bluuebunny/crossref_metadata_2025 huggingface dataset:
A tradeoff between bacteriophage resistance and bacterial motility is mediated by the Rcs phosphorelay in Escherichia coli
Authors: Burmeister Alita R. , Tewatia Harleen , Skinner Chloé
Published: August 2024

Across the tree of life, pleiotropy is thought to constrain adaptation through evolutionary tradeoffs. However, few examples of pleiotropy exist that are well explained at the genetic level, especially for pleiotropy that is mediated by multiple genes. Here, we describe a set of pleiotropic mutations that mediate two key fitness components in bacteria: parasite resistance and motility. We subjected Escherichia coli to strong selection by phage U136B to obtain 27 independent mucoid mutants. Mucoidy is a phenotype that results from excess exopolysaccharide and can act as a barrier against viral infection but can also interfere with other cellular functions. We quantified the mutants’ phage resistance using efficiency of plaquing assays and swimming motility using swim agar plates, and we sequenced the complete genomes of all mutants to identify mucoid-causing mutations. Increased phage resistance co-occurred with decreased motility. This relationship was mediated by highly parallel (27/27) mutations to the Rcs phosphorelay pathway, which senses membrane stress to regulate exopolysaccharide production. Together, these results provide an empirical example of a pleiotropic relationship between two traits with intermediate genetic complexity.
ARHGAP12 suppresses F-actin assembly to control epithelial tight junction mechanics and paracellular leak pathway permeability
Authors: Tambrin Hana Maldivita , Liu Yun , Zhu Kexin , Teng Xiang , Toyama Yusuke , Miao Yansong , Ludwig Alexander
Published: August 2024

Tight junctions (TJ) separate body compartments and control the paracellular transport of ions, solutes, and macromolecules across epithelial barriers. There is evidence that claudin-based ion transport (the pore pathway) and the paracellular transport of macromolecules (the leak pathway) are independently regulated processes. However, how leak pathway permeability is controlled is not well understood. Here we have identified the Cdc42/Rac GTPase activating protein ARHGAP12 as a novel and specific regulator of the leak pathway. ARHGAP12 is recruited to TJ via an interaction between its SH3 domain and the TJ protein ZO-2. Using a combination of biochemical and biophysical approaches, in vitro actin polymerisation assays, and permeability assays in MDCK-II cells, we show that ARHGAP12 suppresses N-WASP-mediated F-actin assembly at TJ to dampen junctional tension. This promotes paracellular leak pathway permeability without affecting ion flux. Mechanistically, we demonstrate that the ARHGAP12 tandem WW domain interacts directly and in a multivalent manner with an array of PPxR motifs in the proline-rich domain of N-WASP. This interaction is sufficient to suppress SH3 domain-mediated N-WASP oligomerisation and Arp2/3-driven F-actin assembly in vitro. Collectively our data demonstrate a critical role for ARHGAP12 in suppressing junctional F-actin assembly and tension to promote the flux of small macromolecules across the TJ.
A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer
Authors: de Almeida Francisca Nunes , Vasciaveo Alessandro , Antao Ainsley Mike , Zou Min , Di Bernardo Matteo , de Brot Simone , Rodriguez-Calero Antonio , Chui Alexander , Wang Alexander L.E. , Floc’h Nicolas , Kim Jaime Y. , Afari Stephanie N. , Mukhammadov Timur , Arriaga Juan Martín , Lu Jinqiu , Shen Michael M. , Rubin Mark A. , Califano Andrea , Abate-Shen Cory
Published: August 2024

Although localized prostate cancer is relatively indolent, advanced prostate cancer manifests with aggressive and often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we leveragedSleeping Beauty (SB)transposon mutagenesis in a mouse model based on prostate-specific loss-of-function ofPtenandTp53. Compared with control mice,SBmice developed more aggressive prostate tumors, with increased incidence of metastasis. Notably, a significant percentage of theSBprostate tumors display NEPC phenotypes, and the transcriptomic features of theseSBmouse tumors recapitulated those of human NEPC. We identified commonSBtransposon insertion sites (CIS) and prioritized associated CIS-genes differentially expressed in NEPC versus non-NEPCSBtumors. Integrated analysis of CIS-genes encoding for proteins representing upstream, post-translational modulators of master regulators controlling the transcriptional state ofSB-mouse and human NEPC tumors identifiedsirtuin 1(Sirt1) as a candidate mechanistic determinant of NEPC. Gain-of-function studies in human prostate cancer cell lines confirmed that SIRT1 promotes NEPC, while its loss-of-function or pharmacological inhibition abrogates NEPC. This integrative analysis is generalizable and can be used to identify novel cancer drivers for other malignancies.

Using an unbiased forward mutagenesis screen in an autochthonous mouse model, we have investigated mechanistic determinants of aggressive prostate cancer. SIRT1 emerged as a key regulator of neuroendocrine prostate cancer differentiation and a potential target for therapeutic intervention.
Stepwise Bayesian Machine Learning Uncovers a Novel Gene Regulatory Network Component in Neural Tube Development
Authors: Xing Chen , Sakumura Yuichi , Kokaji Toshiya , Kunida Katsuyuki , Sasai Noriaki
Published: August 2024

Recent advancements in machine learning-based data processing techniques have facilitated the inference of gene regulatory interactions and the identification of key genes from multidimensional gene expression data. In this study, we applied a stepwise Bayesian framework to uncover a novel regulatory component involved in differentiation of specific neural and neuronal cells. We treated naive neural precursor cells with Sonic Hedgehog (Shh) at various concentrations and time points, generating comprehensive whole-genome sequencing data that captured dynamic gene expression profiles during differentiation. The genes were categorized into 224 subsets based on their expression profiles, and the relationships between these subsets were extrapolated. To accurately predict gene regulation among subsets, known networks were used as a core model and subsets to be added were tested stepwise. This approach led to the identification of a novel component involved in neural tube patterning within gene regulatory networks (GRNs), which was experimentally validated. Our study highlights the effectiveness of in silico modeling for extrapolating GRNs during neural development.
c-Abl Kinase Targets Tight Junction Protein ZO-2 in Regulation of Cell Migration and Morphology
Authors: Choi Doo Eun , Gweon Bomi , Notbohm Jacob , Liu Xue-song , Fredberg Jeffrey J.
Published: August 2024

c-Abl is a non-receptor tyrosine kinase involved in the regulation of cell migration and morphogenesis, but underlying mechanism remains unclear. Here, we report the identification of tight junction protein ZO-2 as a bona fide substrate of c-Abl. We show that c-Abl directly binds to and phosphorylates the C-terminus of ZO-2. In addition, c-Abl stimulates the activity of JAK1, which subsequently phosphorylates the N-terminus of ZO-2. Using the RNAi-mediated knockdown/rescue strategy, we demonstrate that c-Abl regulates cellular morphology and migration through targeting ZO-2 for phosphorylation. c-Abl activity is also associated with decreased traction forces exerted on the cell substrate and reduced monolayer tension, thus corroborating c-Abl kinase activity-mediated inhibition of cell migration. Collectively, our data uncover ZO-2 as a novel mediator for c-Abl-dependent regulation of cell migration.
Spatial model of cell-fate choice uncovers strong links between tissue morphology and tissue regeneration
Authors: Mani Somya , Tlusty Tsvi
Published: August 2024

Tissues in multicellular organisms are immensely diverse: animal tissues include sheet-like epithelia, bundles of syncitial muscle fibres and the branched and interconnected nerves, while plants contain sheet-like epidermis and highly organized bundles of vascular tissue. However, at the microanatomical level, tissues are notably similar in that they are organized into distinct domains: domains are characterized by their cellular compositions and hold precise adjacency relations among each other. These morphological similarities are surprising because multicellularity has evolved multiple times independently. Separately, tissues also hold a remarkable functional similarity: across all multicellular organisms, including poor regenerators such as mammals, tissues routinely heal from injuries. The cellular organization within tissues, as well as the ability regenerate result from developmental processes: cells divide, die, differentiate and migrate according to cues they receive from their neighborhoods.

We ask two interlinked questions: What diversity of tissue morphology can simple developmental processes generate? And is tissue morphology related to tissue regeneration? We address these questions using an agent based model of cell-fate decisions where cells use simple rules to respond to their cellular neighborhoods

Our model produces a rich diversity of tissue morphologies: By simply tuning the density of cellular interactions and the propensity of cellular differentiation, we produce tissues that go from disordered and sparse to tissues organized into dense and contiguous domains. Importantly, tissue morphology was strongly linked to regeneration in the model: the ability to heal was highly enriched in densely packed, contiguous tissues. Moreover, the predominant mode of tissue healing in the model recapitulates natural mechanisms: tissues healed through the replacement of injured cells through cell-division in adjacent regions. Our work generates experimentally testable predictions on the effects of manipulating cellular interactions on tissue morphology and in turn, on tissue regeneration.
Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity
Authors: Beentjes Sjoerd Viktor , Kaczmarczyk Julia , Cassar Amanda , Samms Gemma Louise , Hejazi Nima S. , Khamseh Ava , Ponting Chris P.
Published: August 2024

Myalgic Encephalomyelitis (ME; sometimes referred to as chronic fatigue syndrome [CFS]) is a relatively common and female-biased disease of unknown pathogenesis that profoundly decreases patients’ health-related quality-of-life. ME/CFS diagnosis is hindered by the absence of robustly-defined and specific biomarkers that are easily measured from available sources such as blood, and unaffected by ME/CFS patients’ low level of physical activity. Previous studies of blood biomarkers have not yielded replicated results, perhaps due to low study sample sizes (n <100). Here, we use UK Biobank (UKB) data for up to 1,455 ME/CFS cases and 131,303 population controls to discover hundreds of molecular and cellular blood traits that differ significantly between cases and controls. Importantly, 116 of these traits are replicated, as they are significant for both female and male cohorts. Our analysis used semi-parametric efficient estimators, an initial Super Learner fit followed by a one-step correction, three types of mediators, and natural direct and indirect estimands, to decompose the average effect of ME/CFS status on molecular and cellular traits. Strikingly, these trait differences cannot be explained by ME/CFS cases’ restricted activity. Of 3,237 traits considered, ME/CFS status had a significant effect on only one, via the “Duration of walk” (UKB field 874) mediator. By contrast, ME/CFS status had a significant direct effect on 290 traits (9%). As expected, these effects became more significant with increased stringency of case and control definition. Significant female and male traits were indicative of chronic inflammation, insulin resistance and liver disease. Individually, significant effects on blood traits, however, were not sufficient to cleanly distinguish cases from controls. Nevertheless, their large number, lack of sex-bias, and strong significance, despite the ‘healthy volunteer’ selection bias of UKB participants, keep alive the future ambition of a blood-based biomarker panel for accurate ME/CFS diagnosis.
The Effects of Social Distancing Policy on the Changes of Floating Population in Korea
Authors: Oh Jaehwan , Choi Minsu , Lee Kwang-soo
Published: August 2024

Objectives

In response to the World Health Organization’s declaration of the COVID-19 pandemic in March 2020, nations worldwide, including Korea, implemented social distancing as a critical Non-Pharmaceutical Intervention (NPI) to curb the spread of the disease. Social distancing measures aimed to reduce person-to-person contact through various strategies such as facility restrictions, gathering limitations, travel bans, and lockdowns.

Methods

This study investigated the impact of social distancing policies on the floating population across 229 administrative districts in Korea. The dependent variable was the total floating population, while the independent variable was the social distancing stage of the week, focusing on stages that prevailed for more than half of each week. Control variables included sex ratio, season, and the number of weekly holidays.

Results

Descriptive analysis and t-tests were conducted to examine the variables, and Panel GEE analysis was performed to analyze changes in the floating population with the social distancing stage. The analysis revealed a significant decrease in the floating population when transitioning from stage 5 to stage 4 of social distancing. This indicates that stricter gathering restrictions and increased local government autonomy effectively reduced person- to-person contact.

Discussion

These findings underscore the importance of targeted social distancing measures in mitigating transmission risks during infectious disease outbreaks. The study provides valuable insights for future policymaking on infectious diseases, offering relevant data to inform effective public health strategies and responses. Understanding the impacts of such measures can help refine approaches to managing future pandemics and ensuring public health safety.
Common DNA sequence variation influences epigenetic aging in African populations
Authors: Meeks Gillian L. , Scelza Brooke , Asnake Hana M. , Prall Sean , Patin Etienne , Froment Alain , Fagny Maud , Quintana-Murci Lluis , Henn Brenna M. , Gopalan Shyamalika
Published: August 2024

Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ‡Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.
MED26-enriched condensates drive erythropoiesis through modulating transcription pausing
Authors: Zhu Shicong , Zhang Xiaoting , Li Na , Zhao Xinying , Li Man , Xie Si , Yue Qiuyu , Li Yunfeng , Li Dong , Wu Fan , Zhang Zile , Feng Ziqi , Zhang Yiyang , Choi Wonhyung , Jia Xinyi , Deng Yuelin , Hu Qi , Yao Xingyun , Gao Xiaofei , Lee Hsiang-Ying
Published: August 2024

The Mediator complex regulates various aspects of hematopoietic development, but whether composition of the Mediator complex undergoes dynamic changes for diversifying transcription and functional outputs is unknown. Here, we found that MED26, a subunit in the core Mediator complex, played a distinctive role in facilitating transcription pausing essential for erythroid development. While most Mediator subunits drastically decreased during this process, MED26 remained relatively abundant. Intriguingly, in the early stages, more than half of MED26 occupancy sites did not co-localize with MED1, a representative Mediator subunit, suggesting these subunits exert context-dependent gene regulation. We revealed that MED26-enriched loci were associated with RNA polymerase Ⅱ pausing. MED26 manifested a markedly preferential recruitment of pausing-related factors, leading to an increase in Pol Ⅱ pausing critical for genome-wide transcription repression during erythropoiesis. Moreover, MED26 exhibited pronounced condensate-forming capability, which was necessary for its function in promoting erythropoiesis and recruiting pausing-related factors. Collectively, this study provides mechanistic insights into the functional coordination of distinct Mediator subunits during development and highlights the switch of transcription condensates towards a MED26 enriched form, which modulates transcription pausing to facilitate transcription repression and erythroid development.
Persistent legacy effects on soil microbiota facilitate plant adaptive responses to drought
Authors: Ginnan Nichole A. , Custódio Valéria , Gopaulchan David , Ford Natalie , Salas-González Isai , Jones Dylan H. , Wells Darren M. , Moreno Ângela , Castrillo Gabriel , Wagner Maggie R.
Published: August 2024

Both chronic and acute drought alter the composition and physiology of the soil microbiota, favoring the selection of microbes with functional traits that preserve fitness in these challenging conditions1. This drought-adapted microbiota may influence water-use efficiency mechanisms in host plants. Currently, it is largely unknown how this soil microbial drought legacy manifests at the molecular and physiological levels and how it influences microbe-dependent plant responses to drought in diverse natural soils. Here, to infer how drought legacy affects soil microbiota composition and function, we collected soils spanning two distinct and geographically distant precipitation gradients. By controlling for variation in numerous other soil properties including porosity and elemental profiles, we identified a group of bacterial taxa that are highly sensitive to water availability and critical for the formation of soil drought memory. Next, by imposing an acute experimental drought we show that this microbial drought legacy is robust to short-term perturbations. Furthermore, we reveal that soil microbiota from historically dry climates buffered a wild grass species native to the precipitation gradient, but not the domesticated crop species maize, from the negative effects of subsequent acute drought. In particular, microbiota with a legacy of chronic water limitation altered the expression of a small subset of host genes that mediate the effect of acute drought on transpiration and intrinsic water use efficiency. Our results reveal how long-term exposure to water stress alters soil microbial communities and demonstrate the resulting “legacy effects” on the drought responses of neighboring plants.
Characterizing features affecting local ancestry inference performance in admixed populations
Authors: Honorato-Mauer Jessica , Shah Nirav N. , Maihofer Adam X. , Zai Clement C. , Belangero Sintia , Nievergelt Caroline M. ,   Psychiatric Genomics Consortium for PTSD Ancestry Working Group, Santoro Marcos , Atkinson Elizabeth
Published: August 2024

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using Local Ancestry Inference (LAI). Accurate LAI is crucial to ensure downstream analyses reflect the genetic ancestry of research participants accurately. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America’s primary continental ancestries – African (AFR), Amerindigenous (AMR), and European (EUR). Simulating LD-informed admixed haplotypes under a variety of 2 and 3-way admixture models, we implemented a standard LAI pipeline, testing three reference panel compositions to quantify their overall and ancestry-specific accuracy. We examined LAI miscall frequencies and true positive rates (TPR) across simulation models and continental ancestries. AMR tracts have notably reduced LAI accuracy as compared to EUR and AFR tracts in all comparisons, with TPR means for AMR ranging from 88-94%, EUR from 96-99% and AFR 98-99%. When LAI miscalls occurred, they most frequently erroneously called European ancestry in true Amerindigenous sites. Using a reference panel well-matched to the target population, even with a lower sample size, LAI produced true-positive estimates that were not statistically different from a high sample size but mismatched reference, while being more computationally efficient. While directly responsive to admixed Latin American cohort compositions, these trends are broadly useful for informing best practices for LAI across other admixed populations. Our findings reinforce the need for inclusion of more underrepresented populations in sequencing efforts to improve reference panels.
Proteome asymmetry in mouse and human embryos before fate specification
Authors: Iwamoto-Stohl Lisa K. , Petelski Aleksandra A. , Meglicki Maciej , Fu Audrey , Khan Saad , Specht Harrison , Huffman Gray , Derks Jason , Jorgensen Victoria , Weatherbee Bailey A.T. , Weberling Antonia , Gantner Carlos W. , Mandelbaum Rachel S. , Paulson Richard J. , Lam Lisa , Ahmady Ali , Vasquez Estefania Sanchez , Slavov Nikolai , Zernicka-Goetz Magdalena
Published: August 2024

Pre-patterning of the embryo, driven by spatially localized factors, is a common feature across several non-mammalian species1–4. However, mammals display regulative development and thus it was thought that blastomeres of the embryo do not show such pre-patterning, contributing randomly to the three lineages of the blastocyst: the epiblast, primitive endoderm and trophectoderm that will generate the new organism, the yolk sac and placenta respectively4–6. Unexpectedly, early blastomeres of mouse and human embryos have been reported to have distinct developmental fates, potential and heterogeneous abundance of certain transcripts7–12. Nevertheless, the extent of the earliest intra-embryo differences remains unclear and controversial. Here, by utilizing multiplexed and label-free single-cell proteomics by mass-spectrometry13, we show that 2-cell mouse and human embryos contain an alpha and a beta blastomere as defined by differential abundance of hundreds of proteins exhibiting strong functional enrichment for protein synthesis, transport, and degradation. Such asymmetrically distributed proteins include Gps1 and Nedd8, depletion or overexpression of which in one blastomere of the 2-cell embryo impacts lineage segregation. These protein asymmetries increase at 4-cell stage. Intriguingly, halved mouse zygotes display asymmetric protein abundance that resembles alpha and beta blastomeres, suggesting differential proteome localization already within zygotes. We find that beta blastomeres give rise to a blastocyst with a higher proportion of epiblast cells than alpha blastomeres and that vegetal blastomeres, which are known to have a reduced developmental potential, are more likely to be alpha. Human 2-cell blastomeres also partition into two clusters sharing strong concordance with clusters found in mouse, in terms of differentially abundant proteins and functional enrichment. To our knowledge, this is the first demonstration of intra-zygotic and inter-blastomere proteomic asymmetry in mammals that has a role in lineage segregation.
Exploring SNP Filtering Strategies: The Influence of Strict vs Soft Core
Authors: Taouk Mona L. , Featherstone Leo A. , Taiaroa George , Seemann Torsten , Ingle Danielle J. , Stinear Timothy P. , Wick Ryan R.
Published: August 2024

Phylogenetic analyses are crucial for understanding microbial evolution and infectious disease transmission. Bacterial phylogenies are often inferred from single nucleotide polymorphism (SNP) alignments, with SNPs as the fundamental signal within these data. SNP alignments can be reduced to a ‘strict core’ by removing those sites which do not have data present in every sample. However, as sample size and genome diversity increase, a strict core can shrink markedly, discarding potentially informative data. Here, we propose and provide evidence to support the use of a ‘soft core’ that tolerates some missing data, preserving more information for phylogenetic analysis. Using large datasets ofNeisseria gonorrhoeaeandSalmonella entericaserovar Typhi, we assess different core thresholds. Our results show that strict cores can drastically reduce informative sites compared to soft cores. In a 10,000-genome alignment ofSalmonella entericaserovar Typhi, a 95% soft core yielded 10 times more informative sites than a 100% strict core. Similar patterns were observed inNeisseria gonorrhoeae. We further evaluated the accuracy of phylogenies built from strict and soft-core alignments using datasets with strong temporal signals. Soft-core alignments generally outperformed strict cores in producing trees displaying clock-like behaviour; for instance, theNeisseria gonorrhoeae95% soft core phylogeny had a root-to-tip regressionR2of 0.50 compared to 0.21 for the strict-core phylogeny. This study suggests that soft-core strategies are preferable for large, diverse microbial datasets. To facilitate this, we developedCore-SNP-filter(github.com/rrwick/Core-SNP-filter), an open-source software tool for generating soft-core alignments from whole-genome alignments based on user-defined thresholds.

IMPACT STATEMENT

This study addresses a major limitation in modern bacterial genomics – the significant data loss observed in large datasets for phylogenetic analyses, often due to strict-core SNP alignment approaches. As bacterial genome sequence datasets grow and diversity increases, a strict-core approach can greatly reduce the number of informative sites, compromising phylogenetic resolution. Our research highlights the advantages of soft-core alignment methods which tolerate some missing data and retain more genetic information. To streamline the processing of alignments, we developedCore-SNP-filter(github.com/rrwick/Core-SNP-filter), a publicly available resource-efficient tool that filters alignments to informative and core sites.

DATA SUMMARY

All genomic sequence reads used in this study were already publicly available and accessions can be found in Supplementary Dataset 1. Supplementary methods and all code can be found in the accompanying GitHub repository: (github.com/mtaouk/Core-SNP-filter-methods).
Effects of maximal speed locomotor training on spatiotemporal gait changes in individuals with chronic stroke: A secondary analysis of a randomized controlled trial
Authors: Pressler Daria , Schwab-Farrell Sarah M. , Reisman Darcy S. , Billinger Sandra A. , Boyne Pierce
Published: August 2024

Objective

To investigate longitudinal changes in spatiotemporal gait parameters after maximal versus moderate speed locomotor training in chronic stroke, by comparing short-burst high-intensity interval training (HIIT) versus moderate-intensity aerobic training (MAT). Compared to MAT, short-burst HIIT was hypothesized to exhibit greater improvement in non-paretic step length.

Design

Secondary analysis from the HIT-Stroke randomized controlled trial

Setting

Three rehabilitation research centers

Participants

Individuals with chronic stroke and residual walking limitations (N=55)

Interventions

Participants were randomized to short-burst HIIT (N=27) or MAT (N=28) for 45 minutes of walking practice, 3 times weekly, over 12 weeks. HIIT involved 30-second bursts of maximum walking speed, targeting >60% heart rate reserve (HRR). MAT involved continuous walking, targeting 40%-60% HRR.

Main Outcome Measure(s)

Mean spatiotemporal gait parameter changes between groups, averaging the 4-week, 8-week, and 12-week estimates minus baseline. The primary measure of interest was non-paretic step length, an indicator of paretic propulsion and biomechanical efficiency.

Results

Non-paretic step length increased significantly more in the HIIT group (+4.4 cm [95% CI, 1.9, 6.9]) compared to the MAT group (+0.1 [-2.5, 2.7]; HIIT vs. MAT p = .01). Both groups demonstrated significant increases in cadence, paretic step length, and bilateral single support time, and significant decreases in the coefficient of variation (CV) for stride velocity, stride time, and stride length. Symmetry measures did not significantly change in either group.

Conclusions

Greater increases in non-paretic step length with short-burst HIIT suggest that maximal speed training may yield greater increases in paretic propulsion, a marker of biomechanical efficiency. Both moderate and maximal speed training (MAT and HIIT) appear to reduce spatiotemporal variability, possibly indicating improved gait stability.
Multivariable Mendelian Randomization Analysis Reveals the Protective Effect of Restless Legs Syndrome against Lower Limb Venous Diseases and Pulmonary Embolism
Authors: Zhang Ru-Yu , Wen Cheng , Geng Ru-Lin , Su Jie-Hua , Liu Xiao-Huan , Lai Zhuo-Ying , Tao En-Xiang , Li Fu-Jia
Published: August 2024

Abstract Objectives: Lower limb immobility is a significant risk factor for peripheral vascular diseases, such as venous thromboembolism (VTE). Restless legs syndrome (RLS) is characterized by an irresistible urge to move the lower limbs to alleviate discomfort. The impact of RLS on lower limb vascular diseases is unclear. Methods: This study used a two-sample Mendelian Randomization (MR) approach to assess the effect of RLS on the risk of seven arterial and seven venous diseases. Conducted in three stages, the study used different RLS datasets for discovery (Didriksen et al.) and replication (EU-RLS-GENE consortium) analyses across all the stages to ensure robust conclusions. Univariable MR (UVMR) was applied to analyze the causal relationship between RLS and 14 vascular diseases. Multivariable MR (MVMR) included covariates like BMI, smoking status, alcohol intake, and educational attainment. In the final stage, accelerometer-based physical activity at 12 different time were incorporated in MVMR analysis to determine if RLS influences lower limb vascular diseases by increasing limb activity. Results: RLS was associated with a reduced risk of six venous diseases, including varicose veins, superficial phlebitis, VTE, and pulmonary embolism. These findings remained robust after adjusting for covariates but lost significance after accounting for nighttime physical activity. Conclusion: RLS may lower the risk of venous diseases and pulmonary embolism by increasing nocturnal limb activity. This finding is particularly relevant for pregnant women and individuals with renal impairment, who are at high risk for both RLS and VTE. Further research is needed to validate these conclusions.
The post-viral GPNMB+immune niche persists in long-term Covid, asthma, and COPD
Authors: Wu Kangyun , Zhang Yong , Yin-DeClue Huiqing , Sun Kelly , Mao Dailing , Crouch Erika C. , Byers Derek E. , Holtzman Michael J.
Published: August 2024

Epithelial injury calls for a regenerative response from a coordinated network of epithelial stem cells and immune cells. Defining this network is key to preserving the repair process for acute resolution, but also for preventing a remodeling process with chronic dysfunction. We recently identified an immune niche for basal-epithelial stem cells using mouse models of injury after respiratory viral infection. Niche function depended on an early sentinel population of monocyte-derived dendritic cells (moDCs) that provided ligand GPNMB to basal-ESC receptor CD44 for reprogramming towards chronic lung disease. These same cell and molecular control points worked directly in mouse and human basal-ESC organoids, but the findings were not yet validated in vivo in human disease. Further, persistence of GPNMB expression in moDCs and M2-macrophages in mouse models suggested utility as a long-term disease biomarker in humans. Here we show increased expression of GPNMB localized to moDC-macrophage populations in lung tissue samples from long-term Covid, asthma, and COPD. The findings thereby provide initial evidence of a persistent and correctable pathway from acute injury to chronic disease with implications for cellular reprogramming and inflammatory memory.

New and noteworthy

Recent work indicates that a sentinel immune niche provides GPNMB to epithelial stem cells to drive structural remodeling and disease as exemplified by the response to respiratory viral injury. The present study provides initial evidence that this niche can be detected in humans in the context of comparable diseases (long-term Covid, asthma, and COPD) also linked to viral infection. The results support a persistent mechanism for inflammatory disease that might be correctable with GPNMB blockade directly or indirectly through related signaling pathways.
Integrative multi-omics reveal glial signatures associated with accelerated cognitive decline in Alzheimer’s disease
Authors: Schneegans Eléonore , Fancy Nurun , Thomas Michael , Adair Emily , Willumsen Nanet , Papageorgopoulou Marianna , Chau Vicky , Cheung To Ka Dorcas , Muirhead Robert C.J. , Whitwell Harry , Yagoubi Riad , Zhang Xiaowen , McGarry Aisling , Schilder Brian M , Matthews Paul M. , Jackson Johanna S
Published: August 2024

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive cognitive decline and memory loss caused by both genetic and environmental factors. Synapse dysfunction and loss are strongly related to cognitive decline in AD. This study integrates genomic, transcriptomic, proteomic and immunohistological (multi-omics) data and longitudinal cognitive data across several AD cohorts to elucidate the molecular drivers associated with astrocytes and microglia involved in these processes. Our findings demonstrate that activation of microglia and astrocytes occurs in specific cell subsets that are enriched in AD risk genes. Transcriptomic evidence for early microglial activation precedes immunohistological expression of severe neuropathology. Proteomic markers of astrocytic response appear to be most strongly associated with accelerated cognitive decline. However, we also found that brains from donors with a history of more rapid cognitive decline showed evidence for reduced SNAP25-VAMP interactions indicative of synaptic dysfunction, exhibited higher neurotoxic astrocyte reactivity, and were associated with the expression of neuronal markers of injury. Related molecular signatures in cerebrospinal fluid and plasma may provide biomarkers to identify patients at higher risk for rapid cognitive decline. Together, our results connect glial activation to synaptic dysfunction and cognitive decline in AD and highlight roles for microglial activation in the genesis of AD and later astrocyte activation as a potential determinant of clinical symptom progression.
Repetitive Transcranial Magnetic Stimulation Modulates Brain Connectivity in Children with Self-limited Epilepsy with Centrotemporal Spikes
Authors: She Xiwei , Qi Wendy , Nix Kerry C. , Menchaca Miguel , Cline Christopher C. , Wu Wei , He Zihuai , Baumer Fiona M.
Published: August 2024

Objective

Interictal epileptiform discharges (IEDs) alter brain connectivity in children with epilepsy; this connectivity change may be a mechanism by which epilepsy induces cognitive deficits. Here, we test whether repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, modulates connectivity and reduces IEDs in children with epilepsy.

Methods

Nineteen children with self-limited epilepsy with centrotemporal spikes (SeLECTS) participated in a cross-over study comparing the impact of active vs. sham rTMS on IEDs and brain connectivity. SeLECTS is an epilepsy syndrome affecting the motor cortex, and prior studies show that motor cortices become pathologically hyper-connected to frontal and temporal language cortices. Using a crossover design, we compared the effect of single doses of active versus sham motor cortex rTMS. Connectivity, which was quantified by the weighted phase lag index (wPLI), was measured before and after rTMS using single pulses of TMS combined with EEG (spTMS-EEG). Analyses focused on six regions: bilateral motor cortices and bilateral inferior frontal and superior temporal regions. IEDs were counted in the five minutes before and after rTMS.

Results

Active, but not sham, rTMS significantly and globally decreased wPLI connectivity between multiple regions, with the greatest reductions seen in the superior temporal region connections in the stimulated hemisphere. Additionally, there was a trend suggesting that rTMS decreases IED frequency.

Interpretation

These findings underscore the potential of low-frequency rTMS to target pathologic hyperconnectivity and reduce IEDs in children with SeLECTS and potentially other pediatric epilepsy syndromes, offering a promising avenue for therapeutic intervention.
Impact of unequal testing on vaccine effectiveness estimates across two study designs: a simulation study
Authors: Bodner Korryn , Wang Linwei , Kustra Rafal , Kwong Jeffrey C. , Sander Beate , Sbihi Hind , Irvine Michael A , Mishra Sharmistha
Published: August 2024

Observational studies are essential for measuring vaccine effectiveness. Recent research has raised concerns about how a relationship between testing and vaccination may affect estimates of vaccine effectiveness against symptomatic infection (symptomatic VE). Using an agent-based network model and SARS-CoV-2 as an example, we investigated how differences in the likelihood of testing by vaccination could influence estimates of symptomatic VE across two common study designs: retrospective cohort and test-negative design. First, we measured the influence of unequal testing on symptomatic VE estimates across study designs and sampling periods. Next, we investigated if the magnitude of bias in VE estimates from unequal testing was shaped by the level of immune escape (vaccine efficacy against susceptibility and against infectiousness) and underlying epidemic potential (probability of transmission). We found that unequal testing led to larger biases in the cohort design than the test-negative design and that biases were largest with lower efficacy against susceptibility. We also found the magnitude of bias was moderated by the sampling period, efficacy against infectiousness, and probability of transmission, with more pronounced moderating effects in the test-negative design. Our study illustrates that VE estimates across study designs require careful interpretation, especially in the presence of epidemic and immunological heterogeneity.
No evidence that retinol is protective for skin cancer
Authors: Helder Marloes , Pandeya Nirmala , Seviiri Mathias , Olsen Catherine M. , Whiteman David C. , Law Matthew H.
Published: August 2024

With over 1.5 million new cases annually, skin cancers are the most commonly diagnosed group of cancers worldwide. Among these, melanoma and keratinocyte cancers (KC), comprising squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are predominant. Retinol, a vitamin A derivative, is essential in the regulation of growth and differentiation of epidermal cells. Moreover, retinol exhibits antioxidant properties, protecting the skin against ultra-violet (UV) radiation induced oxidative damage.

Existing research on the impact of retinol on melanoma, SCC and BCC development shows mixed results. Several dietary intake studies have suggested that higher retinol levels reduce skin cancer risk, however, others have failed to find this association.

We used two-sample Mendelian randomization (MR) to explore if there is a causal relationship between retinol and the risk of developing melanoma, SCC or BCC. Genetically predicted circulating retinol levels were obtained from a genome wide association study (GWAS) meta-analysis of the INTERVAL (N=11,132) and METSIM (N=6,136) cohorts. Melanoma (30,134 cases and 375,188 controls), SCC (10,557 cases and 537,850 controls) and BCC (36,479 cases and 540,185 controls) risks were derived from published GWAS meta-analyses. We conducted two MR approaches. In the first MR we used a single SNP (rs10882283) that is associated with the levels of Retinol Binding Protein 4 (RBP4) as an instrument variable (IV) for circulating retinol levels. In the second MR we used all independent genetic variants that were strongly associated (P < 5 × 10−8) with retinol levels as IVs. Odds ratios (OR) for skin cancer were calculated for a one standard deviation (SD) increase in genetically predicted retinol levels.

The single IV approach revealed that retinol levels were not significantly associated with risk of melanoma (OR = 1.04 [95% confidence interval 0.83, 1.31], P = 0.72), SCC (OR = 1.15[0.87, 1.51], P = 0.32) or BCC (OR = 1.06 [0.90, 1.23], P = 0.50). Similar null results were observed with the multiple IV approach for melanoma (OR = 1.03 [0.95, 1.11], P = 0.54), SCC (OR = 1.01 [0.91, 1.13], P = 0.83), and BCC (OR = 1.04 [0.96, 1.12], P = 0.38).

In conclusion, we found no evidence that circulating retinol levels were causally associated with the development of melanoma, SCC and BCC.
Unsupervised detection of SARS-CoV-2 mutations and lineages in Norwegian wastewater samples using long-read sequencing
Authors: Garcia Ignacio , Riis Rasmus Kopperud , Moen Line Victoria , Rohringer Andreas , Madslien Elisabeth Henie , Bragstad Karoline
Published: August 2024

The COVID-19 pandemic has underscored the importance of virus surveillance in public health and wastewater-based epidemiology (WBE) has emerged as a non-invasive, cost-effective method for monitoring SARS-CoV-2 and its variants at the community level. Unfortunately, current variant surveillance methods depend heavily on genomic databases with data derived from clinical samples, which can become less sensitive and representative as clinical testing and sequencing efforts decline. In this paper, we introduce HERCULES (High-throughput Epidemiological Reconstruction and Clustering for Uncovering Lineages from Environmental SARS-CoV-2), an unsupervised, database-independent method that uses long-read sequencing of a single 1 Kb fragment of the Spike gene. HERCULES identifies and quantifies mutations and lineages without requiring database-guided deconvolution, enhancing the detection of novel variants. We evaluated HERCULES on Norwegian wastewater samples collected from July 2022 to October 2023 as part of a national pilot on WBE of SARS-CoV-2. Strong correlations were observed between wastewater and clinical sample data in terms of prevalence of mutations and lineages. Furthermore, we found that SARS-CoV-2 trends in wastewater samples were identified one week earlier than in clinical data. Our results demonstrate HERCULES' capability to identify new lineages before their detection in clinical samples, providing early warnings of potential outbreaks. The methodology described in this paper is easily adaptable to other pathogens, offering a versatile tool for environmental surveillance of new emerging pathogens.
Early founder effects have determined paternal population structure in the Faroe Islands
Authors: Mann Allison E. , Magnussen Eyðfinn , Tillquist Christopher R.
Published: August 2024

The Faroe Islands are a small archipelago located in the North Atlantic likely colonized by a small group of founders sometime between 50 and 300 CE. Post colonization, the Faroese people have been largely isolated from admixture with mainland and other island populations in the region. As such, the initial founder effect and subsequent genetic drift are likely major contributors to the modern genetic diversity found among the Faroese. In this study, we assess the utility of Y-chromosomal microsatellites to detect founder effect in the Faroe Islands through the construction of haplotype networks and a novel empirical method, mutational distance from modal haplotype histograms (MDM), for the visualization and evaluation of population bottlenecks. We compared samples from the Faroe Islands and Iceland to possible regional source populations and documented a loss of diversity associated with founder events. Additionally, within-haplogroup diversity statistics reveals lower haplotype diversity and richness within both the Faroe Islands and Iceland, consistent with a small founder population colonizing both regions. However, in the within-haplogroup networks, the Faroe Islands are found within the larger set of potential source populations while Iceland is consistently found on isolated branches. Moreover, comparisons of within-haplogroup MDM histograms document a clear founder signal in the Faroes and Iceland, but the strength of this signal is haplogroup-dependent which may be indicative of more recent admixture or other demographic processes. The results of the current study and lack of conformity between Icelandic and Faroese haplotypes implies that the two populations were founded by different paternal gene pools and there is no detectable post-founder admixture between the two groups.
Characterisation of coastal reef fish assemblages across an estuarine-urbanisation gradient using underwater visual survey and environmental DNA metabarcoding
Authors: Pei Yu-De , Heard Joseph , Xu Wenqian , Leung Shara K. K. , Yung Charmaine C. M. , Wyatt Alex S. J.
Published: August 2024

The ongoing urbanisation of coastlines around the globe jeopardises biodiversity, including coastal marine fishes. In many places, baseline data on fish communities are inadequate for understanding the ecological and conservation impacts of this urbanisation. Here, we document spatiotemporal patterns in fish diversity (at genus level) across an estuarine gradient around Hong Kong, a highly urbanised coastal megacity bordering the estuary of the Pearl River, the second largest river in the People’s Republic of China. We combined underwater visual census (UVC) with eDNA metabarcoding (eDNA) to overcome challenges associated with the high turbidity of Hong Kong’s aquatic environment that limits the capacity for visual observations. Similar to previous studies, UVC and eDNA captured different components of the fish community, sharing only 36.5 % fish genera in common. Nevertheless, we recorded 17 % of the known fish diversity and provided a comprehensive picture of patterns in fish diversity across the gradient, despite limited sampling effort. Fish richness was reduced by 1.6-to 3-fold under the highly turbid estuarine conditions found around Lantau compared to other regions. However, overall, there were only moderate changes in the fish community regionally. Seasonal variations in fish richness and assemblage structure were observed using both approaches, taken to reflect changes in fish behaviour, physiology, and naturally occurring events (i.e., spawning and recruitment) between seasons. A notable, consistent reduction in eDNA richness in the semi-enclosed Port Shelter might reflect limited exchange of water and genetic materials. A total of eleven species that had not been previously reported from Hong Kong were detected. These potentially novel species, as well as other ecologically and economically important species in Hong Kong, might be insufficiently protected from unregulated fishing activities due to the limited spatial coverage of marine protected areas.