. In so doing, we captured ∼350 V8 targets, revealing critical insight into how this virulence factor can modulate neutrophil functionality on various levels relevant toS. aureusdisease progression. We recorded cleavage of proteins necessary for neutrophil adhesion and migration, a fundamental process necessary for pathogen clearance. Furthermore, we highlight V8 cleavage of proteins involved in important neutrophil defense tactics, such as degranulation and reactive oxygen species production. This protease may also facilitate bacterial dissemination via the intentional activation of neutrophil apoptosis. Collectively, this work deepens our understanding of host-pathogen interaction and begins to unravel howS. aureusproteases can induce immune dysregulation through the targeting of leukocytes.

Importance

During infectionStaphylococcus aureusmust engage and evade the host immune system in order to successfully cause disease. As neutrophils represent the frontline of defense against invadingS. aureuscells, it becomes increasingly important to decode how this bacterium subverts their host-defense tactics. While the contributing role to neutrophil engagement for manyS. aureusvirulence factors have been elucidated, the effects of their proteases remain largely unclear. Here, we present a novel method for global protease substrate identification, TAGS-CR, and use it to identifyS. aureusV8 protease targets in human neutrophils. These include factors that not only govern general neutrophil function but moreover, their defense mechanisms, such as migration, degranulation, oxidative defense, phagocytosis and apoptosis.
Inferring Cell-Type-Specific Co-Expressed Genes from Single Cell Data
Authors: Shan Xinning , Zhao Hongyu
Published: November 2024

Background

Cell-type-specific gene co-expression networks are widely used to characterize gene relationships. Although many methods have been developed to infer such co-expression networks from single-cell data, the lack of consideration of false positive control in many evaluations may lead to incorrect conclusions because higher reproducibility, higher functional coherence, and a larger overlap with known biological networks may not imply better performance if the false positives are not well controlled.

Results

In this study, we have developed an efficient and effective simulation tool to derive empirical p-values in co-expression inference to appropriately control false positives in assessing method performance. We studied the power of the p-value-based approach in inferring cell-type-specific co-expressions from single-cell data using both simulated and real data. We also highlight the need to adjust for random overlaps between the inferred and known networks when the number of selected correlated gene pairs varies substantially across different methods. We further illustrate the expression level bias in known biological networks and the impact of such bias in method assessment.

Conclusion

Our study indicates the importance of controlling false positives in the inference of co-expressed genes to achieve more reliable results and proposes a simulation-based p-value method to achieve this.
Structure of the TXNL1-bound proteasome
Authors: Gao Jingjing , Nardone Christopher , Yip Matthew C.J. , Chino Haruka , Gu Xin , Mirman Zachary , Rale Michael J. , Paulo Joao A. , Elledge Stephen J. , Shao Sichen
Published: November 2024

Proteasomes degrade diverse proteins in different cellular contexts through incompletely defined regulatory mechanisms. Here, we report the cryo-EM structure of thioredoxin-like protein 1 (TXNL1) bound to the 19S regulatory particle of proteasomes via interactions with PSMD1/Rpn2, PSMD4/Rpn10, and PSMD14/Rpn11. These interactions are necessary for the ubiquitin-independent degradation of TXNL1 upon cellular exposure to metal- or metalloid-containing oxidative agents, thereby establishing a structural basis for the stress-induced degradation of TXNL1.