bluuebunny/crossref_metadata_2025 huggingface dataset:
SCN5A variant type-dependent risk prediction in Brugada syndrome
Authors: Aizawa Takanori , Makiyama Takeru , Huang Hai , Imamura Tomohiko , Fukuyama Megumi , Sonoda Keiko , Kato Koichi , Hisamatsu Takashi , Nakamura Yuko , Hoshino Kenji , Ozawa Junichi , Suzuki Hiroshi , Yasuda Kazushi , Aoki Hisaaki , Kurita Takashi , Yoshida Yoko , Suzuki Tsugutoshi , Nakamura Yoshihide , Ogawa Yoshiharu , Yamagami Shintaro , Morita Hiroshi , Yuasa Shinsuke , Fukuda Masakazu , Ono Makoto , Kondo Hidekazu , Takahashi Naohiko , Ohno Seiko , Nakagawa Yoshihisa , Ono Koh , Horie Minoru
Published: February 2025

Aims

The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated.

Methods and results

We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa < 65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14–45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0–14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155).

Conclusion

We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.
War Trauma and Strength: A Qualitative Study of Participants in the Vietnamese Insights into Cognitive Aging Program (VIP)
Authors: Vu Uyen T M , Farias Sarah Tomaszewski , Hinton Ladson , Park Van T , Tiet Quyen Q , Whitmer Rachel A , Heuer Sierra , Nguyen Boi-san , Meyer Oanh L
Published: February 2025

Objectives

Vietnamese Americans are the fourth-largest Asian subgroup in the United States (US), but little qualitative work has been done on their war and migration experiences. In this study, we delineated the war-related traumas and strength in participants of the Vietnamese Insights into Cognitive Aging Program (VIP).

Methods

VIP is a longitudinal study of 548 Vietnamese Americans aged 65+ years living in Northern California. During visit 1, a semi-structured interview was conducted on participants’ life and experiences in Vietnam and immigration to the US. Using data at one of the recruitment sites, interviews of participants having the highest total self-reported traumas were transcribed in Vietnamese (N=43) for coding and analysis following a thematic approach.

Results

Participants were 73.2 years old on average (SD=5.48). Most were male (67.4%) and had attempted to escape Vietnam by boat at least once (67%). Two major themes were found: (1) experiences of adversity and suffering, which included subthemes on tough life experiences during the war, imprisonment and hard life after the war, escaping by boat and living in the refugee camps, witnessing or hearing about others’ traumas during the war and escape, and experiences of loss; and, (2) personal fortitude and gratitude, which included subthemes on fortitude and endurance, personal skills to cope and navigate, and perceived “luck and blessings.”

Discussion

Results from this study revealed various traumas and aspects of strength. These findings can contribute to future VIP research on cognitive aging and inform research and practice on health disparities.
The Effect of Heat and Fermentation Treatments of Soybean Meal on Performance, Immune System, Microbial Population, Intestinal Morphology, and PepT1 Gene Expression in Broiler Chickens
Authors: Miraalami Nariman , Mousavi Seyed Naser , Abedini Mohammad Reza , Asgari Jafarabadi Ghobad
Published: February 2025

We investigated the effects of replacing raw soybean meal (RSM) with autoclaved soybean meal (ASBM) and fermented soybean meal by Lactobacillus plantarum (FSBMLP) and Bacillus pumilus (FSBMBP) on the performance, microbial population, intestinal morphology, immune system, and PepT1 gene expression in broiler chickens. One-day-old male Ross 308 broiler chicks (n=800) were utilized in a fully randomized design featuring eight treatments and five replicates, and each replicate consisted of 20 chicks. The experimental treatments included: 1) a control group ((RSM)-based diet), 2) a basal diet + ASBM, 3) a basal diet + 2% FSBMLP, 4) basal diet + 4% FSBMLP, 5) basal diet + 6% FSBMLP, 6) basal diet + 2% FSBMBP, 7) basal diet + 4% FSBMBP, and 8) basal diet + 6% FSBMBP. The results showed significant improvements in feed conversion ratio and body weight gain throughout the experiment for broiler chickens receiving various FSBMLP levels and 4% and 6% FSBMBP compared to the controls (P<0.05). The group receiving 6% FSBMLP also demonstrated significantly higher antibody titers against Newcastle disease virus and Gumboro disease, along with increased IgG and total immunoglobulin levels in response to sheep red blood cells (SRBCs), compared to the controls (P<0.05). Additionally, the Lactobacillus population in the ileum and villus height in the jejunum were significantly higher in chickens fed FSBMLP than in the control group (P<0.01). Furthermore, chickens fed 6% FSBMLP showed a significant increase in PepT1 gene expression compared to the control group (P<0.05). Overall, the results suggested that replacing 6% of RSM with FSBMLP in broiler chicken diets improved growth performance, immune function, intestinal health, and PepT1 gene expression compared to ASBM and FSBMBP.
Transcription-replication conflicts drive R-loop-dependent nucleosome eviction and require DOT1L activity for transcription recovery
Authors: Werner Marcel , Trauner Manuel , Schauer Tamas , Ummethum Henning , Márquez-Gómez Elizabeth , Lalonde Maxime , Lee Clare S K , Tsirkas Ioannis , Sajid Atiqa , Murriello Augusto C , Längst Gernot , Hamperl Stephan
Published: February 2025

Progressing transcription and replication machineries profoundly impact their underlying chromatin template. Consequently, transcription-replication conflict (TRC) sites are vulnerable to chromatin and epigenome alterations, provoking genome instability. Here, we engineered an inducible TRC reporter system using a genome-integrated R-loop-prone sequence and characterized the dynamic changes of the local chromatin structure inflicted by TRCs, leading to reduced nucleosome occupancy and replication fork blockage. Strikingly, inducing a small number of TRCs on the genome results in a measurable global replication stress response. Furthermore, we find a TRC-dependent increase in H3K79 methylation specifically at the R-loop forming TRC site. Accordingly, inhibition of the H3K79 methyltransferase DOT1L leads to reduced transcriptional output and an exacerbated DNA damage response, suggesting that deposition of this mark is required for effective transcription recovery and resolution of TRCs. Our work shows the molecular dynamics and reveals a specific epigenetic modifier bookmarking TRC sites, relevant to cancer and other diseases.
Evaluating short-term survivors of glioblastoma: A proposal based on SEER registry data
Authors: Tomita Yusuke , Otani Yoshihiro , Omae Ryo , Mizuta Ryo , Ishida Joji , Hirotsune Nobuyuki , Tanaka Shota
Published: February 2025

Background

Glioblastomas (GBMs) are central nervous system tumors with a poor prognosis and limited treatment options. Although small subsets of GBM patients survive longer than 3 years, there is little evidence regarding the prognostic factors of GBM. Therefore, we conducted a thorough characterization of GBM in the United States.

Methods

We queried the Surveillance, Epidemiology and End Results database between 2000 and 2021 to extract age-adjusted incidence rates (AAIR), age-adjusted mortality rates (AAMR), and survival data for GBM. We compared trends in AAIR, AAMR, and survival time across age groups 0–14, 15–39, 40–69, and 70+ years. Also, we employed the Fine-Gray competing risk model among short-term survivors (STSs), defined as those with a survival time of 6 months or less, and long-term survivors (LTSs), defined as those with a survival time of 3 years or more.

Results

This study included 60,615 incident GBM cases, 54,998 GBM-specific deaths, and 47,207 GBM patients with available survival time between 2000 and 2021. The mortality-to-incidence ratio was constant among STSs, whereas it increased with age among LTSs. Higher age and male sex were significantly associated with GBM-specific death among LTSs, whereas non-Hispanic White and less intensive treatments were associated with GBM-specific deaths among STSs. Interestingly, higher age was significantly associated with other causes of death among STSs.

Conclusions

STSs partially consist of populations who died from causes other than GBM. It is important to include only GBM-specific deaths in STS groups to conduct reproducible research comparing STSs and LTSs.
Dogs fed a high protein, low carbohydrate diet have elevated postprandial plasma glucagon and amino acid concentrations and tend to have lower glucose concentrations compared to two different moderate protein, moderate carbohydrate diets
Authors: Banton Sydney , Raheb Shari , Singh Pawanpreet , Cant John P , Shoveller Anna K
Published: February 2025

As dog owners continue to seek to feed their dogs similarly to themselves, there is demand for high protein, low carbohydrate (HPLC) diets. The consumption of HPLC diets can improve glycemic control, similarly to high fiber diets. However, the effects of HPLC and high fiber diets on cardiac function have yet to be evaluated in healthy dogs. The objective of the present study was to investigate the glucose, insulin, glucagon and amino acid (AA) postprandial response and echocardiographic measurements in laboratory-housed, adult large breed dogs fed a commercially available HPLC, a moderate protein, moderate carbohydrate (MPMC), or a commercially available MPMC, high fiber, ‘metabolic’ diet for 42 days. This study was conducted as a 3x3 Latin Square where dogs received: 1) a commercial HPLC diet (48% of metabolizable energy (ME) from protein, 10% of ME from nitrogen-free extract; NFE), 2) a MPMC diet (28% of ME from protein, 39% of ME from NFE) formulated with the same ingredients as HPLC or 3) a MPMC, high fiber, ‘metabolic’ (MET) diet (30% of ME from protein, 37% of ME from NFE) as a commercial control. An echocardiogram and a 12-h glucose, insulin and glucagon response and 6-h AA meal response were performed on day 42 of feeding. Data were analyzed using proc glimmix in SAS (version 9.4). All echocardiographic parameters remained within a healthy reference range for dogs of this size. Dogs fed HPLC had a larger net area under the curve (NetAUC) for plasma glucagon (P < 0.001) compared to dogs fed MPMC and MET, a smaller NetAUC for glucose: insulin (P = 0.039) compared to dogs fed MPMC but MET was similar to both. Glucose NetAUC tended to be different among treatments (P = 0.057), where dogs fed MPMC had a greater netAUC than dogs fed HPLC and dogs fed MET tended to have a greater netAUC than HPLC. Dogs fed HPLC had greater concentrations of Ile, Leu, Lys, Thr, Tyr and Val over time compared to dogs fed MPMC and MET, and dogs fed MET had greater concentrations of Gln and Met over time compared to dogs fed HPLC and MPMC (P < 0.05). Dogs fed a HPLC diet may have improved glucose uptake compared to dogs fed a MPMC diet. This research provides the first insight into the cardiometabolic health of dogs consuming three diets differing in their protein, carbohydrate and fiber content.
Preoperative Iron Supplementation Mitigates the Risk Of Postoperative Complications Associated with Iron Deficiency Anemia Following Lumbar Spinal Fusion
Authors: Jain Rishubh , Farias Michael J. , Singh Manjot , Pisani Claire , Nassar Joseph E. , Diebo Bassel G. , Daniels Alan H.
Published: February 2025

Study Design.

Retrospective cohort study.

Objective.

Evaluate postoperative outcomes in lumbar fusion patients with preoperative iron deficiency anemia (IDA) on iron supplementation.

Background.

IDA has been associated with impaired cognition, compromised immune response, and increased risk of morbidity and mortality following surgery. However, little is known about the relationship between IDA and postoperative complications among patients undergoing lumbar fusion, as well as about the impact of preoperative iron supplementation on these outcomes.

Methods.

A national all-payer claims database was queried for adult patients who underwent lumbar spinal fusion between 2010 to 2022. Patients were initially stratified by a preoperative diagnosis of IDA and matched 1:1 based on age, sex, and medical comorbidities. IDA patients were further stratified by preoperative iron supplementation use and similarly matched. Postoperative complications and hospital costs were compared using chi-square, t-test, and multivariate logistic regressions.

Results.

The matched cohorts consisted of 27,669 patients, with mean age of 59 years and 89% female sex. IDA patients had higher rates of pulmonary embolism, acute kidney infection, deep venous thromboembolism, surgical site infection, urinary tract infection, blood transfusion, 90-day readmission rates, and hospital length of stay (all P<0.001). IDA patients on preoperative iron supplementation had lower rates of acute kidney injury, hematoma, pulmonary embolism, surgical site infection, urinary tract infection, stroke, 90-day readmission rates, and 90-day total hospital costs (all P<0.001). Non-IDA patients on preoperative iron supplementation similarly had lower rates of many of these complications as well.

Conclusion.

IDA was associated with increased risk of 90-day postoperative medical complications and hospital resource utilization. However, preoperative oral iron supplementation mitigated these risks. Further research is critical to understand how pre- or peri-operative iron supplementation can be used to optimize patients’ hematologic status before lumbar fusion to maximize clinical outcomes.

Level of Evidence.

IV
IGD: A simple, efficient genotype data format
Authors: DeHaas Drew , Wei Xinzhu
Published: February 2025

Motivation

While there are a variety of file formats for storing reference-sequence-aligned genotype data, many are complex or inefficient. Programming language support for such formats is often limited. A file format that is simple to understand and implement – yet fast and small – is helpful for research on highly scalable bioinformatics.

Results

We present the Indexable Genotype Data (IGD) file format, a simple uncompressed binary format that can be more than 100 times faster and 3.5 times smaller thanvcf.gzon Biobank-scale whole-genome sequence data. The implementation for reading and writing IGD in Python is under 350 lines of code, which reflects the simplicity of the format.

Availability

A C++ library reading and writing IGD, and tooling to convert .vcf.gzfiles, can be found athttps://github.com/aprilweilab/picovcf. A Python library is athttps://github.com/aprilweilab/pyigd
Butterflies Are Shrinking: Evidence from the Past Century
Authors: Zografou Konstantina , Knop Eva , Sewall Brent J , Adamidis George C , Schweiger Oliver , Semertzidis Theodoros , Stalidis Panagiotis , De Moraes Consuelo M , Mescher Mark C , Whitaker Melissa RL , Greeff Michael , Anagnostellis Konstantinos M , Brokaki Marina , Kaltsouni Eleftheria , Dimaki Maria , Kati Vassiliki
Published: February 2025

Climate change has had strong impacts on biodiversity, including well-documented shifts in the distributions and phenology of species. Reductions in body size represent a third pervasive biological response; it has garnered significantly less attention despite great ecological relevance. Theoretical frameworks-the temperature-size rule, Bergmann's rule, and James's rule-predict that warmer temperatures are associated with smaller body sizes in ectotherms. In contrast, empirical evidence concerning this pattern is mixed across both taxa and environments. In the present study, we applied computer vision techniques to historical data from two large butterfly museum collections, totaling 593 species across 10 terrestrial biomes over more than a century, in order to investigate long-term trends in butterfly body size. We measured forewing length through both manual image analyses and automated computer vision algorithms proxying body size and analyzed trends by using generalized additive models in order to consider a temporal, biome-specific pattern assessment. We have tested two hypotheses: that butterfly body size (1) declines over time, in conjunction with increasing ambient temperatures, in agreement with the temperature-size rule, and (2) its variation is more marked in warm, dry biomes. Results indicate a significant overall reduction in the body size of butterflies during the last century and that this reduction is indeed more pronounced in those biomes facing higher rises in temperature. These findings constitute large-scale evidence in support of the temperature-size rule and indicate a potential ecological impact of climate change on butterfly populations.
Primitive steroidogenesis in mast cells: A novel regulatory mechanism for mast cell function
Authors: Pramanik Jhuma , Zhao Qiuchen , Yamashita-Kanemaru Yumi , Hussein Hosni , Homer Natalie Z. M. , Chakraborty Soura , Shaji Sanu K. , Okkenhaug Klaus , Roychoudhuri Rahul , Mahata Bidesh
Published: February 2025

Mast cells, ancient immune sentinels, are crucial in immune responses, tissue homeostasis and inflammatory pathologies. This study unveils a previously unknown regulatory mechanism in mast cell biology:de novosteroidogenesis. Through comprehensive multi-omics analysis and functional assays, we demonstrate that mast cells express Cyp11a1 and produce pregnenolone, representing a primitive form of steroidogenesis. This cell-intrinsic steroidogenic pathway is essential for mast cell development, survival, and functional regulation. Genetic abrogation of mast cell steroidogenesis leads to exaggerated inflammatory and anaphylactic responsesin vivo. Our integrative approach reveals extensive transcriptional and proteomic remodelling during mast cell regranulation, with steroidogenesis playing a pivotal role in coordinating recovery and tissue repair processes. We uncover significant sexual dimorphism in mast cell proteomes and a global uncoupling of transcriptional and translational programmes. These findings advance our understanding of mast cell physiology and provide a foundation for developing targeted therapies for mast cell-associated pathologies.
Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF
Authors: Bugga Paramesha , Mushala Bellina A.S. , Stoner Michael W. , Manning Janet R. , Bhattarai Nisha , Sharifi-Sanjani Maryam , Vandevender Amber , Mooli Raja G.R. , Ramakrishnan Sadeesh K. , Kaufman Brett A. , Shiva Sruti S. , Happe Cassandra L. , Mullet Steven J. , Gelhaus Stacy L. , Jurczak Michael J. , Scott Iain
Published: February 2025

The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow, representing over half of heart failure cases in the United States. As no specific medication for HFpEF exists, treatment guidelines focus on the management of comorbidities related to metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote the disease. These same comorbidities also drive pathology in non-cardiac tissues, and the links between cardiometabolic disease presentations in different organs are increasingly being recognized. Preclinical studies on the potential crosstalk between HFpEF and metabolic disease in the liver (e.g. metabolic-associated fatty liver disease; MAFLD) have focused on how liver dysfunction may affect the heart, particularly through the release of secreted liver proteins. This may reflect the situation in the clinic, where incident MAFLD is a risk factor for future HFpEF development. Here, in contrast to this developing paradigm of liver-initiated cardiac disease, we report for the first time a defect in cardiac metabolism related to the mitochondrial metabolic protein GCN5L1 that drives hepatic steatosis and MAFLD in HFpEF.
Metabolomics characterisation of cassava pre-breeding populations with enhanced whitefly tolerance
Authors: Perez-Fons L , Bohorquez-Chaux A , Gomez-Jimenez MI , Becerra Lopez-Lavalle LA , Fraser PD
Published: February 2025

Cassava (Manihot esculentaCrantz) provides food security for over 500 million people in Sub-Saharan Africa (SSA). Whitefly (Bemisia tabaci) is a pest in this region that result in ca. 50% crop yield losses. Thus, it is important to develop approaches that will generate new varieties tolerant to this pest to advance food security in the region. Two parental cassava varieties, ECU72 tolerant to whiteflies and COL2246 a susceptible line have been used to generate bi-parental populations. The F1 generation has been screened for whitefly resistance and progeny identified displaying enhanced tolerance. From designated F1 tolerant progeny, F2 families have been generated and phenotyped. The tolerance to whiteflies in the F2 population was further enhanced. Untargeted metabolomics was used to characterise whitefly susceptible and tolerant sub-groups. PCA of the molecular features generated clustering of accessions into whitefly resistant and susceptible groups and differentiating metabolite biomarkers were identified. The most significant metabolite marker for resistance being the chemical feature 316.0924. Although not consistent among all whitefly resistance sub-groups targeted LC-MS analysis revealed several pathways displaying perturbed levels. These include cyanogenic glycosides, apocarotenoids and phenylpropanoid super-pathway comprising of hydroxycinnamic acids, flavonoids and proanthocyanidins. Thus, the generation of a bi-parental population for whitefly tolerance/susceptibility enabled the identification of quantitative metabolite markers, the pathways contributing to tolerance, the underlying modes of action associated with resistance and the potential for the development of future high-throughput low-cost proxy markers. The approach also provides generic insights into future breeding strategies utilising bi-parental progeny for the enhancement of traits.

SUMMARY.

SIGNIFICANCE STATEMENT.
A simple network of proprioceptive reflexes can produce a variety of bipedal gaits
Authors: Bunz Elsa K. , Haeufle Daniel F. B. , Schmitt Syn , Geijtenbeek Thomas
Published: February 2025

Proprioception is crucial for movement, yet the role of proprioceptive reflexes in legged locomotion is still poorly understood. While previous simulation studies have shown great potential for reflex-based control strategies, these controllers are typically catered to specific gaits, using hand-crafted feedback pathways that are linked to specific gait phases. In this work, we explore the control capabilities of a simple reflex controller that consists of only monosynaptic and antagonistic length and force feedback pathways with constant gains. Despite its simplicity, we found our control framework capable of producing a wide variety of natural gaits, including walking and hopping, forwards and backwards, and running in different variations and at different velocities – without requiring any rhythmic inputs or high-level state machines modulating the feedback gains. Our work highlights the important role and flexibility of proprioceptive reflexes and suggests a necessary re-evaluation of their role in locomotion. Due to its simplicity and flexibility, our control framework provides a solid basis for the development of higher level neuromuscular control systems.

Author summary

Human locomotion is characterized by an impressive versatility and humans transition naturally between different gaits. However, the neural mechanisms underlying human motor control are not fully understood and remain controversial. The two widely accepted basic components of the neural circuitry involved in locomotion are central pattern generators (CPG) and spinal reflexes, leading to a long-standing debate on their respective roles. Neuromusculoskeletal models can be employed to study the role of these neural control structures in simulation. Until now, these models mostly focus on walking and require an additional component like a state-machine or CPG besides reflexes to generate rhythmic activation of muscles. In this work, we propose a controller that can generate different rhythmic gaits like walking and hopping, forwards and backwards, as well as running, based solely on simple reflexes known to exist in the mammalian spinal cord. We challenge the current view of the role of rhythm-generating components and show the remarkable potential of reflexes for locomotion control. To our knowledge, this is the first work showing that versatile locomotion can be achieved solely based on reflexes without the need of a CPG. Our results contribute to the understanding of human motor control and are relevant for the control of robots, exoskeletons, prostheses and ortheses.
BESTDR: Bayesian quantification of mechanism-specific drug response in cell culture
Authors: McDonald Thomas O. , Bruno Simone , Roney James P. , Zervantonakis Ioannis K. , Michor Franziska
Published: February 2025

Understanding drug responses at the cellular level is essential for elucidating mechanisms of action and advancing preclinical drug development. Traditional dose-response models rely on simplified metrics, limiting their ability to quantify parameters like cell division, death, and transition rates between cell states. To address these limitations, we developedBayesian Estimation of STochastic processes for Dose-Response(BESTDR), a novel framework modeling cell growth and treatment response dynamics to estimate concentration-response relationships using longitudinal cell count data. BESTDR quantifies rates in multi-state systems across multiple cell lines using hierarchical modeling to support high-throughput screening. We validated BESTDR with synthetic and experimental datasets, demonstrating its robustness and accuracy in estimating drug response. By integrating mechanistic modeling of cytotoxic, cytostatic and other effects, BESTDR enhances dose-response studies, facilitating robust drug comparisons and mechanism-specific analyses. BESTDR offers a versatile tool for early-stage preclinical research, paving the way for drug discovery and informed experimental design.
EpiFoundation: A Foundation Model for Single-Cell ATAC-seq via Peak-to-Gene Alignment
Authors: Wu Juncheng , Wan Changxin , Ji Zhicheng , Zhou Yuyin , Hou Wenpin
Published: February 2025

Foundation models exhibit strong capabilities for downstream tasks by learning generalized representations through self-supervised pre-training on large datasets. While several foundation models have been developed for single-cell RNA-seq (scRNA-seq) data, there is still a lack of models specifically tailored for single-cell ATAC-seq (scATAC-seq), which measures epigenetic information in individual cells. The principal challenge in developing such a model lies in the vast number of scATAC peaks and the significant sparsity of the data, which complicates the formulation of peak-to-peak correlations. To address this challenge, we introduceEpiFoundation, a foundation model for learning cell representations from the high-dimensional and sparse space of peaks. Epi-Foundation relies on an innovative cross-modality pre-training procedure with two key technical innovations. First, EpiFoundation exclusively processes the non-zero peak set, thereby enhancing the density of cell-specific information within the input data. Second, EpiFoundation utilizes dense gene expression information to supervise the pre-training process, aligning peak-to-gene correlations. EpiFoundation can handle various types of downstream tasks, including cell-type annotation, batch correction, and gene expression prediction. To train and validate EpiFoundation, we curatedMiniAtlas, a dataset of 100,000+ single cells with paired scRNA-seq and scATAC-seq data, along with diverse test sets spanning various tissues and cell types for robust evaluation. EpiFoundation demonstrates state-of-the-art performance across multiple tissues and diverse downstream tasks.
Genome-Wide Uncertainty-Moderated Extraction of Signal Annotations from Multi-Sample Functional Genomics Data
Authors: Hamilton Nolan H. , McMichael Benjamin D. , Love Michael I. , Furey Terrence S.
Published: February 2025

Motivation

Most genome-wide consensus profiles of regulatory features consist of discrete binary annotations, or “peaks”, identified as enriched in functional genomics data targeting loci with a particular molecular phenotype, e.g., accessible chromatin or a transcription factor binding site. Despite the established practical utility of this paradigm, these annotations can limit the representation of quantitative signal data to rigid boundaries and mask informative spatial and structural features in signals. We reasoned that a more robust integration of numeric data from multiple samples could elucidate higher-resolution genome-wide profiles for improved molecular state characterizations. This integration poses several fundamental challenges due to dynamic, sample-specific noise patterns that vary in their effects across the genome and render straightforward data aggregation approaches vulnerable to signal dilution or distortion.

Results

We propose Consenrich, a genome-wide state-estimation scheme for extraction of consistent underlying signals given functional sequencing data from multiple samples. Consenrich addresses fundamental challenges inherent in this task by implementing a biologically-informed model for signal and variance propagation that treats nonstationary noise processes to yield a genome-wide signal track of positional estimates and measures of uncertainty. We demonstrate improved multi-sample signal estimation and noise attenuation of Consenrich on real, heterogeneous functional genomics data compared to least-squares smoothing filters and straightforward “alignment merging” strategies. We highlight immediate practical appeal of this improved signal extraction performance for both traditional consensus peak calling tasks and address the potential for unique analyses not possible with simple binary peak calls.

Availability and Implementation

A software implementation of Consenrich accompanied by several practical usage examples and documentation is hosted athttps://github.com/nolan-h-hamilton/Consenrich.
Leveraging spatial scale and temporal variation to optimize estimates of invasive spread rates
Authors: Keller Joseph , De Bona Sebastiano , Helmus Matthew R.
Published: February 2025

Estimating the extent and speed of an invasive species’ spread is crucial for optimizing surveys and management, but this estimation is challenging due to the scale-dependent nature of spread. For instance, when discretizing occurrence data to grids to estimate the extent of invaded ranges, larger cells can decrease boundary precision, while smaller cells can increase the risk of missing invaded areas. Moreover, on shorter timescales such as year-to-year comparisons, spread rates can exhibit lags, accelerations, and slowdowns. We present a multiscale spread optimization methodology developed for the spotted lanternfly (Lycorma delicatula), a pest impacting grapes that is spreading westward across the continental United States. We analyzed a dataset of >900,000 occurrence records covering spread from this pest’s initial detection in eastern Pennsylvania in 2014 to its invasion front in Chicago, IL, in 2023. First, we delineated the annual U.S. invasion front using square grids with varying cell sizes and α-convex hulls with different boundary resolutions. For each method and scale, we regressed invaded range area against year using both simple linear and logistic nonlinear models. Coarser spatial scales yielded faster estimated spread rates, and logistic models outperformed linear regressions, indicating a lag, acceleration, and slowdown in annual spread rate. Next, to determine the spatial scale that best captured the invasion front boundary, we used cross-validation, optimizing the Fβmetric, which balances recall and precision. Emphasizing recall generally favored coarser spatial scales, and α- convex hulls outperformed grid-based methods in delineating invasion fronts. Finally,L. delicatulahas dispersed long distances from its primary epicenter, establishing satellite populations. We delineated each satellite population each year since its inception using optimized α-hull values and measured their year-to-year boundary expansion. Like the primary epicenter, these satellite populations showed accelerating expansion, at least until merging with the primary invasion. Overall, the expansion rate of the primary invasion has slowed since 2017, decreasing from a maximum of 21 km/year, possibly due in part to control efforts, although the exact cause remains unresolved. Considering spatial scale and temporal variation can optimize the analysis of invasive spread and motivate early interventions to manage nascent epicenters before their spread accelerates.
Beyond Proxies: Towards ecophysiological indicators of drought resistance for forest management
Authors: Copie Alice , Scotti-Saintagne Caroline , Lefèvre François , Cochard Hervé , Delzon Sylvain , Dumas Pierre-Jean , Gounelle Damien , Herbette Stephane , Jean Florence , Mariotte Nicolas , Mencuccini Maurizio , Scotti Ivan , Martin-StPaul Nicolas
Published: February 2025

As drought-induced mortality increases globally in forest biomes, it becomes necessary for foresters to have access to reliable predictors of species vulnerability to drought and mortality risk under different climatic scenarios. On the one hand, there exist several “operational” indicators of drought resistance, which are based on observations, expert knowledge and species bioclimate (e.g.Ellenberg, Rameau, ClimEssences). On the other hand, as traits can now be measured at high throughput, functional traits (such as plant hydraulic traits) have been increasingly used to assess species’ vulnerability to hydraulic failure, a key process of tree mortality under drought. However, this mechanistic approach has never been compared to the operational approach. In this study, we review if indicators commonly used by foresters provide information onAbiesspecies’ vulnerability to hydraulic failure. We measured a set of traits in a common garden experiment of closely related MediterraneanAbiesspecies. These traits were used as inputs to the SurEau model to compute a single indicator of vulnerability (Time to Hydraulic Failure -THF) and to assess mortality risk in future climate. We found that among circum-Mediterranean firs, a highTHFwas mainly due to high water losses after stomatal closure. Some operational indicators are good proxies ofTHF, however they are not available for all species, reduce a species to a single value and have the same limitations as species distribution models. We argue that the ecophysiological approach could help foresters in species selection and in estimating the risk faced by forest tree species in a changing climate. While accounting for the variability of traits, hydraulic models can be forced with different climatic scenarios allowing hydraulic failure risk assessment by the end of the century.

Highlights

Integrating ecophysiological traits in a process-based model allows the computation of an accurate indicator of vulnerability: the Time to Hydraulic Failure (THF).

ForAbiesspecies, ”operational” indicators,i.e.indicators used by foresters and land managers, are mutually consistent and can be simplified proxies of the vulnerability to hydraulic failure.

More research on intra-specific variability is needed to assess the evolutionary potential of Euro-MediterraneanAbiesspecies.
Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation
Authors: Abir Ariful Haque , Benz Julia , Frey Benjamin , Bruns Heiko , Gaipl Udo S. , Schober Kilian , Mougiakakos Dimitrios , Mielenz Dirk
Published: February 2025

Fate decisions of T helper (Th) cells are tightly linked to their metabolic states, but precise mechanistic links remain unknown, especially in humans. Usingin vitrostimulation in combination with gene editing we studied how metabolic regulation shapes human Th1 cell identity and effector function. Differentiated Th1 cells displayed elevated STAT1 phosphorylation at Tyr701 and Ser727 as well as heightened T-bet and IFNγ expression, which were dampened by CRISPR/Cas9-mediated STAT1 deletion. Metabolic profiling revealed enhanced glycolytic activity in Th1 in comparison to Act.T cells, evidenced by increased extracellular acidification rate, ATP production via glycolysis, glucose uptake, lactate secretion and NADH abundance. SCENITH analysis demonstrated elevated glycolysis-dependent anabolic activity of Th1 cells. Inhibition of glycolysis reduced IFNγ production and STAT1 phosphorylation independent of JAK1/2 activity, STAT1 abundance or SHP-2 activity, implicating glycolysis directly in sustaining STAT1-mediated Th1 functionality. Mechanistically, O-Glycosylation, facilitated by O-Glycosyltransferase, emerged as pivotal in modulating STAT1 activity, as evident through immunoprecipitation and Western blot analysis. Pharmaceutical O-Glycosyltransferase inhibition prevented Th1 differentiation as well as STAT1 O-glycosylation. CRISPR/Cas9 mediated mutation of the O-glycosylation sites Ser499 and Thr510 sites diminished STAT1 Ser727 phosphorylation and IFNγ synthesis. Together, this study highlights glycolysis as key regulator of human Th1 cell identity and effector function, with STAT1 O-Glycosylation selectively maintaining Th1 effector capacity. This mechanism could be explored to safeguard Th1 cells in antiviral immunity and autoimmunity.

Graphical abstract
Recent thymic emigrants are preferentially recruited into the memory pool during persistent infection
Authors: Hilt Zachary T. , Reynaldi Arnold , Steinhilber Megan , Zhang Shide , Wesnak Samantha P. , Smith Norah L. , Davenport Miles P , Rudd Brian D.
Published: February 2025

Cytomegalovirus (CMV) leads to a unique phenomenon known as ‘memory inflation,’ where antigen-specific memory CD8+ T cells continue to accumulate in the peripheral tissues during the latent stage of infection. However, it is still not clear how the inflating pool of memory CD8+ T cells is generated and maintained. In this study, we used murine cytomegalovirus (MCMV) as a model of persistent infection and fate-mapping mice to determine the dynamics of CD8+ T cell recruitment into the memory pool. We found that neonatal exposure to CMV leads to an expansion of newly made CD8+ T cells (recent thymic emigrants, RTEs), which are maintained in the long-lived memory compartment. In contrast, CD8+ T cells made during the latent phase of infection (mature CD8+ T cells) contribute little to the memory pool. We also observed notable phenotypic differences between RTEs and mature cells. Whereas RTEs present at the time of infection gave rise to more effector memory cells, the cells produced later in infection were biased towards becoming central memory cells. Importantly, the preferential recruitment of RTEs into the effector memory pool also occurs during adult exposure to CMV. Collectively, these data demonstrate that persistent infection expands the RTE population, and timing of infection dictates whether neonatal or adult RTEs are ‘locked in’ to the memory pool.

Author Summary

Following infection with CMV, CD8+ T cells accumulate in the blood and peripheral organs over time, a feature termed ‘memory inflation’. However, it is not clear whether memory inflation is due to the continuous recruitment of cells made during the latent stage of infection or expansion of CD8+ T cells that were present at the time of infection. To address this question, we used a fate-mapping mouse model and examined the recruitment of CD8+ T cells that were produced during different stages of infection. Surprisingly, we discovered that CD8+ T cells exported from the thymus just prior to infection are preferentially recruited and maintained in the memory pool. In contrast, CD8+ T cells made during the latent stage contribute minimally to the inflating pool and exhibit a less differentiated phenotype. These results provide a new conceptual framework for understanding how the memory pool is generated and maintained after persistent viral infection.
Proteomic Landscape of Pattern Triggered Immunity in the Arabidopsis Leaf Apoplast
Authors: Chen Hsiao-Chun , Newton Carter J. , Diaz Gustavo , Zheng Yaochao , Kong Feng , Yao Yao , Yang Li , Kvitko Brian H.
Published: February 2025

The apoplast is a critical interface in plant-pathogen interactions particularly in the context of pattern-triggered immunity (PTI), which is initiated by recognition of microbe-associated molecular patterns (PAMPs). Our study characterizes the proteomic profile of the Arabidopsis apoplast during PTI induced by flg22, a 22 amino acid bacterial flagellin epitope, to elucidate the output of PTI. Apoplastic washing fluid (AWF) was extracted with minimal cytoplasmic contamination for LC-MS/MS analysis. We observed consistent identification of PTI enriched and depleted peptides across replicates with limited correlation between total protein abundance and transcript abundance. We observed topological bias in peptide recovery of receptor-like kinases with peptides predominantly recovered from their ectodomains. Notably, tetraspanin 8, an exosome marker, was enriched in PTI samples. We additionally confirmed increased concentrations of exosomes during PTI. This study enhances our understanding of the proteomic changes in the apoplast during plant immune responses and lays the groundwork for future investigations into the molecular mechanisms of plant defense under recognition of pathogen molecular patterns.
IQI: Individualized Quantitative trait loci (QTL) Index
Authors: Xu Jing , Sun Chen , Tao Junxian , Wei Siyu , Dong Yu , Guo Xuying , Tian Hongsheng , Chen Haiyan , Ma Yingnan , Lyu Wenhua , Bi Shuo , Zou Yuping , She Wei , Zhang Chen , Kang Jingxuan , Kong Fanwu , Zhang Mingming , Lyu Hongchao , Jiang Yongshuai
Published: February 2025

There is currently no standard efficient method to precisely detecting and characterizing the difference of quantitative trait loci (QTL) effect among groups and/or populations at individual level. The main reason is that the traditional global regression based QTL analyses can only derive an overall effect of genetic variants on the quantitative trait in a specific group. It is a big challenge to obtain the individual-level QTL effect, which is necessary for accurate testing and precise characterization. Here, we first proposed an individualized QTL index (IQI) that represents the degree of regulation between genetic variants and the trait for each individual. Based on IQI, Differential QTL (DQ) analysis framework was presented to accurately detect the case-control differences in more detail. In addition, IQI can be a new feature/biomarker applied to various accurate bioinformatics analysis, such as differential analysis, disease prediction, and survival analysis. Overall, IQI affords a new perspective on pathogenic mechanisms and will facilitate the study of genetic regulation more detailedly and precisely.
ERGA-BGE Reference Genome ofLoboptera subterranea: a cave adapted cockroach endemic to the Canary Islands
Authors: López Heriberto , Oromí Pedro , Belles Xavier , Ylla Guillem , Escudero Nuria , Fernández Rosa , Böhne Astrid , Gut Marta , Aguilera Laura , Alioto Tyler , Ferreira Francisco Câmara , Gómez-Garrido Jèssica , Cruz Fernando , Monteiro Rita
Published: February 2025

Species of the genusLobopterafrom the Canary Islands are adapted to life in subterranean environments, exceptLoboptera canariensisandLoboptera decipienswhich inhabit epigean, often influenced by human activities. The genome ofLoboptera subterraneaprovides a valuable resource for understanding the genetic basis of how the CanarianLobopteraspecies evolved and thrived in subterranean environments.

A total of 14 contiguous chromosomal pseudomolecules were assembled from the genome sequence. This chromosome-level assembly encompasses 2.7 Gb, composed of 486 contigs and 90 scaffolds, with contig and scaffold N50 values of 13.1 Mb and 202.7 Mb, respectively.
CD4+Mucosal-associated Invariant T (MAIT) cells express highly diverse T cell receptors
Authors: Kaur Rimanpreet , Mehanna Nezar , Pradhan Atul , Xie Danielle , Li Kelin , Aubѐ Jeffrey , Rosati Barbara , Carlson David , Vorkas Charles K.
Published: February 2025

Mucosal-associated invariant T cells are highly conserved innate-like T cells in mammals recognized for their high baseline frequency in human blood and cytotoxic effector functions during infectious diseases, autoimmunity, and cancer. While the majority of these cells express a conserved CD8αβ+ TRAV1-2 T cell receptor recognizing microbially-derived Vitamin B2 intermediates presented by the evolutionarily conserved major histocompatibility complex I-related molecule, MR1, there is an emerging appreciation for diverse subsets that may be selected for in humans with distinct functions, including subpopulations that co-express CD4. Prior work has not examined T cell receptor (TCR) heterogeneity in CD4+MAIT cells, largely due to bias of identifying human MAIT cells as CD8+TRAV1-2+cells. In this study, we adopted an unbiased single-cell TCR-sequencing approach of total MR1-5-OP-RU-tetramer-reactive T cells and discovered that CD4+MAIT cells express highly diverse TRAV1-2 negative TCRs. To specifically characterize this TCR repertoire, we analyzed VDJ sequences of single MR1-5-OP-RU tetramer+MAIT cells across two datasets and identified distinct TCR usage among CD4+MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J chain and CDR3 sequences. Non-TRAV1-2 MAIT cell TCRs were also enriched after in vitro expansion, including withMycobacterial tuberculosis. These results indicate that mature human CD4+MAIT cells adopt distinct TCR usage from the canonical TRAV1-2+CD8+subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select them.
Measuring morphogen transport over multiple spatial scales in live zebrafish embryos
Authors: Nelanuthala Ashwin V. S. , Saha Bitan , Sankaran Jagadish , Carney Tom J. , Sampath Karuna , Wohland Thorsten
Published: February 2025

Morphogenesis is controlled by signalling morphogens that form gradients across the embryo. The gradient formation requires that the low molecular weight morphogens slow down their diffusion by at least one order of magnitude. However, the precise slow-down of diffusion across the relevant micrometre scales has not been directly observed. Here, we develop and employ Single-Plane Illumination Microscope based spatial Fluorescence Cross-Correlation Spectroscopy (SPIM-sFCCS) to directly measure the diffusion coefficient of the morphogen Squint in early zebrafish embryos as a function of topography and length scale. We show that Squint’s diffusion coefficient changes on length scales that are commensurate with the diameter of the intercellular spaces in the embryo and that the slow-down is regulated by receptor binding. The slowdown can be reduced by either the knockdown of Activin receptor 2b, a receptor for Squint, or the overexpression of Lefty2, an inhibitor of Squint. Based on our results and supporting simulations, we propose an interstitial space-dependent transient receptor binding and diffusing mechanism to explain this slowdown, which is crucial for gradient formation and embryonic patterning.