bluuebunny/crossref_metadata_2025 huggingface dataset:
BrainGT: Multifunctional Brain Graph Transformer for Brain Disorder Diagnosis
Authors: Shehzad Ahsan , Yu Shuo , Zhang Dongyu , Abid Shagufta , Cheng Xinrui , Zhou Jingjing , Xia Feng
Published: August 2024

Brain networks play a crucial role in the diagnosis of brain disorders by enabling the identification of abnormal patterns and connections in brain activities. Previous studies exploit the Pearson’s correlation coefficient to construct functional brain networks from fMRI data and use graph learning to diagnose brain diseases. However, correlation-based brain networks are overly dense (often fully connected), which obscures meaningful connections and complicates subsequent analyses. This dense connectivity poses substantial performance challenges to traditional graph transformers, which are primarily designed for sparse graphs. Consequently, this results in a notable reduction in diagnostic accuracy. To address this challenging issue, we propose a multifunctional brain graph transformer model for brain disorders diagnosis, namely BrainGT, which is capable of constructing multifunctional brain networks rather than a dense brain network from fMRI data. It utilizes the fusion of self-attention and cross-attention mechanisms to learn important features within and across multiple functional brain networks. Classification (diagnosis) experiments conducted on three real fMRI datasets (i.e., ADNI, PPMI, and ABIDE) demonstrate the superiority of the proposed BrainGT over state-of-the-art methods.

Impact Statement

The proposed BrainGT model represents a substantial advancement in computational neuroscience, offering a promising tool for more accurate and efficient diagnosis of brain disorders. By constructing multifunctional brain networks from fMRI data, BrainGT overcomes the limitations of traditional graph transformers and correlation-based brain networks. This innovation has profound implications across social, economic, and technological dimensions. Socially, BrainGT can enhance the quality of life for individuals with brain disorders by enabling more accurate diagnoses, leading to more effective treatments and better patient outcomes. Economically, BrainGT has the potential to reduce healthcare costs by streamlining the diagnostic process and potentially reducing the need for more expensive or invasive procedures. Technologically, BrainGT pushes the boundaries of AI and neuroscience, opening new avenues for research and development. It demonstrates the potential of AI to handle complex and dense data structures, with applications that could extend to other fields.
Evaluation of a One Health public health program based on minimum inputs to control Taenia solium in Madagascar
Authors: ANDRIA-MANANJARA Diana Edithe , Raliniaina Modestine , Rakotoarinoro Mihaja , Nely José A , Razafindraibe Nivohanitra , Ramiandrasoa Sylvia Noromanana , Ramahefasoa Betthelhein , Rakotoarison Valisoa Claude , Torgerson Paul R. , Cardinale Eric , Rasamoelina Harena Andriamanivo , Edosoa Glenn , Fleury Agnès , Mwape Kabemba E. , Abela Bernadette , Lightowlers Marshall W. , Donadeu Meritxell
Published: August 2024

Cysticercosis in humans caused by the parasite Taenia solium is one of the World Health Organization’s Neglected Tropical Diseases. The parasite is transmitted between the human host and pigs. Efforts to prevent the disease have relied mainly on treatment of people with anthelmintics. However to date there is no practical and effective control method that has been delivered as a public health program. Here we describe a large-scale, minimum inputs T. solium control program implemented as a public health program in Madagascar. Initially pigs were vaccinated for porcine cysticercosis and medicated with oxfendazole, after which only young piglets and pigs imported into the program area were targeted for interventions. After piglet interventions were in place and on-going, a single mass drug administration (MDA) was delivered to the human population with a taeniacide. The outcomes were assessed one year after the human treatment, by comparing pre-and post-intervention levels of human T. solium taeniasis and porcine cysticercosis caused by T. solium.  Over a twenty-two-month period, 96,735 pig vaccinations were delivered and during the MDA, 117,216 people received taeniacide. Ninety percent of the pig population were receiving vaccination and medication at the end of the intervention period. Coverage of the eligible human population by the MDA was 62.5%. Human taeniasis was found to be 1.25% prior to the MDA and 0.6% one year after the MDA. Prior to the intervention 30.8% of slaughter-age pigs had viable T. solium infection whereas no viable infection was detected in any pig treated in the program.  The program successfully demonstrated effective control of T. solium transmission using minimum inputs and delivered as a public health program. Sustained control and expansion of the program could potentially lead to the elimination of the disease being a public health problem in Madagascar.
Deciphering causal relationships between cell type-specific genetic factors and brain imaging-derived phenotypes and disorders
Authors: Yang Anyi , Zhao Xingzhong , Yang Yucheng T. , Zhao Xing-Ming
Published: August 2024

The integration of expression quantitative trait loci (eQTLs) and genome-wide association study (GWAS) findings to identify causal genes aids in elucidating the biological mechanisms and the discovery of potential drug targets underlying complex traits. This can be achieved by Mendelian randomization (MR), but to date, most MR studies investigating the contribution of genes to brain phenotypes have been conducted on heterogeneous brain tissues and not on specific cell types, thus limiting our knowledge at the cellular level. In this study, we employ a MR framework to infer cell type-specific causal relationships between gene expression and brain-associated complex traits, using eQTL data from eight cell types and large-scale GWASs of 123 imaging-derived phenotypes (IDPs) and 26 brain disorders and behaviors (DBs). Our analysis constructs a cell type-specific causal gene atlas for IDPs and DBs, which include 254 and 217 potential causal cell type-specific eQTL target genes (eGenes) for IDPs and DBs, respectively. The identified results exhibit high cell type specificity, with over 90% of gene-IDP and 80% of gene-DB associations being unique to a single cell type. We highlight shared cell type-specific patterns between IDPs and DBs, characterize the putative causal pathways among cell type-specific causal eGenes, DBs and IDPs, and reveal the spatiotemporal expression patterns of these cell type-specific causal eGenes. We also demonstrate that cell type-specific causal eGenes can characterize the associations between IDPs and DBs. In summary, our study provides novel insights into the genetic foundations at the cellular level that influence brain structures, disorders and behaviors, which reveals important implications for therapeutic targets and brain health management.
Patient-Reported Characteristics of Pernicious Anaemia:A first step to initiate James Lind Alliance Priority Setting Partnership Driven Research
Authors: Thain Alfie , Visser Petra , Hart Kathryn , Nexo Ebba , McCaddon Andrew , Hannibal Luciana , Wolffenbuttel Bruce HR , Green Ralph , Ward Nicola , Seage Catherine Heidi , Owen Julian , Burchell Katrina , Dib Marie-Joe , Ahmadi Kourosh R
Published: August 2024

Objective

Pernicious anaemia (PA) is characterised by vitamin B12 deficiency due to autoimmune-mediated loss of gastric parietal cells and intrinsic factor. The Pernicious Anaemia Society (PAS) identified 10 research priorities for PA through a James-Lind Alliance Priority Setting Partnership (JLA-PSP). This study aimed to survey PAS members to identify and characterise a cohort of patients to form a PA research repository.

Methods

An online survey was designed using SurveyMonkey, comprising 21 questions on diagnosis, comorbidities, family history, and management. The survey was sent to 3,482 PAS members (April-September 2022) via the PAS website and email.

Results

Atotal of 1,191 PAS members completed the survey. Among individuals with a probable (n=471) or suspected PA (n=500) diagnosis, 84% were UK-based, and 81% were female, with an age range of 23-93 years. Diagnosis was predominantly based on low serum B12 (50%), positive intrinsic factor (38%), and/or parietal cell autoantibodies (15%). Diagnostic delays were common, with 37% waiting ≥3 years for a diagnosis. Nearly half had one or more other autoimmune diseases. One-third reported having at least 2 and up to 7 family members with PA or other autoimmune diseases. Vitamin B12 treatment frequency varied widely, ranging from daily to 3-monthly injections.

Conclusion

This study highlights gaps in current diagnostic and management approaches for PA, paving the way for future work in line with the JLA-PSP research priorities. By characterising a cohort of PA patients and compiling baseline data, we provide a foundation for research to develop more effective diagnostic and management strategies.
Modeling the drivers of differential Typhoid Conjugate Vaccine (TCV) impact in Pakistan: force of infection and age-specific duration of protection
Authors: Kraay Alicia N.M. , Yousafzai Mohammad T. , Qureshi Sonia , Gauld Jillian , Qamar Farah N.
Published: August 2024

Background

While trials have demonstrated high efficacy of typhoid conjugate vaccine (TCV), data on effectiveness are limited. We report initial impacts and predict future benefits of TCV from two provinces in Pakistan.

Methods

We used blood culture-confirmed typhoid cases from the Surveillance for Enteric Fever in Asia Project (SEAP) and Impact assessment of Typhoid conjugate vaccine following introduction in Routine Immunization Program of Pakistan (ITRIPP) to estimate the population-level impact of vaccination (2018-2023). We used regression models to estimate initial impacts and an agent-based model to predict future benefits.

Findings

In Sindh, typhoid incidence was higher and cases were younger compared with Punjab. TCV reduced incidence by 48.9% in Sindh (95% CI: 47.3-50.3%) and 66.2% in Punjab (95% CI: 64.7%, 67.6%) over the first 2 years after vaccine rollout but declined each year. In Sindh, waning was quicker and models predicted that population incidence would stabilize near pre-vaccine levels in 2024. An additional campaign could provide short-term, but not long-term, benefits. In contrast, in Punjab, incidence is projected to remain low for several years, and the standard vaccine program may be sufficient. However, follow up data from Punjab are needed to better characterize waning immunity.

Interpretation

TCV has reduced incidence in Pakistan, but protection varies by site. Standard vaccine policy may be sufficient to control incidence in settings with moderate transmission. However, in settings with particularly high incidence and/or short duration of protection, alternative strategies to reduce the force of infection may be needed.

Funding

Bill & Melinda Gates Foundation
Unpacking sources of transmission in HIV prevention trials with deep-sequence pathogen data – BCPP/ Ya Tsie study
Authors: Magosi Lerato E. , Tchetgen Tchetgen Eric , Novitsky Vlad , Pretorius Holme Molly , Moore Janet , Bachanas Pam , Lebelonyane Refeletswe , Fraser Christophe , Moyo Sikhulile , Hurwitz Kathleen E. , Gaolathe Tendani , Goyal Ravi , Makhema Joseph , Lockman Shahin , Essex Max , De Gruttola Victor , Lipsitch Marc
Published: August 2024

To develop effective HIV prevention strategies that can guide public health policy it is important to identify the main sources of infection in HIV prevention studies. Accordingly, we devised a statistical approach that leverages deep- (or next generation) sequenced pathogen data to estimate the relative contribution of different sources of infection in community-randomized trials of infectious disease prevention. We applied this approach to the Botswana Combination Prevention Project (BCPP) and estimated that 90% [95% Confidence Interval (CI): 81 – 93] of new infections that occurred in individuals in communities that received combination prevention (including universal HIV test-and-treat) originated from individuals residing in communities outside of the trial area. We estimate that the relative impact of the intervention was greater in rural geographically isolated communities with limited opportunity for imported infections compared to communities neighboring major urban centers. Treating people with HIV limits the spread of infection to uninfected individuals; accordingly, counterfactual modeling scenarios estimated that a nationwide application of the intervention could have reduced transmissions to recipients in trial communities by 59% [3 – 87], much higher than the observed 30% reduction. Our results suggest that the impact of the BCPP trial intervention was substantially limited by sources of transmission outside the trial area, and that the impact of the intervention could be considerably larger if applied nationally. We recommend that studies of infectious disease prevention consider the impact of sources of transmission beyond the reach of the intervention when designing and evaluating interventions to inform public health programs.
Temporal and interaction dynamics of dengue cases, entomological and meteorological variables in Melaka, Malaysia: A multivariate time series analysis
Authors: Alipitchay Shazelin , Alias Muhammad Aswad , Hamid Sharifah Nur Shahirah Syed Abdul , Hamzah Rabizah , Mansor Norain , Ab. Hamid Nurulhusna , Othman Hidayatulfathi
Published: August 2024

The interaction between dengue cases, entomological and meteorological variables has remained intricate for decades. Validated facts are important to form robust decision making with the adoption of safer and sustainable efforts. This study aims to elucidate the relationship between the variables in the long run and short-term dynamic focusing in Melaka, Malaysia, in an attempt to improve the understanding of the variables and their temporal associations. This study quantifies the variables on their temporal associations, potential time lags, and dynamic interplays between all the variable data sets. The research applies a Johansen Cointegration Test and Vector Error Correction Model to validate long term run and examine short-term deviations among dengue cases, temperature, ovitrap and sticky ovitrap data from 2020-2022. Empirical findings prove that temperature, sticky ovitrap index (SOI) and ovitrap index (OI) has a significant and unique long-run equilibrium relationship with dengue cases. The short-term equilibrium results display a robust causality between variables. The model fit elucidates 74.2% of the dynamics. The VECM model provides an excellent trade-off between goodness of fit and complexity in describing the variables examined. Previous dengue occurrences predicted a surge of new dengue cases while preserving the cyclical pattern. The model predicts the utility and efficacy of sticky ovitraps. It also validates ovitrap use as a surveillance tool and offers substantiation of the influence of temperature on the progression of dengue cases.
A high-fiber, low-fat diet improves the symptoms and metabolic profile of patients with Crohn’s disease
Authors: Abreu Maria T. , Quintero Maria A. , Garces Luis , Hazime Hajar , Killian Rose , Faust Katerina M. , Mendygral Payton , Pignac-Kobinger Judith , Mangarelli Cristiana , Santander Ana M. , Fernández Irina , Solis Norma , Ortega Mailenys , Damas Oriana M. , Proksell Siobhan , Kerman David H. , Deshpande Amar R. , Seminerio Jennifer , Hashash Jana A.L. , Harvey Philip , Barrera Ingrid , Crane Tracy
Published: August 2024

Background

Crohn’s disease (CD) is characterized by intestinal inflammation. Diet is a risk factor for inflammatory bowel diseases such as CD and represents a promising adjunctive treatment, yet there are few well-controlled dietary intervention studies in CD patients. Fiber may have beneficial effects; however, most CD patients are told to avoid high-fiber foods. We conducted a longitudinal patient-preference study to examine the effect of a catered low-fat, high- fiber diet (theMi-IBD diet) on CD symptoms, inflammation, and the microbiome.

Methods

CD patients (n=73) received one-time diet counseling (Group 1, n=23), theMi-IBD diet (Group 2, n=26), or theMi-IBD diet along with a healthy household control (Group 3, n=24 patient- HHC dyads). TheMi-IBD diet was catered for 8 weeks, and CD symptoms were recorded. Serum samples were collected to measure inflammatory marker levels and evaluate systemic changes via proteomic analyses (SomaScan Discovery v4.1 assays). Stool samples were collected to perform metabolomic analyses.

Results

At baseline, CD patients had a low-fiber, high-fat diet. One-time diet counseling did not result in dietary changes. In contrast, catering led to marked dietary changes in CD patients (increased fiber intake, decreased fat intake; all ps < 0.001) and high adherence rates (96%). Group 3 exhibited improvements in CD symptoms (PRO2 and sCDAI scores). Proteomic analysis revealed higher baseline serum levels of proinflammatory proteins (SAA and CRP) in CD patients than in HHCs; these levels decreased with the catered diet. The diet also improved fecal metabolites related to protein and energy metabolism as well as markers of oxidative stress and inflammation in CD patients.

Conclusion

A nonpharmacological approach involving a high-fiber, low-fat diet to manage CD was well tolerated, even by patients with fibrostenotic CD. These findings fill a gap in development of dietary recommendations for CD patients.

Clinical trial registration

This trial was registered atClinicalTrials.gov(ID:NCT04213729).
Isolating the genetic component of mania in bipolar disorder
Authors: Merola Giuseppe Pierpaolo , Zvrskovec Johan , Wang Rujia , Li Yuen Kaye , Castellini Giovanni , Ricca Valdo , Coleman Jonathan , Vassos Evangelos , Breen Gerome
Published: August 2024

Objective

Bipolar disorder typically features episodes of mania and depression, frequently accompanied by psychosis. While progress has been made in understanding the genetics of depression and psychosis, mania remains underexplored.

Methods

We employed Genomic Structural Equation Modeling to subtract the genetic effects of schizophrenia and major depressive disorder (MDD) from bipolar disorder to identify a genetic trait specific to mania.

Results

The SEM model revealed significant loadings for “mania” (0.67, p<0.001), “psychosis” (0.58, p<0.001), and “depression” (0.29, p<0.001) factors, with mania, MDD and schizophrenia explaining 45%, 8% and 34% of the variance in bipolar disorder, respectively. Seven significant genomic regions associated with mania were identified. Key regions include rs9834970 (3q12.1, previously associated with lithium response), rs6992333 (8q13.1, brain structure), and rs12206087 (6q14.3, intelligence and cortical surface). Additionally, mania exhibited distinct genetic correlations compared to bipolar disorder across psychiatric, substance abuse, somatic, social, and neurological traits, including significantly higher correlations with intelligence (rg=0.08 vs −0.07) and educational attainment (rg=0.17 vs 0.12), and an unexpected reduced correlation with risky sexual behavior (rg=0.14 vs 0.27).

Conclusions

These findings enhance understanding of bipolar disorder’s genetic architecture, potentially offering a more bipolar disorder-specific GWAS.
LSD600: the first corpus of biomedical abstracts annotated with lifestyle–disease relations
Authors: Nourani Esmaeil , Makri Evangelia-Mantelena , Mao Xiqing , Pyysalo Sampo , Brunak Søren , Nastou Katerina , Jensen Lars Juhl
Published: August 2024

Lifestyle factors (LSFs) are increasingly recognized as instrumental in both the development and control of diseases. Despite their importance, there is a lack of methods to extract relations between LSFs and diseases from the literature, a step necessary to consolidate the currently available knowledge into a structured form. As simple co-occurrence-based relation extraction (RE) approaches are unable to distinguish between the different types of LSF-disease relations, context-aware transformer-based models are required to extract and classify these relations into specific relation types. No comprehensive LSF–disease RE system existed, primarily due to the lack of a suitable corpus for developing it. We present LSD600, the first corpus specifically designed for LSF-disease RE, comprising 600 abstracts with 1900 relations of eight distinct types between 5,027 diseases and 6,930 LSF entities. We evaluated LSD600’s quality by training a RoBERTa model on the corpus, achieving an F-score of 68.5% for the multi-label RE task on the held-out test set. We further validated LSD600 by using the trained model on the two Nutrition-Disease and FoodDisease datasets, where it achieved F-scores of 70.7% and 80.7%, respectively. Building on these performance results, LSD600 and the RE system trained on it can be valuable resources to fill the existing gap in this area and pave the way for downstream applications.
Improved characterization of gene-environment interactions for vitamin D through variance quantitative trait loci
Authors: Lu Tianyuan , Zhang Wenmin , Robinson-Cohen Cassianne , Engelman Corinne D , Lu Qiongshi , de Boer Ian H , Sun Lei , Paterson Andrew D
Published: August 2024

Background Understanding gene-environment interaction effects influencing vitamin D status may refine nutrition and public health strategies for vitamin D deficiency. Recent methodological advances have enabled the identification of variance quantitative trait loci (vQTLs) where gene-environment interaction effects are enriched. Objectives To identify vQTLs for serum 25-hydroxy vitamin D (25OHD) concentration and characterize potential gene-environment interaction effects of vQTLs. Methods We conducted vQTL discovery for 25OHD using a newly developed quantile integral linear model in the UK Biobank individuals of European (N = 313,514), African (N = 7,800), East Asian (N = 2,146), and South Asian (N = 8,771) ancestries, respectively. We tested for interaction effects between the identified vQTL lead variants and 18 environmental, biological, or lifestyle factors, followed by multiple sensitivity analyses. Results We identified 19 independent vQTL lead variants (p-value <5x10-8) in the European ancestry population. No vQTLs were identified in the non-European ancestry populations, likely due to limited sample sizes. A total of 32 interaction effects were detected with a false discovery rate <0.05. While known gene-season of measurement interaction effects were confirmed, additional interaction effects were identified involving modifiable risk factors, including time spent outdoors and body mass index. The magnitudes of these interaction effects were consistent within each locus upon adjusting for season of measurement and other covariates. We also identified a gene-sex interaction at a vQTL that implicates DHCR7. Integrating transcript- and protein-level evidence, we found that the sex-differentiated genetic effects may act through sex-biased expression of DHCR7 isoforms in skin tissues due to alternative splicing. Conclusions Through the lens of vQTLs, we identified additional gene-environment interaction effects affecting vitamin D status apart from season of measurement. These findings may provide new insights into the etiology of vitamin D deficiency and encourage personalized prevention and management of associated diseases for at-risk individuals.
Aortic root anatomy and impact on new-onset conduction abnormalities after transcatheter aortic valve implantation
Authors: Layoun Habib , Kassab Joseph , Chedid El Helou Michel , El Dahdah Joseph , Iskandar Odette , Ali Majeed Saidan Maryam Muhammad , Abushouk Abdelrahman , Isogai Toshiaki , Reed Grant , Puri Rishi , Wazni Oussama M. , Krishnaswamy Amar , Harb Serge , Kapadia Samir
Published: August 2024

Background

Angulation of virtual basal ring (VBR), also known as aortic annulus, in relation to sino-tubular joint (STJ) may lead to greater exposure of implanted stent to the conduction system, consequently increasing the risk of LBBB.

Objective

To measure VBR-STJ angle and explore its impact on the development of LBBB post TAVR.

Methods

Patients undergoing TAVR using the Sapiens 3 valve between 2016 and 2021, without pre-TAVR conduction anomalies were included. The angle between the VBR and the ascending aorta was measured as the angle between the VBR plane and the plane of the STJ on cardiac CT, along with the annulus dimensions. TAVR implantation depth was measured on intra-procedural fluoroscopy images.

Results

1204 patients were included, with 145 having new-onset LBBB. The VBR-STJ angle was significantly greater in the new-onset LBBB group (7.3 ± 4.7 vs 5.9 ± 4.6, p=0.002), and the difference in implantation depth between the levels of right and none coronary cusp (RCC and NCC) was significantly correlated with the VBR-STJ angle (r=0.1, p=0.03). This angle was further associated with new-onset LBBB after adjustment to patient and procedural characteristics (OR 1.08 CI: [1.04, 1.13], p<0.001).

Conclusion

Patients developing LBBB have larger VBR-STJ angle which was associated with greater depth of implantation of the TAVR valve below the RCC compared to the NCC. Precise understanding of the aortic root anatomy can help to predict onset of LBBB which in turn can inform decision making regarding optimal way of treating aortic stenosis and may improve procedure planning.

Condensed abstract

This study explores the impact of the virtual basal ring (VBR) to the sino-tubular junction (STJ) angle on the development of new-onset left bundle branch block (LBBB) post TAVR. The angle was measured in 1204 patients who underwent TAVR, with 145 developing LBBB post TAVR. The measured angle was significantly higher in patient with new-onset LBBB and was independently correlated with new-onset LBBB. These findings emphasize the importance of understanding the aortic root anatomy to improve TAVR planning and reduce the incidence of LBBB.
Is it me or the train moving? Humans resolve sensory conflicts with a nonlinear feedback mechanism in balance control
Authors: Assländer Lorenz , Albrecht Matthias , Gruber Markus , Peterka Robert J.
Published: August 2024

Humans use multiple sensory systems to estimate body orientation in space. A predominant concept for the underlying multisensory integration (MSI) is the linear summation of weighted inputs from individual sensory systems. The sensory contributions change depending on context and environmental conditions. These changes are typically attributed to ‘reweighting’ by some higher order mechanism. We provide evidence for a conceptually different mechanism that 1) performs a multisensory correction if the reference of a sensory input moves in space and is therefore unreliable and 2) combines the corrected sensory inputs with fixed weights. The correction is based on a sensory reconstruction of the sensory reference frame motion (RFM) and allows humans to automatically counteract erroneous inputs, e.g., when looking at a moving train. The proposed RFM estimator contains a nonlinear deadzone that blocks corrections at slow velocities. We first demonstrate that this mechanism accounts for the apparent changes in sensory contributions. Secondly, we hypothesized that such a nonlinearity would distort balance responses to perturbations in a very specific way. We predicted such distortions in body sway using a balance control model. Experiments using visual scene movements confirmed the predictions. The findings indicate that the central nervous system resolves sensory conflicts by an internal reconstruction of the cause of the conflict. Thus, the mechanism links the concept of causal inference to shifts in sensory contributions, providing a cohesive picture of MSI for the estimation of body orientation in space.
Spatiotemporal Single-Cell Roadmap of Human Skin Wound Healing
Authors: Liu Zhuang , Li Dongqing , Bian Xiaowei , Luo Lihua , Björklund Åsa K. , Li Li , Zhang Letian , Chen Yongjian , Guo Lei , Gao Juan , Cao Chunyan , Wang Jiating , He Wenjun , Xiao Yunting , Zhu Liping , Annusver Karl , Gopee Huda , Bennett Clare L. , Kasper Maria , Haniffa Muzlifah , Sommar Pehr , Xu Landén Ning
Published: August 2024

Wound healing is vital for human health, yet the details of cellular dynamics and coordination in human wound repair remain largely unexplored. To address this, we conducted single-cell and spatial transcriptomics analyses on human skin and acute wound tissues through inflammation, proliferation, and remodeling phases of wound repair from the same individuals, monitoring the cellular and molecular dynamics of human skin wound healing at an unprecedented spatiotemporal resolution. This singular roadmap reveals the cellular architecture of the wound margin and identifies FOSL1 as a critical driver of re-epithelialization. It shows that pro-inflammatory macrophages and fibroblasts sequentially support keratinocyte migration like a relay race across different healing stages. Comparison with single-cell data from venous and diabetic foot ulcers uncovers a link between failed keratinocyte migration and impaired inflammatory response in chronic wounds. Additionally, comparing human and mouse acute wound transcriptomes underscores the indispensable value of this roadmap in bridging basic research with clinical innovations.

Highlights

A spatiotemporal atlas to explore humanin vivogene expression across wound healing

Wound margin architecture unveils a model for human re-epithelialization

Distinct healing challenges in venous ulcers and diabetic foot ulcers

Unique human healing traits emerge in cellular heterogeneity and gene expression
Fluralaner treatment of chickens kills the southern house mosquito,Culex quinquefasciatus
Authors: Knape Koyle , Tian Yuexun , Durden Cassandra , Adams Dayvion R. , Garza Macie , Carey John B. , Hamer Sarah A. , Hamer Gabriel L.
Published: August 2024

The control of zoonotic and vector-borne pathogens is challenging due to the limited availability of intervention tools. West Nile virus (WNV) is an example of globally distributed zoonotic arbovirus that circulates betweenCulexspecies mosquitoes and avian hosts, with spillover transmission to humans, resulting in disease cases. Interventions delivering systemic insecticides to vertebrate hosts used by vector species, known as xenointoxication, are potential tools for managing vector populations by creating toxic bloodmeals. In this study, we evaluated the impact of three systemic insecticides on the mortality ofCx. quinquefasciatus: fenbendazole (Safe-Guard® Aquasol), ivermectin (Ivomec® Pour-On), and fluralaner (Bravecto®). We found no significant difference in the feeding rates of mosquitoes that fed on treated chickens compared to those fed on untreated chickens, suggesting that the treatment did not repel mosquitoes. The mortality ofCx. quinquefasciatusmosquitoes feeding on fluralaner-treated chickens was significantly higher (p < 0.01) than those fed on control chickens at 3 and 7 days post-treatment, but this effect was not observed in mosquitoes fed on chickens treated with fenbendazole or ivermectin. No differences in mortality were observed among the groups at 14, 26, or 56 days post-treatment. These data support fluralaner as a xenointoxication tool to controlCx. quinquefasciatuspopulations and decrease the risk of human exposure to their associated pathogens.
High-throughput unsupervised quantification of patterns in the natural behavior of marmosets
Authors: Menegas William , Corbett Erin , Beliard Kimberly , Xu Haoran , Parmar Shivangi , Desimone Robert , Feng Guoping
Published: August 2024

Recent advances in genetic engineering have accelerated the production of nonhuman primate models for neuropsychiatric disorders. To use these models for preclinical drug testing, behavioral screening methods will be necessary to determine how the model animals deviate from controls, and whether treatments can restore typical patterns of behavior. In this study, we collected a multimodal dataset from a large cohort of marmoset monkeys and described typical patterns in their natural behavior. We found that these behavioral measurements varied substantially across days, and that behavioral state usage was highly correlated to the behavior of cagemates and to the vocalization rate of other animals in the colony. To elicit acute behavioral responses, we presented animals with a panel of stimuli including novel, appetitive, neutral, aversive, and social stimuli. By comparing these behavioral conditions, we demonstrate that outlier detection can be used to identify atypical responses to a range of stimuli. This data will help guide the study of marmosets as models for neuropsychiatric disorders.
A wheat tandem kinase sensor activates an NLR helper to trigger immunity
Authors: Chen Renjie , Chen Jian , Outram Megan A. , Powell Oliver R. , Arndell Taj , Gajendiran Karthick , Wang Yan L. , Ayliffe Michael A. , Blundell Cheryl , Figueroa Melania , Sperschneider Jana , Vanhercke Thomas , Tang Dingzhong , Xu Yang , Zhong Guitao , Gardener Catherine , Yu Guotai , Gourdoupis Spyridon , Jaremko Łukasz , Matny Oadi , Steffenson Brian J. , Boshoff Willem H. P. , Meyer Wilku B. , Arold Stefan T. , Dodds Peter N. , Wulff Brande B. H.
Published: August 2024

Most plant resistance genes encode membrane-anchored receptor-like proteins or intracellular nucleotide-binding and leucine-rich repeat (NLR) receptors. In wheat and barley, tandem kinases (TKs) have emerged as a new class of resistance determinants. To understand the modus operandi of the wheat stem rust resistance protein Sr62TK, we identified two genetic interactors— a host gene required for Sr62TKfunction and the corresponding fungal AvrSr62 effector. We discovered that theSR62locus consists of a digenic module encoding Sr62TKand an NLR (Sr62NLR). AvrSr62 binds to the N-terminal kinase of Sr62TK. This triggers displacement of the C-terminal kinase allowing it to recruit Sr62NLRfor activation of immune responses. Understanding the mechanism of this two-component resistance complex will help engineering and breeding for durable resistance.
Multimodal Spatial Proteomic Profiling in Acute Myeloid Leukemia
Authors: Ly Christopher P. , Veletic Ivo , Pacheco Christopher D. , Dasdemir Enes , Jelloul Fatima Z. , Ferri-Borgongo Sammy , Basi Akshay V. , Gomez Javier A. , Root Jessica L. , Reville Patrick K. , Sharma Padmanee , Basu Sreyashi , Quesada Andres E. , Bueso-Ramos Carlos , Manshouri Taghi , Garcia Miriam , Burks Jared K. , Abbas Hussein A.
Published: August 2024

Acute myeloid leukemia (AML) resides in an immune rich microenvironment, yet, immune-based therapies have faltered in eliciting durable responses. Bridging this paradox requires a comprehensive understanding of leukemic interactions within the bone marrow microenvironment. We optimized a high-throughput tissue-microarray based pipeline for high-plex spatial immunofluorescence and mass cytometry imaging on a single slide, capturing immune, tumor, and structural components. Using unbiased clustering on the spatial K function, we unveiled the presence of tertiary lymphoid-like aggregates in bone marrow which we validated using spatial transcriptomics and an independent proteomics approach. We then found validated TLS signatures predictive of outcomes in AML using an integrated public 480 patient transcriptomic dataset. By harnessing high-plex spatial proteomics, we open the possibility of discovering of novel structures and interactions that underpin leukemic immune response. Further, our study’s methodologies and resources can be adapted for other bone marrow diseases where decalcification and autofluorescence present challenges.
Rapid synthesis and screening of natively paired antibodies against influenza hemagglutinin stem via oPool+display
Authors: Ouyang Wenhao O. , Lv Huibin , Liu Wenkan , Mou Zongjun , Lei Ruipeng , Pholcharee Tossapol , Wang Yiquan , Dailey Katrine E. , Gopal Akshita B. , Choi Danbi , Ardagh Madison R. , Talmage Logan , Rodriguez Lucia A. , Dai Xinghong , Wu Nicholas C.
Published: August 2024

Antibody discovery is crucial for developing therapeutics and vaccines as well as understanding adaptive immunity. However, the lack of approaches to synthesize antibodies with defined sequences in a high-throughput manner represents a major bottleneck in antibody discovery. Here, we presented oPool+display, which combines oligo pool synthesis and mRNA display to construct and characterize many natively paired antibodies in parallel. As a proof-of-concept, we applied oPool+display to rapidly screen the binding activity of >300 natively paired influenza hemagglutinin (HA) antibodies against the conserved HA stem domain. Structural analysis of 16.ND.92, one of the identified HA stem antibodies, revealed a unique binding mode distinct from other known broadly neutralizing HA stem antibodies with convergent sequence features. Yet, despite such differences, 16.ND.92 remained broadly reactive and conferredin vivoprotection. Overall, this study not only established an experimental platform that can be applied in both research and therapeutics to accelerate antibody discovery, but also provides molecular insights into antibody responses to the influenza HA stem, which is a major target for universal influenza vaccine development.
Predicting the irrelevant: Neural effects of distractor predictability depend on load
Authors: Lui Troby Ka-Yan , Obleser Jonas , Wöstmann Malte
Published: August 2024

Distraction is ubiquitous in human environments. Distracting input is often predictable, but we do not understand when or how humans can exploit this predictability. Here we ask whether predictable distractors are able to reduce uncertainty in updating the internal predictive model. We show that utilising a predictable distractor identity is not fully automatic but in part depends on available resources. In an auditory spatial n-back task, listeners (n= 33) attended to spoken numbers presented to one ear and detected repeating items. Distracting numbers presented to the other ear either followed a predictable (i.e., repetitive) sequence or were unpredictable. We used electroencephalography (EEG) to uncover neural responses to predictable versus unpredictable auditory distractors, as well as their dependence on perceptual and cognitive load. Neurally, pairs of targets and unpredictable distractors induced a sign-reversed lateralization of pre-stimulus alpha oscillations (∼10 Hz) and larger amplitude of the stimulus-evoked P2 event-related potential component. Under low versus high memory load, distractor predictability increased the magnitude of the frontal negativity component. Behaviourally, predictable distractors under low task demands (i.e., good signal-to-noise ratio and low memory load) made participants adopt a less biased response strategy. We conclude that predictable distractors decrease uncertainty and reduce the need for updating the internal predictive model. In turn, unpredictable distractors might mislead proactive spatial attention orientation, elicit larger neural responses, and put higher demand on memory.
Dual and spatially resolved drought responses in the Arabidopsis leaf mesophyll revealed by single-cell transcriptomics
Authors: Berrío Rubén Tenorio , Verhelst Eline , Eekhout Thomas , Grones Carolin , De Veylder Lieven , De Rybel Bert , Dubois Marieke
Published: August 2024

Drought stress imposes severe challenges on agriculture by impacting crop performance. Understanding drought responses in plants at a cellular level is a crucial first step towards engineering improved drought resilience. However, the molecular responses to drought are complex as they depend on multiple factors including the severity of drought, the profiled organ, its developmental stage or even the cell types therein. Thus, deciphering the transcriptional responses to drought is specially challenging. Here, we investigated tissue-specific responses to mild drought in youngArabidopsis thaliana(Arabidopsis) leaves using single-cell RNA sequencing (scRNA-seq). To preserve transcriptional integrity during cell isolation, we inhibited RNA synthesis using the transcription inhibitor actinomycin D, demonstrating the benefits of transcriptome fixation for studying mild stress responses at single-cell level. We present a curated and validated single-cell atlas comprising 50,797 high-quality cells from almost all known cell types present in the leaf. We show that the mesophyll contains two spatially separated cell populations with distinct responses to drought: one enriched in canonical abscisic acid-related drought-responsive genes, and another one depicting iron starvation responses. Our study thus reveals a dual adaptive mechanism of the leaf mesophyll in response to mild drought and provides a valuable resource for future research on stress responses.
Prior expectations about own abilities bias self-belief formation and hinder subsequent revision
Authors: Schröder Alexander , Czekalla Nora , Mayer Annalina V , Zhang Lei , Stolz David S , Korn Christoph W , Diekelmann Susanne , Luebber Finn , Paulus Frieder M , Müller-Pinzler Laura , Krach Sören
Published: August 2024

Self-beliefs hinge on social feedback, but their formation and revision are not solely based on new information. Biases, such as confirming initial expectations, can lead to inaccurate self-beliefs. This study uses computational modeling to explore how initial expectations and confidence affect self-belief formation and revision in novel behavioral domains. In the first session, participants developed performance self-beliefs through trial-by-trial feedback. In the second session, feedback contingencies were reversed, requiring belief revision for accurate self-beliefs. Results showed a confirmation bias in belief updating, with initial expectations being linked to biased learning during both formation and revision. Higher confidence was associated with reduced belief revision and on average, self-beliefs persisted despite the conflicting evidence. This study extends the literature on confirmation bias to learning in uncharged, novel behavioral domains. Further, it demonstrates the importance of initial expectations and associated confidence for biased self-belief formation and subsequent learning.
Trade-offs between averages and intra-individual variation within vegetative, phenological, and floral traits
Authors: Møller Charlotte , March-Salas Martí , Sobral Mar , Haase Judith , De Frenne Pieter , Scheepens JF
Published: August 2024

Intra-individual trait variation in plants represents an often ignored but important dimension of phenotypic variation that contributes to functional diversity and the dynamics of ecological communities. It can be expressed differently across plant traits, but the induction of intra-individual variation in different trait types under environmental stresses has not yet been explored.

We used the clonal forest herb,Galium odoratum, to investigate intra-individual variation within vegetative, phenological, and floral traits, and trade-offs between trait average and variation under a full-factorial experimental design using drought and shading treatments.

Intra-individual variation (expressed as CV) differed in magnitude between trait types, with vegetative and floral traits showing the highest and lowest CV, respectively. CV occurring in the different traits responded to the drought and shade treatments. Trade-offs between CV and trait averages appeared across most of traits under the different treatment combinations, whereas trade-offs were less pronounced under control conditions.

Drought and shading in forest environments induce trade-offs between intra-individual variation and the average trait expression, indicating the relevance of intra-individual variation for functional adaptations of forest plants to climatic changes. Our findings suggest that plastic responses in intra-individual variation may be an important component for mechanistic adjustments of plants to environmental stresses.
Coupling renewable energy infrastructure planning and biodiversity conservation: a modeling-based framework
Authors: Froidevaux Jérémy S.P. , Le Viol Isabelle , Barré Kévin , Bas Yves , Kerbiriou Christian
Published: August 2024

Reconciling renewable energy planning and biodiversity conservation is urgently needed to address the interconnected crises of climate change and biodiversity loss. However, current strategies to avoid or limit the negative effects of renewable energy on biodiversity still hold major limitations during the planning process that could be overcome with modeling approaches. Here we propose a new applied modeling-based framework aiming to determine potential threats posed by proposed or built projects to biodiversity. By capitalizing on large-scale standardized citizen science biodiversity data to create reference scales of biodiversity levels, this approach aims to better inform the Ecological Impact Assessment (EIA) process at different stages pre- and post-project construction. We demonstrate the practical application of the framework using bat and onshore wind energy development in France as a case study. We reveal that current approaches in renewable energy planning failed to identify sites of biodiversity significance with >90% of wind turbines approved for construction to be placed in sites of high significance for bats. The risks posed by future wind turbines to bats concern all taxa (that are all protected in the European Union), including species with higher collision risks. We highlight how the proposed modeling-based framework could contribute to a more objective evaluation of pre- and post-construction impacts on biodiversity and become a prevalent component of the EIA decision-making. Its implementation could lead to a more biodiversity-friendly renewable energy planning in accordance with the world-leading target to halt biodiversity decline by 2030.
NuMA is a mitotic adaptor protein that activates dynein and connects it to microtubule minus ends
Authors: Colombo Sabina , Michel Christel , Speroni Silvia , Ruhnow Felix , Gili Maria , Brito Claudia , Surrey Thomas
Published: August 2024

Nuclear mitotic apparatus protein (NuMA) is indispensable for the mitotic functions of the major microtubule minus-end directed motor cytoplasmic dynein 1. NuMA and dynein are both essential for correct spindle pole organization. How these proteins cooperate to gather microtubule minus ends at spindle poles remains unclear. Here we use microscopy-basedin vitroreconstitutions to demonstrate that NuMA is a dynein adaptor, activating processive dynein motility together with dynein’s cofactors dynactin and Lissencephaly-1 (Lis1). Additionally, we find that NuMA binds and stabilizes microtubule minus ends, allowing dynein/dynactin/NuMA to transport microtubule minus ends as cargo to other minus ends. We further show that the microtubule-nucleating γ-tubulin ring complex (γTuRC) hinders NuMA binding. This shows that either γTuRC needs to be released or microtubules need to be severed to generate free minus ends before they can be incorporated into spindle poles by dynein/dynactin/NuMA. These results provide new mechanistic insight into how dynein, dynactin, NuMA and Lis1 cooperate to organize spindle poles in cells.