bluuebunny/crossref_metadata_2025 huggingface dataset:
Local postural changes elicit extensive and diverse skin stretch around joints, on the trunk and the face
Authors: Rupani Mia , Cleland Luke D. , Saal Hannes P.
Published: February 2025

Skin stretch, induced by bodily movements, offers a potential source of information about the conformation of the body that can be transmitted to the brain via stretch-sensitive mechanoreceptive neurons. While previous studies have primarily focused on skin stretch directly at joints, here we investigate the extent and complexity of natural skin stretch across various body regions, including the face and trunk. We used a quad-camera set-up to image large ink-based speckle patterns stamped on participants’ skin and calculated the resulting stretch patterns on a millimetre scale during a range of natural poses. We observed that skin stretch associated with joint movement extends far beyond the joint itself, with knee flexion inducing stretch on the upper thigh. Large and uniform stretch patterns were found across the trunk, covering considerable portions of the skin. The face exhibited highly complex and non-uniform stretch patterns, potentially contributing to our capacity to control fine facial movements in the absence of traditional proprioceptors. Importantly, all regions demonstrated skin stretch in excess of mechanoreceptive thresholds, suggesting that behaviourally relevant skin stretch can occur anywhere on the body. These signals might provide the brain with valuable information about body state and conformation, potentially supplementing or even surpassing the capabilities of traditional proprioception.
Bilingual language control during single-language production: does relocation to a new linguistic environment change it?
Authors: de Bruin Angela , Liu Cong , Trenkic Danijela , Coumel Marion
Published: February 2025

A bilingual’s two languages are simultaneously active and competing for selection, even when only one language is used. To manage this competition, bilinguals apply language control. We examined how bilinguals apply control across two single-language tasks and how this language control might adapt to the language environment bilinguals live in. We conducted a longitudinal study with Mandarin–English bilinguals who moved from China to the UK and a control group staying in China. Participants completed a picture-naming task and a verbal-fluency task twice, approximately seven months apart. We examined language order effects by comparing performance in each language when it was used first versus after the other language. While the L2 benefited from being used second, L1 performance benefited less or even deteriorated after L2 use. This suggests bilinguals proactively applied language control, especially during L2 use, to manage the anticipated language competition from the L1. However, these effects did not change after relocation to the UK, nor did they differ between the groups. This suggests that while language control is a core part of language production, the language environment a bilingual lives in might not have a defining impact on the exact way this language control is applied.
The fundamental frequencies of our own voice
Authors: Neamaalkassis Hakam , Boubenec Yves , Fiebach Christian , Muralikrishnan R. , Tavano Alessandro
Published: February 2025

Own actions send a corollary discharge (CD) signal, that is a copy of the planned motor programme, to sensory-specific brain areas to suppress the anticipated sensory response, providing a neural basis for the sense of self. When we speak, the sensory consequences of the fundamental frequency (

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) of our own voice, generated by vocal fold vibrations, are suppressed. However, due to bone/air conduction filtering effects, the

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we self-generate is measurably different from the

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we subjectively perceive as defining our own voice. Using an auditory change deafness paradigm, we parametrically tested the sensitivity to auditory change in the frequency neighbourhoods of objective and subjective own voice pitches and found that participants experience change deafness for both to a similar extent, relative to a control pitch condition. We conclude that when we listen attentively, we are likely to filter out small pitch changes in the vicinity of our own objective and subjective voice

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, possibly as a long-term consequence of speaking-induced suppression mechanisms integrated with individual, perceptual bodily priors.
Towards an Inclusive Conference Experience: Evaluation of the Education & Outreach Symposium at the Microbiology Society Annual Conference 2024
Authors: Lacey Melissa M , Dillon Michael J , Goodman Sean , Easton Victoria , Graham Alison I
Published: February 2025

The Microbiology Society Education & Outreach Symposium serves as a platform for microbiology educators to share contemporary practices with an international audience.  The Symposium is held yearly during the Microbiology Society’s Annual Conference and has become increasingly popular amongst conference attendees.  In an effort to create an inclusive and engaging environment, the 2024 Symposium included contributions from participants at all career stages and from diverse global regions through a variety of presentation formats, including invited talks, offered presentations, flash talks, and posters.  Cabaret-style seating was used to encourage discussion amongst participants and digital tools were used for anonymous feedback and questions after each talk to ensure all voices had an opportunity to be heard.  Here we present an analysis of qualitative and quantitative participant responses addressing two key research questions: 1) Did the Symposium foster an inclusive atmosphere for participants across all career stages? and 2) Was the content engaging and relevant to the audience?  A post-Symposium questionnaire revealed strong positive feedback, with all 18 respondents agreeing or strongly agreeing that the 2024 Symposium was both an inclusive environment and covered interesting topics.  Thematic content analysis of free-text responses emphasised a high appreciation for the Symposium’s diversity in speakers and topics, an inclusive room layout, and overall welcoming feeling.  Feedback from participants, along with the authors’ own reflections, will actively feed into planning for the 2025 Symposium.
Genomic diversity and evolutionary patterns of Edwardsiella ictaluri affecting farmed striped catfish (Pangasianodon hypophthalmus) in Vietnam over 20 years
Authors: Payne Christopher J. , Phuong Vo Hong , Phuoc Nguyen Ngoc , Dung Tu Thanh , Phuoc Le Hong , Crumlish Margaret
Published: February 2025

Edwardsiella ictaluri continues to pose a significant risk to the health and production of striped catfish (Pangasianodon hypophthalmus) in Vietnam. Whilst recent advances in genomic sequencing provide an insight into the global genomic diversity of this important fish pathogen, genome-wide analysis of Vietnamese isolates recovered over time is lacking. In this study, we used a whole-genome sequencing approach to compare the genomes of 31 E. ictaluri isolates recovered over a 20-year period (2001–2021) and performed comparative genomic analysis to explore temporal changes in genome diversity, population structure and mechanisms driving pathogenesis and antimicrobial resistance. Our findings revealed an open pan-genome with 4148 genes and a core genome (3 060 genes) accounting for over two-thirds of the genome. Moreover, we found the genomes sequenced to classify into two distinct lineages and estimated the ancestral origin of these lineages within Vietnam to date back to the 1950s. Plasmids were highly prevalent in Vietnamese E. ictaluri, with isolates harbouring up to four plasmids within their genome. Further, a diverse mobilome was observed with nine different plasmid types detected across the genome collection. Exploration of putative plasmids revealed a diverse set of antimicrobial resistance genes (ARGs) against key antibiotics used in Vietnamese aquaculture and virulence genes associated with protein secretion systems. Correlation analysis revealed the total number of ARGs detected in genomes to increase with isolate recovery time. Whilst the number of virulence genes remained relatively stable, temporal variation was noted in several virulence factors related to motility and immune system modulation. Findings from this study highlight the need for continued genomic surveillance to monitor changes in antimicrobial resistance and pathogenesis, to help inform the development of disease control and management strategies.
Identification of Poly-Metabolite Scores for Diets High in Ultra-Processed Food in an Observational Study with Validation in a Randomized Controlled Crossover-Feeding Trial
Authors: Abar Leila , Steele Eurídice Martínez , Lee Sang Kyu , Kahle Lisa , Moore Steven C. , Watts Eleanor , Matthews Charles E. , Herrick Kirsten A. , Hall Kevin D. , O’Connor Lauren E. , Freedman Neal D. , Sinha Rashmi , Hong Hyokyoung G. , Loftfield Erikka
Published: February 2025

Background: Ultra-processed food (UPF) accounts for a majority of calories consumed in the United States, but the impact on human health remains unclear. We aimed to identify poly-metabolite scores in blood and urine that are predictive of UPF intake. Methods and findings: IDATA participants (n=718), aged 50-74 years, with serially collected blood and urine and up to 6 24-hour dietary recalls (ASA-24s), collected over 12-months, were included in metabolomics analysis, which used ultra-high performance liquid chromatography with tandem mass spectrometry to measure >1000 serum and urine metabolites. Average daily UPF intake was estimated as percentage energy according to the Nova system. Partial Spearman correlations and Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to estimate UPF-metabolite correlations and build poly-metabolite scores of UPF intake, respectively. Scores were tested in a previously conducted randomized, controlled, crossover-feeding trial of 20 domiciled participants who consumed ad libitum diets that were 80% and 0% energy from UPF for 2 weeks each. IDATA participants were 51% female, and 97% completed ³4 ASA-24s. Mean intake was 50% energy from UPF. UPF intake was correlated with 187 (of 952) serum and 284 (of 1111) 24-hour urine metabolites (FDR-corrected P-value ≤ 0.01), including lipid (n=53 serum, n=21 24-hour urine), amino acid (n=33, 59), carbohydrate (n=3, 8), xenobiotic (n=33, 69), cofactor and vitamin (n= 9, 11), peptide (n=7, 6), and nucleotide (n=6, 8) metabolites. Using LASSO regression, 28 serum and 33 24-hour urine metabolites were selected as predictors of UPF intake; biospecimen-specific scores were calculated as a linear combination of selected metabolites. Overlapping metabolites included (S)C(S)S-S-methyl cysteine sulfoxide (rs= -0.19, -0.23), N2-N5-diacetylornithine (rs= -0.26, -0.27), pentoic acid (rs= -0.28, -0.31), and N6-carboxymethyllysine (rs=0.15, 0.21). Within the cross-over feeding trial, the poly-metabolite scores differed, within individual, between UPF diet phases (P-value for paired t-test <0.001). Conclusions: Poly-metabolite scores, developed in IDATA participants with varying diets, are predictive of UPF intake and could advance epidemiological research on UPF and health.
Adapting the BOADICEA breast and ovarian cancer risk models for the ethnically diverse UK population
Authors: Ficorella Lorenzo , Yang Xin , Mavaddat Nasim , Carver Tim , Hassan Hend , Dennis Joe , Tyrer Jonathan , Ho Weang-Kee , Teo Soo-Hwang , Hartman Mikael , Li Jingmei , Eriksson Mikael , Czene Kamila , Hall Per , Rahman Tameera , Bacon Andrew , Hardy Steven , Stokes Adam E. , Donoso Francisca Stutzin , Archer Stephanie , Simard Jacques , Pharoah Paul D. P. , Usher-Smith Juliet A. , Tischkowitz Marc , Easton Douglas F. , Antoniou Antonis C.
Published: February 2025

Background

BOADICEA is a widely used algorithm for predicting breast and ovarian cancer risks, using a combination of genetic and lifestyle/environmental risk factors. However, it has largely been developed using data from individuals of White ethnicity.

Methods

We utilised data from multiple sources to derive estimates for the distributions of risk factors and their effect sizes in major UK ethnic groups (White, Black, South Asian, East Asian, and Mixed). We combined these with ethnicity-specific population cancer incidences to update BOADICEA so that it provides ethnicity-specific risk estimates. We also developed and included a method for deriving adjusted polygenic scores for individuals of mixed genetic ancestry.

Results

The predicted average absolute risks were smaller in all non-White ethnic groups than in Whites, and the risk distributions were narrower. The proportion of women classified as at moderate or high risk of breast or ovarian cancer, according to national guidelines, was considerably smaller in non-White women.

Discussion

The updated BOADICEA (v7), available in the CanRisk tool (www.canrisk.org), is based on estimates more appropriate for non-White women in the UK. Further validation of the model in prospective studies is required. Considering these findings, risk classification guidelines for non- White women may need to be revised.
DDS-E-Sim: A Transformer-Based Generative Framework for Simulating Error-Prone Sequences in DNA Data Storage
Authors: Naznin Mst. Fahmida Sultana , Mondol Swarup Sidhartho , Faruq Adnan Ibney , Sultan Rumi Ahmed Mahir , Saha Debashmita , Islam A. B. M. Alim Al
Published: February 2025

The fast-growing amount of data needs reliable and long-lasting storage solutions. DNA has emerged as a promising medium due to its high information density and long-term stability. However, DNA storage is a complex process where each stage introduces noise and errors, including synthesis errors, storage decay, and sequencing errors, which require error-correcting codes (ECCs) for reliable data recovery. To design an optimal data recovery method, a comprehensive understanding of the noise structure in a DNA data storage channel is crucial. Since running DNA data storage experiments in vitro is still expensive and time-consuming, a simulation model is quite necessary that can mimic the error patterns in the real data and simulate the experiments. Existing simulation tools often rely on fixed error probabilities or are specific to certain technologies. In this study, we present a transformer-based generative framework for simulating errors in a DNA data storage channel. Our simulator takes oligos (DNA sequences to write) as input and generates erroneous output DNA reads that closely resemble the real-life output of common DNA data storage pipelines. It captures both random and biased error patterns, such as k-mer and transition errors, regardless of the process or technology. We demonstrate the effectiveness of our simulator by analyzing two datasets processed with distinct technologies. In the first case, processed with Illumina MiSeq, sequences simulated by DDS-E-SIM exhibit a total error rate deviation of only 0.1\% from the original dataset. The second, processed with Oxford Nanopore Technologies, shows a 0.7\% deviation. Both base-level and k-mer errors closely align with the original dataset. Additionally, our simulator generates 100,743 unique oligos from 35,329 sequences, with each sequence read five times, demonstrating its ability to simulate biased errors and stochastic properties simultaneously. Our simulator outperforms existing simulators with superior accuracy and the ability to handle diverse sequencing technologies.
Rapid structural network changes in bird communities
Authors: Rigal Stanislas , Devictor Vincent , Dakos Vasilis
Published: February 2025

As biodiversity is declining, the dynamics of species interactions is a growing conservation concern. However, estimating and monitoring species interactions across large spatial and temporal scales remain challenging, and thus changes in species interactions and the subsequent networks of interactions remain relatively unexplored. Here, we assess changes in the network structure of common bird communities from France. We estimate associated species pairs using spatial and temporal information for 109 species monitored across 1,969 sites during 17 years. We validate the ecological significance of associated species pairs by testing the relationship between the propensity to be associated and species functional proximity or shared habitat preference. We reconstruct association networks for these intra-guild bird communities and track temporal changes in network layout in terms of size, density of links, modularity and degree distribution. We show that, beyond species change, birds’ local association networks become smaller with a similar relative number of associations that becomes unevenly distributed. These structural changes vary among types of bird communities and may impact community functioning and how communities can cope with global change.
Rhizoctonia theobromaeassociated with a severe witches’ broom outbreak in cassava of the Brazilian rainforest and evidence of its Southeast Asian origin
Authors: Alves Santos de Oliveira Saulo , Sheat Samar , Margaria Paolo , Lopes Lima Adilson , de Araújo dos Santos Jackson , Rocha Hermínio Souza , Fleck da Silveira Helton , Ramos de Jesus Cristiane , Winter Stephan
Published: February 2025

Cassava witches’ broom disease (CWBD) has emerged as a significant threat to cassava production in the Oiapoque region of Amapá, Brazil. Diseased plants exhibit stunted growth, vascular necrosis, abnormal shoot proliferation, and distinctive broom-like appearance. This study aimed to characterize the disease and identify its causal agent(s). The assessment by high-throughput sequencing of total nucleic acids (DNA and RNA) from affected cassava tissues revealedRhizoctonia theobromae(syn.Ceratobasidium theobromae) associated with CWBD. PCR-based detection using species-specific primers confirmed the presence ofR. theobromaein 74% of symptomatic samples. Genetic diversity analysis based on the Ca2+/calmodulin-dependent protein kinase gene showed low variability among Brazilian isolates compared with Asian populations, suggesting their recent introduction. This first report ofR. theobromaecausing CWBD in Brazil follows a recent report of the disease from French Guiana and highlights the urgent need for effective measures to prevent the further spread of this emerging pathogen, which poses a deadly threat to cassava cultivation in the rainforest, a significant risk to cassava production in Brazil, and regions with similar eco-climatic conditions.
Towards machine learning fairness in classifying multicategory causes of deaths in colorectal or lung cancer patients
Authors: Feng Catherine H. , Deng Fei , Disis Mary L. , Gao Nan , Zhang Lanjing
Published: February 2025

Classification of patient multicategory survival outcomes is important for personalized cancer treatments. Machine Learning (ML) algorithms have increasingly been used to inform healthcare decisions, but these models are vulnerable to biases in data collection and algorithm creation. ML models have previously been shown to exhibit racial bias, but their fairness towards patients from different age and sex groups have yet to be studied. Therefore, we compared the multimetric performances of 5 ML models (random forests, multinomial logistic regression, linear support vector classifier, linear discriminant analysis, and multilayer perceptron) when classifying colorectal cancer patients (n=515) of various age, sex, and racial groups using the TCGA data. All five models exhibited biases for these sociodemographic groups. We then repeated the same process on lung adenocarcinoma (n=589) to validate our findings. Surprisingly, most models tended to perform more poorly overall for the largest sociodemographic groups. Methods to optimize model performance, including testing the model on merged age, sex, or racial groups, and creating a model trained on and used for an individual or merged sociodemographic group, show potential to reduce disparities in model performance for different groups. Notably, these methods may be used to improve ML fairness while avoiding penalizing the model for exhibiting bias and thus sacrificing overall performance.
Proximity of Wildfires to Inpatient Healthcare Facilities in California, 2001-2023
Authors: Dresser Caleb , Bedi Neil Singh , Schroeder Andrew , Sergienko Eric , Balsari Satchit
Published: February 2025

Objective

Assess changes in the proximity of wildfires to inpatient healthcare facilities in California during the period 2001 to 2023.

Methods

Retrospective spatial analysis. Distances between each inpatient facility and the nearest wildfire perimeter were computed on an annual basis using data from the California Department of Health Care Access and Information and CAL-FIRE’s Fire and Resource Assessment Program. Temporal changes were analyzed via Kruskal-Wallis and linear models.

Results

The distance from inpatient healthcare facilities in California to nearby wildfires is decreasing by an average of 628 feet per year, while close approaches are increasing; during 2017-2023, there was 53% increase in the number of inpatient beds within five miles of a wildfire as compared with 2001-2008.

Conclusion

Wildfires are occurring closer to inpatient healthcare facilities in California. An increasing proportion of California’s inpatient bed capacity is exposed to nearby wildfires. Policies to reduce risk posed by wildfires, prepare for evacuations, preserve access to healthcare, and ensure safe location of new facilities are urgently needed to ensure the safety of patients and the wellbeing of populations that depend on inpatient healthcare services.
Taxonomic Shifts Correlate to Serum Cytokines in an Antibiotics Model to Study the Murine Gut-Joint Axis
Authors: Villarreal Cameron X. , Chan Deva D.
Published: February 2025

The gut microbiome interacts with many systems throughout the human body. Microbiome disruption reduces bone tissue mechanics but paradoxically slows osteoarthritis progression. The microbiome also mediates inflammatory and immune responses, including serum cytokines. Towards studying how the gut microbiome interacts with synovial joint health and disease (“gut-joint axis”), we examined how antibiotics-induced changes to microbial taxa abundance associated to serum cytokine levels.

Mice (n=8+) were provided ad libitum access to water containing antibiotics (1 g/L neomycin, 1 g/L ampicillin, or 1 g/L ampicillin with 0.5 g/L neomycin) or control water from 5- to 16-weeks old, corresponding in skeletal development to ∼10 to ∼25 years in humans. At humane euthanasia, we collected cecum contents for 16S metagenomics and blood for serum cytokine quantification for comparison to control and among antibiotic groups. We used dimensional reduction techniques, multiomic integration, and correlation to discriminate antibiotic groups and identify specific relationships between high-abundance taxa and serum cytokines.

Antibiotic treatment significantly lowered diversity, altered phylum relative abundance, and resulted in significant association with specific taxa. Dimensional reduction techniques and multiomic integration revealed distinct antibiotic-associated clusters based on genera relative abundance and cytokine serum concentration. Cytokines IL-6, MIP-1B, and IL-10 significantly contributed to antibiotic discrimination, significantly different among antibiotic treatments, and had significant correlations with specific taxa.

Antibiotic treatment resulted in heterogenous response in gut microbiome and serum cytokines, allowing signficnat microbe-cytokine links to emerge. The relationships identified here will enable further investigation of the gut micrbiome’s role in modifying joint health and disease.
Interstitial Cystitis: a phenotype and rare variant exome sequencing study
Authors: Motelow Joshua E. , Malakar Ayan , Krishna Murthy Sarath Babu , Verbitsky Miguel , Kahn Atlas , Estrella Elicia , Kunkel Louis , Wiesenhahn Madelyn , Becket Jaimee , Harris Natasha , Lee Richard , Adam Rosalyn , Kiryluk Krzysztof , Gharavi Ali G. , Brownstein Catherine A.
Published: February 2025

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Though IC/BPS can be hereditary, little is known of its genetic etiology. Using the eMERGE data, we confirmed known phenotypic associations such as gastroesophageal reflux disease and irritable bowel syndrome and detected new associations, including osteoarthrosis/osteoarthritis and Barrett’s esophagus. An exome wide ultra-rare variants analysis in 348 IC/BPS and 11,981 controls extended the previously reported association withATP2C1andATP2A2,implicated in Mendelian desquamating skin disorders, but did not provide evidence for other previously proposed pathogenic pathways such as bladder development, nociception or inflammation. Pathway analysis detected new associations with “anaphase-promoting complex-dependent catabolic process”, the “regulation of MAPK cascade” and “integrin binding”. These findings suggest perturbations in biological networks for epithelial integrity and cell cycle progression in IC/BPS pathogenesis, and provide a roadmap for its future investigation.
Spatiotemporal Analysis of COVID-19 Risk in Malawi: The Impact of Age, Poverty, Population Density, and Environmental Factors
Authors: Afuleni Mwandida Kamba , Hall Ian , House Thomas , Johnson Olatunji
Published: February 2025

Background

Understanding the spatiotemporal variation of COVID-19 transmission and its determinants is crucial for gaining deeper insights into the dynamics of disease spread. Regional and temporal differences in demographics, socioeconomic conditions, and environmental factors shaped the trajectory of the COVID-19 pandemic, underscoring the importance of advanced spatio-temporal modelling. This research aims to construct a spatiotemporal model to examine the relationship between age groups, poverty, population density, precipitation, and COVID-19 risk, as well as to pinpoint high-risk areas.

Methods

Here we present a spatiotemporal statistical analysis using COVID-19 case data from Malawi recorded from 2 April 2020 to 27 March 2022. Bayesian spatiotemporal models were fitted, with weekly confirmed cases as the response variable and demographic, socioeconomic, and environmental factors as predictors.

Results

The findings reveal that spatial and temporal factors, along with age, population density, and poverty, significantly affect observed COVID-19 incidence in Malawi, whereas precipitation does not. The greatest risk was observed during colder months (June–July), December’s festive season, and January. Urban centres and lake-shore districts were disproportionately impacted, with individuals aged 40 − 49 at particularly high risk.

Conclusions

These results emphasise the need to prioritise vaccinations for working-age populations in urban and tourist areas during high-risk periods. Moreover, ensuring adherence to public health guidelines and enhancing healthcare services in these districts is critical.

Key Messages

The age group 40–49 faced a significantly higher risk of COVID-19 compared to all other age groups.

COVID-19 risk is generally low across Malawi during the study period, with Blantyre being a notable exception.

Positive associations were identified between COVID-19 risk and factors such as age, poverty levels, and population density.

Both spatial and temporal dynamics were found to have substantial impacts on COVID-19 transmission risk.
Cumulative remnant cholesterol and major adverse cardiovascular events among adults with type 2 diabetes
Authors: Qian Yu-Wen , Liu Zhong-Yue , Fang Fei , Wang Jia-Min , Shao Xiao-Ping , Jia Yi-Ping , Wu Xian-Bo , Li Fu-Rong , Zhang Wei , Yang Huan-Huan , Chen Guo-Chong , Wang Hai-Peng
Published: February 2025

Background

Individuals with type 2 diabetes are prone to dyslipidemia. The relationship of cumulative exposure to elevated remnant cholesterol (RC) with major adverse cardiovascular events (MACEs) remains unclear for individuals with type 2 diabetes, especially for those with intensive lipid-lowering treatment.

Methods

This study included 5143 participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes trial, who had at least four lipid measurements over the first three years of the trial and did not have MACEs across the measurements. Cumulative RC (cumRC) was calculated considering RC levels at each measurement and the between-measurement time interval. Cox proportional hazards regression models were used to estimate HRs and 95% CIs of MACEs associated with cumRC levels.

Results

During a median follow-up of 6.3 years, 472 participants developed MACEs, including 154 cardiovascular deaths, 211 with nonfatal myocardial infarction, and 148 with nonfatal stroke. After multivariable adjustment for conventional risk factors, higher levels of cumRC were associated with a higher risk of MACEs (HRQ4 vs. Q1= 1.71, 95% CI: 1.31-2.22; P-trend <0.001), with similar associations for cardiovascular death (P-trend = 0.009) and nonfatal myocardial infarction (P-trend <0.001), but no association for nonfatal stroke (P-trend = 0.099). The association of cumRC with the risk of MACEs was consistent across age, sex, and lipid trial assignment groups and remained after further adjusting for baseline RC.

Conclusion

Among adults with type 2 diabetes, cumulative exposure to elevated RC is associated with a higher risk of MACEs, even in the context of intensive lipid management.
Causal relationship of polyunsaturated fatty acids with mental disorders: a systematic review and meta-analysis
Authors: Yao Yiying , Yang Xiaopeng , Yan Junwei , Lv Hongran , Yue Zihan , Yu Jiayao , Ye Mengfei , Lin Xiuqin , Qian Chao , Zhang Huafang , Liu Zheng
Published: February 2025

Mental disorders (MDs) are emerging as a significant threat to global health, with their intricate pathogenesis making the discovery of effective treatments a challenging endeavor. Currently, nutritional intervention, especially polyunsaturated fatty acids (PUFAs), has garnered widespread attention. This review aims to explore the potential causal relationship between PUFAs and MDs using Mendelian randomization (MR) meta-analysis. The study employed two-sample MR technology to analyze the association between PUFAs (including omega-3, omega-3%, omega-6, omega-6%, and the omega-6:omega-3 ratio) and MDs. It utilized data from genome-wide association studies to assess the role of PUFAs in 12 major MDs. The MR analysis revealed a causal link between genetically predicted omega-3 and MDs such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% showed protective effects against certain diseases, including emotional personality disorder. Meanwhile, the inverse correlation between genetically predicted omega-6 and the risk of attention deficit/hyperactivity disorder, as well as the association between a high omega-6:omega-3 ratio and increased risk of depression and other mood disorders, were also supported by meta-analyses. These findings suggest that high levels of omega-3 and omega-3% may reduce the risk of MDs, while a high omega-6:omega-3 ratio may increase the risk. The study highlights the potential of PUFAs, particularly omega-3, in the prevention and treatment of MDs, while also noting the complex interactions between omega-3 and omega-6 and their impact on MDs, which necessitates further research. These findings provide a scientific basis for future clinical trials and the development of dietary intervention measures.
Influence of gut microbiota on oral drug absorption and metabolism
Authors: Nelson Douglas , Veerareddy Vaishnavi , Kashyap Purna C , Tang Xiaojiao , Kalari Krishna R. , Kandimalla Karunya K.
Published: February 2025

Gut bacteria influence host intestinal phenotype in ways that impact drug absorption and metabolism. By comparing colonic tissue from germ-free mice to that of mice colonized with human microbiota, this study evaluates microbiota-driven differences in gene expression, mucosal permeability, and P-gp efflux capacity. Transcriptomic analysis revealed upregulation of genes coding ATP-binding cassette drug transporters P-gp (Abcb1a, Abcb1b), BCRP (Abcg2), and MRP3 (Abcc3), along with increased expression of solute carriers MCT1 (Slc16a1) and OCTN2 (Slc22a5). Immunohistochemistry indicated greater P-gp expression and apical localization in humanized mice. No relevant gene expression changes were observed in human homologs of drug-metabolizing cytochrome P450 enzymes, though cytochrome P450 oxidoreductase (Por) upregulation suggests increased cytochrome activity. Other phase I drug-metabolizing enzymes, including multiple homologs of human carboxylesterase 2 (CES2) and several reductases, were upregulated with high significance. Regarding phase II metabolism, genes encoding most UDP-glucuronosyltransferases and glutathione S-transferases were upregulated, along with the enzymes responsible for synthesizing their corresponding co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated higher permeability to14C-labeled polyethylene glycol 4000 (14C-PEG4000) in germ-free mice than in humanized mice. The14C-PEG4000 permeability differences are in agreement with changes in paracellular tight junctional proteins such as claudins, zonula occludens, and myosin II-related genes. These results demonstrate the broader impact of gut microbiome on oral drug absorption and metabolism and implicate the contributions of gut microbiome to individual variations in drug efficacy and toxicity.
EPICURUS: E-field-based spatial filtering procedure for an accurate estimation of local EEG activity evoked by Transcranial Magnetic Stimulation
Authors: Corominas-Teruel Xavier , Mutanen Tuomas P. , Leto Carlo , Colomina Maria Teresa , Gallea Cécile , Bracco Martina , Valero-Cabré Antoni
Published: February 2025

Background

The concurrent use of Transcranial magnetic stimulation (TMS) with electroencephalography (EEG) is increasingly integrated in research and clinical protocols to provide proof of effect by magnetic pulses. However, a reliable identification of evoked local EEG activity over TMS targeted cortical sites remains still challenging.

Methods

Here we present EPICURUS, a novel EEG spatial filtering approach, by which, individual MRI based simulations of TMS- electrical fields (E-fields) guide the reconstruction of TMS evoked o EEG signals originated in the primary motor cortex, minimizing crosstalk from non relevant more distant sources.

Results

A reduction of late Transcranial Evoked-Potentials (TEPs) components (>100 ms post pulse onset) suggest our E-field-based spatial filter approach efficiently reduced intrusion of non-locally relevant distant sources engaged by TMS, particularly when combined with a suppression of auditory entries.

Conclusion

The individually customized E-field-based spatial filtering procedure here developed for TMS- EEG datasets shows promise improving the spatio-temporal mapping of primary sources activated by magnetic pulses.

HIGHLIGHTS

Concurrent TMS-EEG recordings are a well-established tool to monitor brain state of activity and provide proof of effect and target engagement.

The lack of spatial specificity of EEG prevents an accurate estimation of the locally activated EEG sources, hindering the interpretation of TMS effects.

We here developed a spatial filtering approach for TMS-EEG based on individual estimation of E- field spread following stimulation.

Our E-field spatial filter combined with auditory constraints reduced non-relevant distant signal components and improved the reliability of local EEG estimates.
IFIT3 RNA-binding activity promotes influenza A virus infection and translation efficiency
Authors: Sullivan Owen M. , Nesbitt Daniel J. , Schaack Grace A. , Feltman Elizabeth , Nipper Thomas , Kongsomros Supasek , Reed Sevilla G. , Nelson Sarah L. , King Cason R. , Shishkova Evgenia , Coon Joshua J. , Mehle Andrew
Published: February 2025

Host cells produce a vast network of antiviral factors in response to viral infection. The interferon-induced proteins with tetratricopeptide repeats (IFITs) are important effectors of a broad-spectrum antiviral response. In contrast to their canonical roles, we previously identified IFIT2 and IFIT3 as pro-viral host factors during influenza A virus (IAV) infection. During IAV infection, IFIT2 binds and enhances translation of AU-rich cellular mRNAs, including many IFN-simulated gene products, establishing a model for its broad antiviral activity. But, IFIT2 also bound viral mRNAs and enhanced their translation resulting in increased viral replication. The ability of IFIT3 to bind RNA and whether this is important for its function was not known. Here we validate direct interactions between IFIT3 and RNA using electromobility shift assays (EMSAs). RNA-binding site identification (RBS-ID) experiments then identified an RNA-binding surface composed of residues conserved in IFIT3 orthologs and IFIT2 paralogs. Mutation of the RNA-binding site reduced the ability IFIT3 to promote IAV gene expression and translation efficiency when compared to wild type IFIT3. The functional units of IFIT2 and IFIT3 are homo- and heterodimers, however the RNA-binding surfaces are located near the dimerization interface. Using co-immunoprecipitation, we showed that mutations to these sites do not affect dimerization. Together, these data establish the link between IFIT3 RNA-binding and its ability to modulate translation of host and viral mRNAs during IAV infection.

Importance

Influenza A viruses (IAV) cause considerable morbidity and mortality through sporadic pandemics as well as annual epidemics. Zoonotic IAV strains pose an additional risk of spillover into a naive human population where prior immunity can have minimal effect. In this case, the first line of defense in the host is the innate immune response. Interferon stimulated genes (ISGs) produce a suite of proteins that are front-line effectors of innate immune responses. While ISGs are typically considered antiviral, new work has revealed an emerging trend where viruses co-opt ISGs for pro-viral function. Here, we determine how the ISG IFIT3 is used by IAV as a pro-viral factor, advancing our understanding of IFIT3 function generally as well as specifically in the context of IAV infection.
Study on community knowledge and awareness of invasive species
Authors: Stazione Leonel
Published: February 2025

In a globalized world, invasive species (IS) have significant ecological and socio-economic impacts, emphasizing the need for public awareness and effective management. This work presents a study about environmental perceptions and biological invasion knowledge on both teacher and non-teacher communities, using a semi-structured, online questionnaire. Data on demographic profiles, perceptions of environmental impact and knowledge of biological invasions were compiled. Results revealed that teachers perceived higher environmental and biological invasion impacts than non-teachers. While most respondents acknowledged the high impact of IS, teachers exhibited higher levels of awareness and concern. The unintentional transport of IS was identified as the main threat, and human health concerns were the primary reason for species removal. This study highlights the importance of enhancing environmental education in both formal and non-formal settings to address the impacts of IS. A multidisciplinary approach is recommended to raise public awareness and ensure sustainable management across diverse community sectors.
Structural and Functional Insights into GGCX-FIX Interaction: Implications for Vitamin K-Dependent Bleeding Disorders
Authors: Liu Kang , Li Shixin , Tong Jiangbo , Jiang Nan , Hong Minwen , Gu Yi , Chen Luju , Liang Dan , Jin Yongchao , Zhao Yuan , Hou Dongmei , Huang Jinlin , Tie Jian-Ke , Hao Zhenyu
Published: February 2025

Gamma-carboxylation, catalyzed by γ-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result in vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), which encompasses a broad spectrum of clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge of GGCX’s structure and functional regions hinders our understanding of the consequences of GGCX mutations and the treatment for VKCFD1. This study aimed to identify key functional regions of GGCX and their interactions with VKDPs to better elucidate the molecular mechanisms underlying these diverse clinical symptoms. Using AlphaFold 3 and molecular dynamics simulations, we developed a complex binding model of GGCX, FIX, and reduced vitamin K, which revealed critical regions and residues involved in their interaction. Site-directed mutagenesis and cell-based assays further validated the model, confirming that multisite and regional cooperative binding of FIX to GGCX plays a key role in modulating γ-carboxylation efficiency. Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCX’s dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports the hypothesis that GGCX’s carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants.
Subtype-specific enhancer RNAs define transcriptional regulators and prognosis in breast cancers
Authors: Patel Aamena Y , Zarrineh Peyman , Sheth Jigar H , Mohan Sumitra , Iqbal Mudassar , Nagarajan Sankari
Published: February 2025

Gene expression is tightly controlled by DNA elements called enhancers by associating with lineage-specific transcription factors. These enhancers transcribe non-coding RNAs (called enhancer RNAs or eRNAs). eRNA expression is an early indicator of transcription factor activity and is associated with treatment response and survival in cancer patients. However, the attempts to identify prognostic eRNAs in breast cancers were inadequate, as these studies ignored the heterogenous nature of breast cancers with distinct molecular subtypes. By analysing ∼300,000 eRNA loci profiled using RNA-sequencing datasets from 1,095 breast cancer patients using machine learning approaches, we categorised eRNAs which are specific to breast cancer molecular subtypes and survival. The classified eRNAs were associated with gene pathways related to relevant subtypes. Interestingly, transcription factor analyses highlighted involvement of nuclear receptors other than the estrogen receptor with luminal-specific eRNAs. Basal eRNAs showed association with the transcriptional corepressor TRIM28 and androgen receptor. Luminal eRNAs were associated with better outcomes and Her2 eRNAs with worse outcome in patients. Overall, we demonstrate that machine learning approaches performed on RNA-seq datasets can classify subtype-specific and prognostic eRNAs which can be used to identify critical gene pathways and transcription factor networks in breast cancer.
Single-nuclear transcriptomics of lymphedema-associated adipose reveals a pro-lymphangiogenic stromal cell population
Authors: Westcott Gregory P. , Emont Margo P. , Gulko Anton , Zhou Zhibo , Kim Charissa , Varma Gopal , Tsai Leo L. , O’Donnell Eliza , Loureiro Zinger Yang , Liang Wenle , Jacobs Christopher , Tsai Linus T. , Padera Timothy P. , Singhal Dhruv , Rosen Evan D.
Published: February 2025

Chronic lymphedema is a progressive, disfiguring disease that results from dysfunction of the lymphatic vasculature, causing distal accumulation of interstitial fluid, localized development of tissue edema, and expansion of subcutaneous adipose tissue (SAT). As the molecular mechanisms governing SAT remodeling in this disease are unclear, we performed single-nucleus RNA sequencing on paired control and affected SAT biopsies from patients with unilateral lymphedema. Lymphedema samples were characterized by expansion of SAA+adipocytes, pro-adipogenic stem cells, and proliferation of lymphatic capillaries. AGRIA1+lymphedema-enriched stromal cell population expressingVEGFC,ADAMTS3, andCCBE1was identified, suggesting an enhanced axis of communication between adipose stem and progenitor cells (ASPCs) and lymphatic endothelial cells. Furthermore, lymphedema ASPC-conditioned media promoted lymphatic endothelial tube elongationin vitro. These findings indicate a critical role for ASPCs in regulating adipocyte differentiation and lymphatic vascular remodeling in lymphedema, and provide a valuable resource for better understanding this disease.
Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer’s disease through modulation of Dgat2
Authors: Yadav Archana , Ouyang Xiaosen , Barkley Morgan , Watson John C , Madamanchi Kishore , Kramer Josh , Zhang Jianhua , Melkani Girish
Published: February 2025

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. Mutations in the Amyloid Precursor Protein (APP), and accumulation of Aβ42contribute to AD, however, underlying mechanisms linking beta amyloid to lipid metabolism and neuroinflammation remain unclear. UsingDrosophilamodels, we demonstrate thatAppNLGandAβ42lead to progressive locomotor impairments, disrupted sleep activity, memory deficits, lipid dysregulation, loss of synaptic integrity, and neuroinflammation. Lipid accumulation and neuroinflammation have also been observed in theAppNLG-Fknockin mouse model, supporting their involvement in AD pathogenesis. Furthermore, we demonstrate a role of Diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme in lipid regulation, in modulating AD phenotypes, as Dgat2 and the levels of its potential transcription factors were altered in AD Drosophila and mouse models. InAppNLGandAβ42 DrosophilaAD models,Dgat2knockdown reduced lipid accumulation, restored synaptic integrity, improved locomotor and cognitive function, and attenuated neuroinflammation. Additionally, Dgat2 modulation improved sleep quality and circadian rhythms, further implicating lipid metabolism in AD progression. InAppNLG-Fmice, Dgat2 inhibition mitigated lipid dysmetabolism decreased neuroinflammatory responses, and reduced expression of AD risk genes. These findings underscore the intricate interplay between amyloid pathology, lipid dysregulation, and neuroinflammation, and suggest that targeting Dgat2 may provide a novel therapeutic strategy for mitigating AD-associated dysfunction. Understanding the conserved impact of lipid homeostasis across species offers valuable insights into potential translational interventions for AD.