bluuebunny/crossref_metadata_2025 huggingface dataset:
Human gut microbiota subspecies carry implicit information for in-depth microbiome research
Authors: Trickovic Matija , Kieser Silas , Zdobnov Evgeny M. , Trajkovski Mirko
Published: February 2025

Microbial strains from same species can have distinct functional characteristics owing to their different gene content. As the highest resolution, strains are mainly host-specific, thus obscuring unbiased associations, and hindering deductive research. Here, we comprehensively define the human gut microbiota at consistently-annotated subspecies resolution in an unbiased, cohort-independent manner, and demonstrate that we can generalize across distinct populations worldwide while maintaining specificity and improving interstudy reproducibility. We developed panhashome, a sketching-based method for rapid subspecies quantification and identification of genes that drive the intraspecies variations, and showed that subspecies carry implicit information undetectable at species level. By meta-analysis of colorectal cancer (CRC) datasets, we identified disease-associated subspecies whose sibling subspecies or species are not. Subspecies-based machine-learning CRC diagnostic algorithm outperformed species-level methods by leveraging the unique subspecies-level information. This subspecies catalogue allows identification of genes that drive the functional differences between subspecies as fundamental step in mechanistically understanding microbiome-phenotype interactions.
Integrated deep learning and geo-referencing for drone-based animal tracking with flexible camera angles
Authors: Samad Imran , Sutaria Dipani , Farine Damien R. , Shanker Kartik , Cantor Mauricio
Published: February 2025

The ability of drones to provide detailed information on animals and their surroundings makes them ideal for studying animal behaviour at fine scales. While drones can provide high-resolution images of what animals are doing, they should also, in theory, be able to provide data on where they are. However, reconstructing geo-referenced tracks from drone videos that follow animals is challenging, particularly because current methods require specific drone flight patterns and large computational power.

Here, we combine deep learning and object tracking methods with a novel geo-referencing algorithm which allows us to track individuals across video frames and reconstruct their geo-referenced trajectories. We used a Region-based Convoluted Neural Network to detect animals and a Hungarian tracking algorithm to link detections across video frames, and then geo-referenced each detection in every frame to reconstruct individual trajectories.

We tested our geo-refencing algorithm through multiple drone flights with varying flight parameters over known Ground Control Points. The median (95% CI) geo-referencing error was 2.81 (0.74 – 23.23) meters, which reduced by 50% when the drone camera was positioned between -90° and -40°. Error increased with drone height and camera angle (-90° refers to the camera pointing towards the ground) but was not impacted by drone orientation.

We then demonstrate the utility of our framework with empirical examples using consumer-level drones. First, we tracked a volunteer carrying a high-resolution GPS unit and overlayed their GPS tracks on our estimated tracks to quantify tracking error. Next, we used drone videos of two delphinid species (Tursiops truncates gephyreus, andSousa plumbea) representing varying environmental and flight conditions. We were able to successfully infer individual tracks across all conditions except when individuals formed tight clusters, in which case tracks were assigned a group identifier.

Our framework demonstrates an easy and robust approach to translate drone videos of moving animals into geo-referenced animal tracks which is applicable in many research contexts. A major advance over previous methods is that our algorithm is robust to different camera angles, and provides tracks with accuracy on-par with, or even exceeding, the accuracy from GPS tracking.

Headline

Automated drone-based animal tracking
Cryo-EM reveals a new allosteric binding site at the M5mAChR
Authors: Burger Wessel A. C. , Mobbs Jesse I. , Rana Bhavika , Wang Jinan , Joshi Keya , Gentry Patrick R. , Yeasmin Mahmuda , Venugopal Hariprasad , Bender Aaron M. , Lindsley Craig W. , Miao Yinglong , Christopoulos Arthur , Valant Celine , Thal David M.
Published: February 2025

The M5muscarinic acetylcholine receptor (M5mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site has posed significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M5mAChR and its allosteric binding sites has remained limited. Here, we present a 2.8 Å cryo-electron microscopy structure of the M5mAChR complexed with heterotrimeric Gqprotein and the agonist iperoxo, completing the active-state structural characterization of the mAChR family. To identify the binding site of M5-selective PAMs, we implemented an integrated approach combining mutagenesis, pharmacological assays, structural biology, and molecular dynamics simulations. Our mutagenesis studies revealed that selective M5PAMs bind outside previously characterized M5mAChR allosteric sites. Subsequently, we obtained a 2.1 Å structure of M5mAChR co-bound with acetylcholine and the selective PAM VU6007678, revealing a novel allosteric pocket at the extrahelical interface between transmembrane domains 3 and 4 that was confirmed through mutagenesis and simulations. These findings demonstrate the diverse mechanisms of allosteric regulation in mAChRs and highlight the value of integrating pharmacological and structural approaches to identify novel allosteric binding sites.
CobVar — a comprehensive resource of Vitamin B12-associated genomic variants
Authors: HS Neha , Kilpady Chaitra A , Kamath Akshata A , Ahmed Ashikh , Thomas Tinku , Kurpad Anura V , Sivadas Ambily
Published: February 2025

The importance of vitamin B12(cobalamin) in numerous biological processes, including DNA synthesis and cellular energy production, underscores the need for therapeutic and public health strategies to address B12insufficiency/deficiency in the population. Genetic variations in pathways influencing cobalamin absorption, transport, and metabolism can affect various direct and indirect measures of vitamin B12status. To facilitate a structured approach to studying these genetic factors, we aimed to systematically curate and create a user-friendly web database that offers comprehensive data on genetic variants influencing B12biomarkers. A Pubmed search was performed for 5 B12traits (total serum/plasma B12, holotranscobalamin (active B12), total transcobalamin, holo haptocorrin, and methylmalonic acid) resulting in 493 research publications, of which 47 relevant publications were reviewed further. The database backend was built using MongoDB and the web interface was coded in PHP, JavaScript, HTML and CSS on an Apache HTTP server. We have manually curated and compiled the Cobalamin Associated Genetic Variant (CobVar) database, comprising a total of 324 genetic variant associations for 5 different vitamin B12traits involving 222 unique genetic variants and 84 genes identified across several genome-wide association studies (GWAS) and candidate gene studies. About one-third of the total genetic variant associations have been reported in >1 independent studies and 15 variants in >1 ethnic group. FUT2 gene showed the maximum number of associations for total serum/plasma B12(N=39), followed by MTHFR (N=24) and TCN2 (N=23). The database is accessible online athttps://datatools.sjri.res.in/VBG/. CobVar is a vital resource for researchers and nutritionists, offering quick access to the latest developments in B12-related genetic variant research and serves as a valuable tool for advancing personalized treatment.

Database URL

https://datatools.sjri.res.in/VBG/.
NKG7 is a stable marker of cytotoxicity across immune contexts and within the tumor microenvironment
Authors: Turiello Roberta , Ng Susanna S. , Tan Elisabeth , Voort Gemma van der , Salim Nazhifah , Yong Michelle , Khassenova Malika , Oldenburg Johannes , Rühl Heiko , Hasenaur Jan , Surace Laura , Toma Marieta , Bald Tobias , Hölzel Michael , Corvino Dillon
Published: February 2025

Cytotoxicity is a cornerstone of immune defense, critical for combating tumors and infections. This process relies on the coordinated action of granzymes and pore-forming proteins, with Granzyme B (GZMB) and Perforin (PRF1) being key markers and the most widely studied molecules pertaining to cytotoxicity. However, other human granzymes and cytotoxic components remain underexplored, despite growing evidence of their distinct, context-dependent roles. Natural Killer Cell Granule Protein 7 (NKG7) has recently emerged as a crucial cytotoxicity regulator, yet its expression patterns and function are poorly understood. Using large publicly available single-cell RNA sequencing atlases, we performed a comprehensive profiling of cytotoxicity across immune subsets and tissues. Our analysis highlights NKG7 expression as a strong marker of cytotoxicity, exhibiting a strong correlation with overall cytotoxic activity (r = 0.97) and surpassing traditional markers such as Granzyme B and Perforin in reliability. Furthermore, NKG7 expression is notably consistent across diverse immune subsets and tissues, reinforcing its versatility and robustness as a cytotoxicity marker. These findings position NKG7 as an invaluable tool for evaluating immune responses and a reliable indicator of cytotoxic functionality across biological and clinical contexts.
A method for efficient, rapid, and minimally invasive implantation of individual non-functional motes with penetrating subcellular-diameter carbon fiber electrodes into rat cortex
Authors: Letner Joseph G. , Lam Jordan L. W. , Copenhaver Miranda G. , Barrow Michael , Patel Paras R. , Richie Julianna M. , Lee Jungho , Kim Hun-Seok , Cai Dawen , Weiland James D. , Phillips Jamie , Blaauw David , Chestek Cynthia A.
Published: February 2025

Objective

Distributed arrays of wireless neural interfacing chips with 1-2 channels each, known as “neural dust”, could enhance brain machine interfaces (BMIs) by removing the wired connection through the scalp and increasing biocompatibility with their submillimeter size. Although several approaches for neural dust have emerged, a procedure for implanting them in batches that builds upon the safety and performance of currently used electrodes remains to be demonstrated.

Approach

Here, we demonstrate the feasibility of implanting batches of wireless motes that rest on the cortical surface with carbon fiber electrodes of subcellular diameter (6.8-8.4 µm) that penetrate to a target brain depth of 1 mm without insertion aids. To simulate their implantation, we assembled more than 230 mechanically equivalent motes and affixed them to insertion tools with polyethylene glycol (PEG), a quickly dissolvable and biocompatible material. Then, we implanted mote grids of multiple configurations into rat cortexin vivoand evaluated insertion success and their arrangement on the brain surface using photos and videos captured during their implantation.

Main Results

When placing motes onto the insertion device, we found that they aggregated in molten PEG such that the array pitch was only 5% wider than the dimensions of the mote bases themselves (240 x 240 µm). Overall, we found that motes with this arrangement could be inserted into rat cortex with a high success rate, as 171/186 (92%) motes in 4x4 (N=4) and 5x5 (N=5) square grid configurations were successfully inserted using the insertion device alone. After implantation, measurements of how much motes tilted (22±9°, X̄±S) and had been displaced relative to their original positions were smaller than those measured for devices implanted inside the brain in the literature.

Significance

Collectively, these data establish the viability of safely implementing motes with ultrasmall electrodes and epicortically-situated chips for use in future BMIs.
Monoclonal antibody to Filarial serpin Wb123 impedes the urokinase plasminogen activator receptor mediated Alternative activation of macrophages
Authors: Upadhyay Prince , Munjal Akshay , Mondal Abir , Singh Gagandeep , Mukherjee Soumyadeep , Kaushik Mahesh C , Gupta Puneet K. , Pati Soumya , Singh Shailja
Published: February 2025

Macrophages play a multifaceted role in mounting an immune response against pathogens through phagocytosis, antigen presentation and cytokine production. Activated macrophages are critical for the initiation, maintenance, and resolution of inflammation. They can either be classically activated (Th1 response), which promotes inflammation or alternatively activated (Th2 response), which resolves inflammation. The alternate activation of macrophages, along with diminished T cell response, is thought to be an important immune evasion strategy employed by the filarial parasites. However, the mechanism behind filaria-induced alternate activation remains unclear. In this study, by using in-silico approach we identified filarial serpins which are highly expressed in the infective L3 larval stages. We characterized the filarial serine protease inhibitor, Wb123 and established its role in alternate activation. We observed that Wb123 impairs nitric oxide (NO) and reactive oxygen species (ROS) expression, which plays a crucial role in mounting a strong immune response. Surprisingly, we also observed elevated IL6 expression and phosphorylation of STAT3, indicating IL-6-dependent alternate activation. Our findings indicate that the urokinase plasminogen activator receptor (uPAR) is essential for Wb123-induced alternate activation. Furthermore, we demonstrated that the monoclonal antibody MAbG8 impedes the Wb123-induced alternate activation, as shown by reduced CD163 expression along with increased ROS and uPA expression in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Overall, our study identifies the filarial serpin Wb123 and highlights its potent role in alternative activation. This interaction reveals, for the first time a mechanism exploited by filarial parasites to evade a strong pro-inflammatory immune response.
Biophysical Basis of thein vivoElectroretinogram of the Mouse: Current Source Density Analysis of Genetically and Pharmacologically Isolated Rod photoreceptor-driven Currents
Authors: Allina Gabriel Peinado , Alexander Prescott , Ronning Kaitryn , Burns Marie E. , Pugh Edward N.
Published: February 2025

To better understand the molecular basis of the mouse electroretinogram (ERG) we have developed a biophysical model of the rod photoreceptor layer’s ionic mechanisms and applied current source-density (CSD) analysis to predict the genetically and pharmacologically isolated rod ERGa-wave. The saturatinga-wave is characterized by a rapid relaxation (τ ~ 6 ms) from its maximum that has been hypothesized to be caused by HCN1 channel opening consequent to light-triggered sustained hyperpolarization, or by extracellular flow of capacitive current during hyperpolarization. To test these hypotheses, the CSD model included an ensemble of 11 rods with cell body locations spanning the outer nuclear layer, and with ionic mechanisms -- including CNG channels, NCKX in the outer segment, NKX, Kv2.1 channels in the inner segment, and HCN1 throughout the “non-outer segment” -- fully specified as to axial distributions, voltage dependencies, and the extracellular conductivity of the photoreceptor layer extracellular space. Predicting with CSD the steady-state axial distributions of rod dark current and transretinal potential, and the spatio-temporal response of the activation phase of the rod’s light response to intense stimuli, the analysis confirmed the Robson-Frishman hypothesis that extracellular capacitive current flowing towards the inner segment upon the rapid closure of CNG current plays a major role in shaping the earlya-wave. The CSD analysis also reveals that extracellular current from HCN1 channels opened by the hyperpolarization contributes a net extracellular current flowing toward the ONL that contributes materially to the saturateda-wave relaxation and to setting its plateau level.
Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions
Authors: Yang Junchen , Agrawal Kriti , Stanley Jay , Li Ruiqi , Jacobs Nicholas , Wang Haowei , Lu Chang , Qu Rihao , Clarke Declan , Chen Yuhang , Jiang Yunzhe , Bai Donglu , Zheng Suchen , Fox Howard , Ho Ya-chi , Huttner Anita , Gerstein Mark , Kluger Yuval , Zhang Le , Spudich Serena
Published: February 2025

HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map the transcriptomic and epigenetic landscapes of postmortem human brains from 13 healthy individuals and 20 individuals with HIV who have a history of treatment with ART. Our study spanned three distinct regions—the prefrontal cortex, insular cortex, and ventral striatum—enabling a comprehensive exploration of region-specific and cross-regional perturbations. We found widespread and persistent HIV-associated transcriptional and epigenetic alterations across multiple cell types. Detailed analyses of microglia revealed state changes marked by immune activation and metabolic dysregulation, while integrative multiomic profiling of astrocytes identified multiple subpopulations, including a reactive subpopulation unique to HIV-infected brains. These findings suggest that cells from people with HIV exhibit molecular shifts that may underlie ongoing neuroinflammation and CNS dysfunction. Furthermore, cell–cell communication analyses uncovered dysregulated and pro-inflammatory interactions among glial populations, underscoring the multifaceted and enduring impact of HIV on the brain milieu. Collectively, our comprehensive atlas of HIV-associated brain changes reveals distinct glial cell states with signatures of pro-inflammatory signaling and metabolic dysregulation, providing a framework for developing targeted therapies for HIV-associated neurological dysfunction.
Human differentiated adipocytes can serve as surrogate mature adipocytes for adipocyte-derived extracellular vesicle analysis
Authors: Butsch Bradley L. , Hade Mangesh Dattu , Palacio Paola Loreto , Nguyen Kim Truc , Shantaram Dharti , Noria Sabrena , Brethauer Stacy A. , Needleman Bradley J. , Hsueh Willa , Reátegui Eduardo , Magaña Setty M.
Published: February 2025

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders.
Chronic alcohol consumption enhances the differentiation capacity of hematopoietic stem and progenitor cells into osteoclast precursors
Authors: Hemati Hami , Blanton Madison B. , koura Jude , Khadka Rupak , Grant Kathleen A. , Messaoudi Ilhem
Published: February 2025

Chronic alcohol consumption (CAC) is associated with an enhanced risk of bone fracture, reduced bone density, and osteoporosis. We have previously shown using a rhesus macaque model of voluntary ethanol consumption that CAC induces functional, transcriptomic, and epigenomic changes in hematopoietic stem and progenitor cells (HSPCs) and their resultant monocytes/macrophages, skewing them towards a hyper-inflammatory response. Here, we extended those studies and investigated alterations in osteoclasts, which, in postnatal life, are differentiated from HSPCs and play a critical role in maintaining bone homeostasis. Analysis using spectral flow cytometry revealed a skewing of HSPCs towards granulocyte-monocyte progenitors (GMPs) with the CAC group that was in concordance with an increased number of colony-forming unit-granulocyte/macrophage (CFU-GM). Additionally, HSPCs from animals in the CAC group incubated with M-CSF and RANKL were more likely to differentiate into osteoclasts, as evidenced by increased Tartrate-Resistant Acid Phosphatase (TRAP) staining and bone resorption activity. Moreover, single-cell RNA sequencing of differentiated HSPCs identified three clusters of osteoclast precursors in the CAC group with enhanced gene expression in pathways associated with cellular response to stimuli, membrane trafficking, and vesicle-mediated transport. Collectively, these data show that CAC-derived hematopoietic progenitor cells exhibit a higher capacity to differentiate into osteoclast precursors. These findings provide critical insights for future research on the mechanisms by which CAC disrupts monopoiesis homeostasis and enhances osteoclast precursors, thereby contributing to reduced bone density.
The association between maternal parenting styles and eating disorders among Lebanese university students: The mediating role of the self-assessment dimension of self-esteem
Authors: Sawma Toni , El Khoury-Malhame Myriam , Hayek Tatiana , Mourad Jana , Bou Malhab Sandrella , Rizk Rana
Published: February 2025

Objective

Eating disorders are influenced by an array of distinct factors such as genetics, personality traits, and history of childhood abuse. Recently maternal parenting styles have been investigated as one of the contributing aspects. These styles are intricately connected to children’s self-esteem. As such this study aims to examine the association between maternal parenting styles and eating disorders and better investigate the mediating role of the self-assessment, an essential understudied dimension of self-esteem.

Method

A cross-sectional online study was conducted between November 2023 and May 2024. Around 300 Lebanese university students filled out surveys assessing demographic factors, maternal parenting style, eating disorders, and self-assessment.

Results

We found that different maternal styles distinctly influence the development of eating disorders; with self-esteem mediating the relationship between different maternal parenting styles and eating disorders development. Self-assessment negatively mediated the association between maternal expectations and eating control and dieting, and it negatively mediated the association between maternal permissive and dieting and bulimia. Self-assessment positively mediated the association between maternal control and eating control, dieting, and bulimia.

Discussion

This study mostly provides healthcare professionals and clinical educators with valuable insights into the complex association between parenting and eating disorders and highlights the importance of developing skillsets to boost self-esteem for those at risk of developing eating disorders.
Gender Discrimination and Medical Student Development
Authors: Venkataraman Shruthi , Nguyen Mytien , Chaudhry Sarwat I. , Desai Mayur M. , Fancher Tonya L. , Hajduk Alexandra M. , Mason Hyacinth R. C. , Webber Alexis , Boatright Dowin
Published: February 2025

Background

Despite prevalent gender discrimination in medical education, its influence on personal and professional development, foundational competencies in medical training per the Association of American Medical Colleges (AAMC), remains unclear. This retrospective cross-sectional study assesses how experiences of gender discrimination in medical school influence personal and professional identity formation (PPIF).

Methods

Deidentified student-level data were procured from the AAMC data warehouse for 37,610 MD students who matriculated in 2014-2015 and took the Graduation Questionnaire (GQ) between 2016-2020. Gender discrimination frequency was categorized as ‘Never’, ‘Isolated’, and ‘Recurrent’ from GQ responses to questions about denial of opportunities, offensive remarks, and lower evaluations due to gender. Gender was binarized, due to dataset limitations. PPIF was assessed using two GQ metrics, personal and professional development, and dichotomized.

Results

Female students experienced higher rates of isolated (12.6%) and recurrent (20.1%) gender discrimination than males (4.3% isolated, 6.2% recurrent). Females reported slightly lower personal (71.2%) but similar professional development (92.2%) rates compared to males (73.4% personal, 91.2% professional). Both genders experiencing gender discrimination had lower likelihoods of PPIF than their counterparts without these experiences. If recurrent discrimination occurred, the aRR (95%CI) of professional development was 0.89 (0.87-0.90) for females and 0.78 (0.74-0.81) for males, while for personal development, it was 0.69 (0.67-0.71) for females and 0.61 (0.58-0.66) for males. Compared to females, males showed sharper declines in professional development as discrimination frequency increased from never to isolated (exp(b)=0.93, 95% CI [0.92-0.94], p<0.001) and isolated to recurrent (exp(b)=0.95, 95% CI [0.93-0.97], p<0.001).

Conclusions

Gender discrimination negatively influences PPIF for both female and male medical students. Efforts to combat discrimination in medical training and promote holistic student development should be considered. Future work is needed to understand the influence of gender discrimination on the comprehensive development of gender-diverse medical students.
Uptake and rollout of the World Health Organization-endorsed technologies for Tuberculosis diagnosis in Africa: A systematic review of international evidence 2007-2021
Authors: Iragena Jean de Dieu , Uwimaana Esther , Semugenze Derrick , Komakech Kevin , Katamba Achilles , Martin Anandi , Joloba Moses , Ssengooba Willy
Published: February 2025

Background

The World Health Organization (WHO) has endorsed a range of diagnostic technologies for tuberculosis (TB) over the years, and at least one new endorsement is issued every year. However, little is documented about the uptake status in the WHO African Region (WHO/FR). We assessed the status of uptake of the WHO-endorsed TB diagnostics through a systematic review.

Methods

We conducted a systematic review of the peer-reviewed literature in French or English using PubMed, Google Scholar, and Embase for TB diagnostics endorsed by WHO between January 2007 and December 2017. We considered an extra period until December 2021 for the uptake and roll-out of the recently endorsed technologies and considered publications from the 47 countries in the WHO/AFR. We considered uptake as the use of the test in the country at any level and roll-out of the test as it is being used in the settings in which WHO endorsed for it. A summary number of articles was kept using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagrams (PRISMA) and the study protocol was registered with ISRCTN database. We used qualitative synthesis and quantitative data analysis by STATA version 14.0.

Results

We recorded 3,399 articles searched in peer-reviewed databases, then we eliminated 1683 duplicates and finally kept 1,716 articles for screening and 92 articles qualified for analysis. For the uptake, out of 47 countries, the majority of articles were for Xpert MTB/RIF (XPERT) test 22 (47%), followed by Line Probe Assay (LPA), 10 (21%), and the Mycobacteria Growth Indicator Tube (MGIT) 9 (19%). For the rollout, 11 (24%) countries and 16 (36%) had publications on Lipoarabinomannan (LAM) and XPERT test use respectively. The median years (Interquartile Range: IQR) for uptake were 6 (3.2 - 7.9), 5 (2.5 - 6.5), and 2.5 (3.2 - 7.9) for MGIT, XPERT, and LPA respectively, and lower for other tests. For the rollout, the median years for MGIT, LPA, and XPERT were 7 (3 – 7), 6 (1.6 - 9.4), and 5 (4 - 7) respectively, and lower for other tests.

Conclusion

Our study shows that the uptake and rollout of TB diagnostic technologies upon the endorsement by WHO among WHO AFR countries is slow. Future studies are needed to document the key factors affecting rapid uptake and rollout. Strategies to document a rapid guide to inform rapid uptake and roll-out as well as best practices are highly recommended.
The genomic landscape of syndromic and non-syndromic hearing loss within the 100,000 Genomes Project cohort
Authors: Vestito Letizia , Smedley Damian , Cipriani Valentina , Moore Gudrun E , Stanier Philip , Bowl Michael R , Dawson Sally J , Clement Emma , Bitner-Glindzicz Maria
Published: February 2025

Objective

This study aims to describe the genetic landscape of syndromic and non-syndromic hearing loss (HL) in the UK population using data from the 100,000 Genomes Project (100kGP).

Design

Cohort study

Setting

NHS England

Participants

2,271 families with syndromic and non-syndromic HL recruited to the 100kGP rare disease programme between 2013 and 2018. Participants with at least one Human Phenotype Ontology (HPO) term descendant of the term “Hearing impairment” (HP:0000365) were included; this equated to 5,488 individuals, comprising 2,762 affected individuals and 2,726 unaffected relatives.

Main outcome measure

Diagnostic rate and prevalence of different gene diagnoses by auditory phenotype identified by whole genome sequencing.

Results

The overall diagnostic yield was conservatively estimated at 27.5% (625/2271), with diagnoses identified in 273 different genes. Common causative genes includedUSH2A, GJB2, COL1A1andMYO15A, accounting for approximately 20% of the diagnoses. This diagnostic rate excludes variants of uncertain significance (VUS), variants in genes where HL cannot be confidently attributed to the identified variant, or those still awaiting confirmation. The inclusion of these categories would increase the diagnostic yield to 39.6%. This work describes the 100kGP standard pipeline and supplementary analyses that include the use of Exomiser. Stratification of the cohort allowed quantification of the likelihood of genetic diagnosis with specific phenotypic combinations and identification of positive predictors for a genetic diagnosis by auditory phenotype. A statistically significant increase in diagnostic rate was reported for those with congenital (33.2%), bilateral (27%), and high-frequency (32.4%) hearing subtypes. Furthermore, in patients with HPO terms restricted to the auditory system alone, around 40% of diagnoses were attributed to genes that might have a broader syndromic phenotype (non-syndromic mimics). A high diagnostic yield (56%) was seen in patients with ear and eye abnormalities, largely driven by genes associated with Usher and Wolfram syndrome.

Conclusion

In conclusion, this study offers valuable insights into the complex genomic and phenotypic architecture of both syndromic and non-syndromic HL, which has the potential to improve diagnostic pipelines and inform clinical care.
Validation of a Six-Item Multiple Sclerosis Impact Scale Short Form (MSIS-SF) for Efficient Assessment of Patient-Reported Physical Disturbance
Authors: Sumowski James F. , Levy Sarah
Published: February 2025

Patient-reported outcomes importantly reflect the lived experiences of persons with multiple sclerosis (MS); however, given the broad array of MS symptoms, comprehensive evaluation can be burdensome, especially with lengthy questionnaires. The MS Impact Scale queries twenty different physical difficulties (MSIS-20). In 1150 patients with MS, evaluation of internal consistency indicated redundancy in the MSIS-20 (Cronbach’s alpha: 0.96), but optimal internal consistency (0.90) of a six-item short form (MSIS-SF; first six MSIS items). The MSIS-20 and MSIS-SF showed comparably strong associations with objective physical disability. The MSIS-SF provides a psychometrically robust, less burdensome, and time-efficient option for assessing patient-reported physical disturbance.
Quantifying additive and multiplicative effects of socially stigmatized identities on self-reported overall health
Authors: LeStage Katrine , Vogel Robert , Vogel Julia Moore
Published: February 2025

Individuals with one or more socially stigmatized identities experience extensive health disparities. However, most studies consider the effects of only individual stigmatized identities. Further, the effects of individual identities and their intersections on overall health have not been quantified. We used participant-reported survey data collected in theAll of UsResearch Program and released to the controlled tier in April 2023 to statistically estimate the first and second order effects of 47 stigmatized identities on self-reported overall health. After using false discovery rate to adjust for testing multiple hypotheses, 29 individual stigmas had statistically significant effects on self-reported overall health and 116 pairs of stigmas did. All significant individual effects were negative or neutral except for skin cancer. Those with the largest negative effect on self-rated overall health are difficulty walking or climbing stairs, unemployed or unable to work, difficulty with errands, and low educational attainment. Pairs of intersecting stigmas had a mix of negative and positive incremental effects, indicating that some stigmatized identities are negative modifiers, such as depression, and other combinations are less negative that the sum of their individual negative effects, such as having difficulty with multiple types of activities of daily living. Taken together, there are numerous pairs of stigmatized identities that significantly affect self-reported overall health and therefore should be considered in research and clinical care.
Application of bidirectional Mendelian randomization to assess the relationship between the gut microbiome and esophageal cancer
Authors: Chataway James , Hamilton Georgina , Hatcher Charlie , Wade Kaitlin H.
Published: February 2025

Background

Esophageal cancer is the seventh most common cancer worldwide and typically carries a poor prognosis. Whilst smoking, alcohol and obesity are established risk factors, they do not fully account for disease variability and, increasingly, the gut microbiome has been implicated as a possible novel risk factor in observational studies. Mendelian randomization (MR), a technique that uses genetic variants as proxies for exposures to improve causal inference, is more robust to reverse causality and confounding, which typically bias observational studies.

Methods

We used summary statistics from large genome-wide association studies (GWASs) of both the gut microbiome and esophageal cancer phenotypes to conduct two-sample bidirectional MR analyses to investigate the causal relationship between 14 microbial traits and three esophageal cancer phenotypes: esophageal adenocarcinoma (EA), Barrett’s esophagus (BE) and both EA and BE as a combined phenotype (BE/EA). Where MR analyses provided evidence of causality between these phenotypes, several sensitivity analyses were conducted to interrogate its validity of MR assumptions.

Results

When assessing the causal role of the gut microbiome on esophageal cancer, there was little evidence that any microbial trait had a causal effect on any of the three esophageal cancer traits. In the reverse direction, MR analyses provided evidence that EA had a causal effect on two microbial traits. Specifically, an approximate doubling of the genetic liability to EA increased the odds of presence (vs. absence) of an unclassified group of bacteria within theFirmicutesphylum (odds ratio (OR): 1.66; 95% CI: 1.02, 2.70) and decreased the relative abundance of bacteria within theButyricicoccusgenus by 0.23 standard deviations (95% CI: 0.07, 0.40). However, importantly, sensitivity analyses showed that these observed effects were likely biased by horizontal pleiotropy and, thus, results should be interpreted with caution.

Conclusions

Although initial analyses provided evidence of EA influencing two microbial traits, further sensitivity analyses indicated that these results were likely biased and unlikely to reflect causality. This highlights the importance of using robust MR methodology with appropriate sensitivity analyses, particularly in the setting of microbial traits, where host genetic effects are poorly understood and likely to be complex.
Virtual World Coupling with Photosynthesis Evaluation for Synthetic Data Production
Authors: Baker Dirk N. , Giraud Mona , Göbbert Jens Henrik , Scharr Hanno , Riedel Morris , Hvannberg Ebba Þóra , Schnepf Andrea
Published: February 2025

In this work, we couple the functional-structural plant model CPlantBox to the Unreal Engine by exploiting the implemented raytracing pipeline to evaluate light influx on the plant surface. There are many approaches for photosynthesis computation and light evaluation, though they typically are limited by versatility, compute speed, or operate on much coarser resolutions. This work specifically addresses the concern that data generation pipelines tend to be unresponsive and do not include model-based knowledge as part of the generation pipeline. Using established photosynthesis solvers, we model the interaction between the Unreal Engine and the FSPM to measure physical properties in the virtual world. This is successful if we are able to reproduce experimental results using an in silico model. As part of the pipeline, we generate a surface geometry and utilize material shaders that are designed to establish a baseline surface model for light interception and transmission, based on simple parameter sets that can be calibrated. Using a Selhausen field experiment as baseline, we reproduce the photosynthesis effectiveness of the plants in the 2016 winter wheat experiments. Our pipeline is deeply intertwined with data generation and has been proven to perform well at scale. In this work, we build on our previous work by showcasing both a simulation study of a light evaluation as well as quantifying how well our system performs on high-performance computing systems.
DMRU: Generative Deep-Learning to unravel condition specific cytosine methylation in plants
Authors: Gupta Sagar , Kumar Anchit , Kesarwani Veerbhan , Shankar Ravi
Published: February 2025

Epigenetic regulation of gene expression is a complex and multifaceted process that plays a crucial role in plant development and adaptation. DNA methylation at cytosines has been shown to influence gene expression by regulating chromatin structure and accessibility. Some approaches have been developed to identify DNA methylation but none of them are capable to tell the condition specific DNA methylation, making them hardly of any use. Here, we report a first of its kind an explainable Deep Encoders-Decoders generative system, DMRU, which learns the relationship between transcritpome status and DNA methylation states at any given time. It was also found that instead of looking for homology to relate condition specificity of DNA methylation marks across species, GC similarity is more relevant to the specificity of DNA methylation patterns. The developed approach, DMRU, is capable to discover the methylated cytosines in total independence from data volume and species specific models, and works with same performance across different species in universal manner. In a comprehensive benchmarking study across a huge volume of experimental data covering different conditions and species, it has consistently achieved >90% accuracy. With this all, DMRU brings a completely new chapter in methylated cytosine discovery through generative AI, giving a strong alternative to costly bisulfite sequencing experiments, saving enormous amount of time and money. DMRU may have significant impact on the development of novel strategies for crop improvement and biotechnology applications, while accelerating the research in the field of epigenomics and gene regulation. DMRU is freely available as a web-server athttps://scbb.ihbt.res.in/DMRU/index.php.
Water parameters and hydrodynamics in rivers and caves hostingAstyanax mexicanuspopulations reveal macro-, meso- and micro-habitat characteristics
Authors: Legendre Laurent , Père Stéphane , Rebaudo François , Espinasa Luis , Rétaux Sylvie
Published: February 2025

The Mexican tetra (Astyanax mexicanus) has emerged as a leading model for evolutionary biology and the study of adaptation to extreme subterranean environments. The river-dwelling morphs of the species are distributed in Mexico and Texas, while the blind and cave-adapted morphs inhabit the karstic caves of the Sierra Madre Oriental in northeastern Mexico. Although the molecular, cellular and genetic underpinnings ofAstyanaxcavefish evolution are being elucidated, our understanding of its habitat and environment remains limited, thereby constraining the interpretations of its morphological, physiological, and behavioral adaptations. In particular, the physico-chemical parameters of the water and the hydrological regimes to which cavefish are subjected remain largely unexplored. From 2009 to 2024, we have recorded the physico-chemical parameters of the water in whichAstyanax mexicanuscavefish and surface fish are found in the El Abra and La Colmena regions of the states of San Luis Potosí and Tamaulipas, Mexico. Data were collected using a variety of devices and probes, including both point and longitudinal measurements of water quality. A total of 13 caves out of the 33 knownAstyanaxcaves and 27 surface stations (rivers, springs, ponds) were sampled. The comparison of epigean and hypogean waters showed strong signatures of the two macro-habitats. As compared to surface, cave water was fresher, much less conductive and highly anoxic. Moreover, at the meso-habitat level, a comparison between caves revealed significant differences in both specific water parameters and hydrological regimes. One- or two-year longitudinal recordings demonstrated that some caves exhibited relatively stable hydrological regimes, while others experienced multiple, sudden and significant fluctuations. Finally, distinct pools within a single cave showed notable differences, displaying a highly reproducible increase in water temperature as a function of depth or distance from the cave entrance, and revealing specificities at the micro-habitat level. Our comprehensive dataset on cave water quality and hydrodynamics is interpreted in the context of an integrated view of cave biology and the evolution of cave organisms. Our findings have significant implications for understanding the evolution of cavefishes and the biology of the species in general.
Sensory neurons shape macrophage identity via TGF-β signalling
Authors: Kolter Julia , Döring Clarissa-Laura , Baasch Sebastian , Alsumati Reem , Mansoori Moghadam Zohreh , Gres Vitka , Lohrmann Florens , da Silva Gabriel Victor Lucena , Silva Conceicao Elidianne Anibal , Buchegger Theresa , Doumard Layal , Voisin Benjamin , Lachmann Nico , Kierdorf Katrin , Flacher Vincent , Henneke Philipp
Published: February 2025

Macrophages play integral roles in maintaining homeostasis and function in their tissues of residence. In the skin, prenatally seeded and highly specialized macrophages physically interact with sensory nerves and contribute to their regeneration after injury. However, mechanisms underlying the development and maintenance of this potentially lifelong commitment of macrophages to nociceptors remain largely elusive. Here, we found that infiltrating myeloid progenitor cells approached the sprouting axons of sensory nerves and gradually adopted a nerve-associated macrophage-like profile. This change in identity was steered and maintained by the immediate microenvironment, in particular TGF-β, which was locally activated by the physical interaction with nerves and integrin-mediated cleavage. Following injury, TGF-β driven specification of macrophages essentially supported nerve regeneration. Overall, we identified TGF-β as a central mediator governing local imprinting and long-term specialization of macrophages in the skin, providing insights into the bidirectional communication between macrophages and sensory nerves.
Organisation of axial regions of isolated mitotic chromosomes visualised by cryo correlative light and electron tomography
Authors: Patra Gurudatt , Harastani Mohamad , Samejima Kumiko , Remnant Lucy , Troffer-Charlier Nathalie , Crucifix Corrine , Durand Alexandre , Marechal Nils , Lutz Yves , Steyer Anna M. , Yang Zhengyi , Hagen Wim J. H. , Earnshaw William C. , Eltsov Mikhail
Published: February 2025

The formation of mitotic chromosomes is essential for the accurate segregation of genetic material during cell division. Increasing evidence suggests that chromosome formation involves the reorganization of DNA into loops anchored within chromosomal axial regions, whose structural organization remains insufficiently characterized. Taking advantage of DT40 cells, an avian cell model characterized by the presence of a range of chromosome sizes from 3.2-197 Mb, we have established a preparation of entire close-to-native native mitotic chromosomes for cryogenic correlative light and electron microscopy (cryo-CLEM). The size of the smallest chromosomes allows imaging of their axial regions without further thinning. Cryo-electron tomography of the chromosome axial regions reveals the presence of heterogeneous non-histone macromolecular densities (NHMDs), approximately 30–45 nm in size, interspersed within chromatin/DNA regions. We propose that NHMDs may contain condensins and contribute to chromosome architecture. In addition to NHMDs, we identified dense clusters of particles, similar in size, near the chromosome surface, likely associated with ribosomal components. To quantitatively differentiate NHMDs from these surface clusters, we developed an analytical approach based on particle interspacing and spatial distribution within the chromosome volume. By establishing a cryo-CLEM workflow for whole, near-native mitotic chromosomes, our study provides a foundation for investigating their ultrastructural architecture.