bluuebunny/crossref_metadata_2025 huggingface dataset:
The bHLH transcription factor gene EGL3 accounts for the natural diversity in Arabidopsis fruit trichome pattern and morphology
Authors: Méndez-Vigo Belén , Arteaga Noelia , Murillo-Sánchez Alba , Alba Sonia , Alonso-Blanco Carlos
Published: December 2024

The number and distribution of trichomes, i.e. the trichome pattern, in different plant organs show a conspicuous inter- and intraspecific diversity across Angiosperms that is presumably involved in adaptation to numerous environmental factors. The genetic and molecular mechanisms accounting for the evolution of trichome patterns have just begun to be elucidated. In this study, we aimed to identify and characterize MALAMBRUNO 1 (MAU1), a locus affecting trichome number in the fruits of Arabidopsis (Arabidopsis thaliana) natural populations. To this end, we developed introgression lines (ILs) from the hairy fruit accession Doñana (Don-0) in the genetic background of the Ler strain with glabrous fruits. Genetic analyses of ILs showed that MAU1 affects fruit trichome patterns through synergistic epistasis with the MYB genes TRICHOMELESS1 (TCL1), GLABRA1 (GL1), and TRIPTYCHON (TRY). In addition, fine mapping and characterization of transgenic lines demonstrated that MAU1 is the bHLH transcription factor gene EGL3, for which Don-0 carries a gain-of-function semidominant allele. Gene expression analyses did not detect differences between EGL3 alleles, thus supporting that a structural missense mutation is the causal nucleotide polymorphism of Don-0. Further phylogenetic analyses of EGL3 showed that most Arabidopsis populations with hairy fruits belong to 3 haplogroups, suggesting that additional EGL3 natural alleles account for fruit trichome development. Finally, the characterization of EGL3 pleiotropy indicates that Don-0 hyperfunction also increases stem trichome branching. We conclude that EGL3 interactions in the core gene regulatory network of trichome development explain the Arabidopsis natural diversity for fruit trichome pattern and morphology.
General SIR model for visible and hidden epidemic dynamics
Authors: Nesteruk Igor
Published: December 2024

To simulate hidden epidemic dynamics connected with asymptomatic and unregistered patients, a new general SIR model was proposed. For some cases, the analytical solutions of the set of 5 differential equations were found which allow simplifying the parameter identification procedure. Two waves of the pertussis epidemic in England in 2023 and 2024 were simulated with the assumption of zero hidden cases. The accumulated and daily numbers of cases and the duration of the second wave were predicted with rather high accuracy. If the trend will not change, the monthly figure of 9 new pertussis cases (as it was in January-February 2023) can be achieved only in May 2025. The proposed approach can be recommended both for simulations and predictions of different epidemics.
A Framework for Autonomous AI-Driven Drug Discovery
Authors: Selinger Douglas W. , Wall Timothy R. , Stylianou Eleni , Khalil Ehab M. , Gaetz Jedidiah , Levy Oren
Published: December 2024

The exponential increase in biomedical data offers unprecedented opportunities for drug discovery, yet overwhelms traditional data analysis methods, limiting the pace of new drug development. Here we introduce a framework for autonomous artificial intelligence (AI)-driven drug discovery that integrates knowledge graphs with large language models (LLMs). It is capable of planning and carrying out automated drug discovery programs at a massive scale while providing details of its research strategy, progress, and all supporting data. At the heart of this framework lies the focal graph - a novel construct that harnesses centrality algorithms to distill vast, noisy datasets into concise, transparent, data-driven hypotheses. We demonstrate that even small-scale applications of this highly scalable approach can yield novel, transparent insights relevant to multiple stages of the drug discovery process and present a prototype system which autonomously plans and executes a multi-step target discovery workflow.

Graphical Abstract
Calprotectin as a sepsis diagnostic marker in critical care: a retrospective observational study
Authors: Lengquist Maria , Sundén-Cullberg Vera , Hyllner Sofie , Koozi Hazem , Larsson Anders , Mellhammar Lisa , Friberg Hans , Schiopu Alexandru , Frigyesi Attila
Published: December 2024

Background

Diagnosing sepsis in critical care remains a challenge due to the lack of gold-standard diagnostics. Calprotectin (S100A8/A9) has been proposed as a diagnostic marker to identify sepsis in critically ill patients. This study evaluated the diagnostic performance of calprotectin and C-reactive protein (CRP) to distinguish between sepsis and non-sepsis on intensive care unit (ICU) admission.

Methods

Admission biobank blood samples from adult patients admitted to four ICUs (2015-2018) were used to analyse calprotectin and CRP. All adult patients were screened retrospectively for the sepsis-3 criteria at ICU admission. The diagnostic performance of calprotectin and CRP was evaluated using receiver operating characteristic (ROC) curves.

Results

We included 4732 patients, of whom 44% had sepsis. Calprotectin levels were higher in sepsis (p<0.001). The area under the receiver operating curve (AUROC) to diagnose sepsis was 0.61 for calprotectin compared to 0.72 for CRP (p<0.001). Among microbiological subgroups of sepsis patients, fungal sepsis had the highest level of calprotectin.

Conclusions

The diagnostic performance of calprotectin in identifying sepsis patients at ICU admission was inferior to that of CRP.
Benefits of Statins as Adjunct Therapy in the Management of Tuberculosis in Patients at a Referral Site in Ghana
Authors: Buabeng Nana Kwaku Bugyei , Amponsah Obed Kwabena Offe , Ayisi-Boateng Nana Kwame , Atawuchugi Paul , Boateng Kyei Emmanuel , Mohammed Aliyu , Buabeng Kwame Ohene , Danquah Cynthia Amaning
Published: December 2024

Background

Repurposing medications that have demonstrated efficacy experimentally for drug-resistant tuberculosis (TB), such as statins, provides an opportunity to sidestep the time span and financial resources required to produce new antimicrobials to surmount resistance. However, this has not been extensively explored particularly in sub-Saharan Africa. This study investigated the benefits of statins as adjunct therapy in patients with TB, including those that are drug-resistant.

Methods

This was a case control study, involving the review of 3-year medical record of patients with tuberculosis on TB therapy with statins as adjunct (the cases), and those on TB therapy but not on statins at the Agogo Presbyterian Hospital in Ghana. The data obtained was analyzed using STATA version 17. Chi square test was used to determine the association between statin use as adjunct for TB therapy and improved outcomes (cure rate).

Results

Statin use in TB therapy as adjunct was associated with an increased incidence of TB cure (p<0.001). The relationship between statin and TB cure was still statistically significant, when age was adjusted for as a confounder in statin exposed individuals, (RR=4.9, p<0.05). Additionally, statins increased the cure rate of TB in the population studied, 6.61 per 100 population, 95% CI, (4.05-10.79) compared to 1.30 per 100 population 95 % CI, (0.65-2.59) in the absence of statins.

Conclusion

Statin use in patients on TB therapy was associated with increased cure. This study has affirmed that statins have potential benefits as an adjunct therapy in TB management.
The ketone body β-Hydroxybutyrate mediated epigenetic chromatin β-hydroxybutyrylation protects kidneys
Authors: Mandal Juthika , Aryal Sachin , Manandhar Ishan , Chakraborty Saroj , Mei Xue , Yeoh Beng San , Mell Blair , Kleinhenz Andrew , Tummala Ramakumar , Yang Tao , Saha Piu , Gunning William T , Vijay-Kumar Matam , Basrur Venkatesha , de la Serna Ivana , Joe Bina
Published: December 2024

Starvation, intermittent fasting and exercise, all of which are recommended lifestyle modifiers share a common metabolic signature, ketogenesis to generate the ketone bodies, predominantly β-hydroxybutyrate. β-hydroxybutyrate exerts beneficial effects across various contexts, preventing or mitigating disease. We hypothesized that these dynamic health benefits of β-hydroxybutyrate might stem from its ability to regulate genome architecture through chromatin remodeling via histone β-hydroxybutyrylation, thereby influencing the transcriptome. Focusing on the kidney, which is an end organ protected by β-hydroxybutyrate, we examined histone β-hydroxybutyrylation-mediated chromatin remodeling. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. Significant β-hydroxybutyrylation was observed in the kidneys and the most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures were enriched with genes related to immune function such as protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which exhibited reduced transcription and translation. These results reveal that renal epigenetic histone β-hydroxybutyrylation, which concurrently modulates both energy metabolism and immune function is a mechanism underlying the dynamic health effects of β-hydroxybutyrate to protect kidneys and lower hypertension.
Flashzoi: An enhanced Borzoi model for accelerated genomic analysis
Authors: Hingerl Johannes C. , Karollus Alexander , Gagneur Julien
Published: December 2024

Accurately predicting how DNA sequence drives gene regulation and how genetic variants alter gene expression is a central challenge in genomics. Borzoi, which models over ten thousand genomic assays including RNA-seq coverage from over half a megabase of sequence context alone promises to become an important foundation model in regulatory genomics, both for massively annotating variants and for further model development. However, its reliance on handcrafted, relative positional encodings within the transformer architecture limits its computational efficiency. Here we present Flashzoi, an enhanced Borzoi model that leverages rotary positional encodings and FlashAttention-2. This achieves over 3-fold faster training and inference and up to 2.4-fold reduced memory usage, while maintaining or improving accuracy in modeling various genomic assays including RNA-seq coverage, predicting variant effects, and enhancer-promoter linking. Flashzoi’s improved efficiency facilitates large-scale genomic analyses and opens avenues for exploring more complex regulatory mechanisms and modeling.
Variation of tooth traits in ecologically specialized and sympatric morphs
Authors: Jónsdóttir Guðbjörg Ósk , Ingimarsson Finnur , Snorrason Sigurður Sveinn , Steele Sarah Elizabeth , Pálsson Arnar
Published: December 2024

Differences in dentition between species relate to feeding specialisations, as examples of tetrapod dentition variation show clearly. The association of tooth traits and specialisations in non-mammalian vertebrates is less studied. We examined variation in dental traits in four sympatric morphs of Arctic charr (Salvelinus alpinus) which differ in feeding specialisations, head and jaw bone morphology. We studied tooth numbers in six bones (dentary, maxilla, premaxilla, palatine, vomer and glossohyal) and tooth angles in one bone (maxilla). We found fluctuating asymmetry in tooth numbers and angles and that the allometry of tooth numbers varied by bone but not morphs. The tooth numbers differed by morphs in four bones (dentary, palatine, vomer and glossohyal). In general, the morphs defined as pelagic had more teeth, and this relates partially to changes in bone shape. There was a difference in maxilla tooth angle, with benthic morphs having teeth which were angled more inwards. Dentary and maxilla tooth number correlated moderately with bone shape, maxilla tooth angle and premaxilla tooth number did not. While it is currently unknown what tooth characteristics are ancestral vs derived in these populations, the marked differences in specific bones presents an opportunity to explore rapid adaptive evolution in dentition.

Statement and Declaration

The authors declare that they have no conflict of interest
Pedigree Painter (PePa): a tool for the visualization of genetic inheritance in chromosomal context
Authors: Pozzi Andrea
Published: December 2024

Background

Data visualization is increasingly important in genomics, enabling researchers to uncover inheritance and recombination patterns across generations. While most existing tools focus on ancestry prediction, they lack functionality for analyzing known ancestries in controlled settings, such as determining parental contributions to offspring genomes. To address this gap, I developedpepa, a lightweight, modular tool that visualizes and quantifies genomic inheritance, designed for beginner and advanced users.

Results

pepais a program for processing VCF files, assigning ancestries to SNPs, and clustering them into biologically meaningful regions. It generates human-readable comparison tables and visualizes inheritance patterns with chromosome paintings through R. Tested on fission yeast,peparevealed non-uniform recombination patterns, with chromosomes largely inherited from one parent and seemingly random recombination. Quantitative analyses showed differences in parental contributions at the nucleotide and gene levels, with some offspring inheriting similar percentages from parents. However, the painted chromosomes revealed that even offspring with similar percentages from one parent rarely inherit the same genomic region, highlighting the importance of this tool in drawing biologically meaningful insights.

Conclusion

pepaprovides an accessible and powerful solution for analyzing genomic inheritance, bridging experimental and computational biology. Its modular design and minimal dependencies allow adaptation to diverse organisms, facilitating intuitive visualization and quantitative insights into recombination dynamics.
The B-type cyclin Clb4 prevents meiosis I sister centromere separation in budding yeast
Authors: Lumbroso Gal , Cairo Gisela , Lacefield Soni , Murray Andrew W.
Published: December 2024

In meiosis, one round of DNA replication followed by two rounds of chromosome segregation halves the ploidy of the original cell. Accurate chromosome segregation in meiosis I depends on recombination between homologous chromosomes. Sister centromeres attach to the same spindle pole in this division and only segregate in meiosis II. We used budding yeast to select for mutations that produced viable spores in the absence of recombination. The most frequent mutations inactivatedCLB4, which encodes one of four B-type cyclins. In two wild yeast isolates, Y55 and SK1, but not the W303 laboratory strain, deletingCLB4causes premature sister centromere separation and segregation in meiosis I and frequent termination of meiosis after a single division, demonstrating a novel role for Clb4 in meiotic chromosome dynamics and meiotic progression. This role depends on the genetic background since meiosis in W303 is largely independent ofCLB4.
Fossil Freshwater Fishes from the Pliocene of northern Colombia and the Palaeogeography of northern South America
Authors: Ballen Gustavo A. , Montes Camilo , Carrillo-Briceño Jorge D. , Bogan Sergio , Reinales Sandra , de Pinna Mario C. C. , Jaramillo Carlos
Published: December 2024

1

Freshwater fishes from northern Colombia are reported from the Sincelejo and Ware formations, of Pliocene age. A total of ten taxa have been identified comprising two orders, five families, and nine genera. Characters from dental morphology, fin spines, and cranial bones are provided as taxonomic tools for the study of fossil fishes. All of the taxa are members of groups currently restricted to drainages east of the Andes, suggesting that physical drainage connection was still present by the Pliocene between the Amazon-Orinoco and trans-Andean drainages such as the Magdalena-Cauca, or that these groups persisted in the trans-Andean region at least until Pliocene times. The generaHemidoras,Serrasalmus, andTrachely-opterichthysare new records for the fossil fish fauna of South America. The genusZungarorepresents a new record for the trans-Andean region, whereas the genusPlatysilurusis for the first time in Colombia. Most of these occurrences also represent the youngest occurrences in the fossil record. Literature records are reidentified asPygocentrusfrom the La Venta fauna and the earily Oligocene in Peru. These assemblages suggest that the Sincelejo and Ware formations were deposited in rivers of large size that were part of a large drainage network connected to the Amazon-Orinoco despite being currently located west of the Andes. These findings suggest that the Cordillera Oriental and the Merida Andes were not dividing yet the drainage network in northern South America by the middle to late Miocene.
A qualitative study exploring how secondary school PE uniform policies influence body image, and PE engagement among adolescent girls
Authors: Porter Alice , Cawley Elin , Chapman Laura , Crisp Charlotte , Wadman Ruth , Barber Sally , Penton-Voak Ian , Attwood Angela , Jago Russell , Bould Helen
Published: December 2024

Background

Many adolescent girls experience body dissatisfaction and have low levels of physical activity. Secondary school Physical Education (PE) offers opportunities for girls to build self-confidence and stay active; however, PE uniforms can be a barrier to participation.

Objectives

To explore how secondary school PE uniform policies influence body image and PE engagement (participation and enjoyment) among adolescent girls, and how these policies could be co-developed in future.

Design

A qualitative study involving focus groups and interviews.

Participants and setting

Forty-four 13-14-year-old girls and six PE staff members from six mixed-sex secondary schools in England.

Data collection and analysis

Using topic guides and participatory activities to aid discussions, we explored PE uniform preferences and the influence on body image and PE engagement with adolescent girls, as well as the PE uniform policy development process with PE staff. Data were analysed using reflexive thematic analysis, supported by NVivo 14.

Results

Three themes were generated. Theme 1, ‘Striking the right balance between choice, comfort and uniformity’, describes the challenges of developing PE uniform policies that offer pupils choice to maximise comfort, whilst maintaining uniformity to ensure smartness, and to reduce social comparison. Theme 2, ‘PE uniforms are “made for boys”’ reflects that current policies can often provide unisex uniforms that don’t fit the female body, or gendered options that limit girls’ choices over style and fit. Theme 3, ‘Self-confidence influences comfort in wearing PE uniform, and in turn PE engagement’ suggests girls with high self-confidence may be less concerned about others’ opinions and how they look, leading to greater PE enjoyment, whereas girls with lower self-confidence described feeling self-conscious, especially in communal changing rooms, which could impact their comfort and PE engagement.

Conclusions

Our findings suggest that developing PE uniform policies, which allow pupils to choose their own bottoms, wear additional layers, and wear PE uniform all day may improve comfort and inclusivity among girls, facilitating better PE engagement.

Strengths and limitations of this study

Our qualitative approach, using participatory activities to prompt discussions, enabled in-depth exploration into how PE uniforms can influence body image and PE engagement among adolescent girls.

Data from adolescent girls and PE staff were triangulated to ensure PE uniform policy recommendations considered both pupil and staff perspectives.

Due to challenges with recruiting schools, our sample was made up of mixed-sex, mainly affluent schools in South West England only.

We had limited representation from pupils of ethnic minority backgrounds and those with low levels of PE enjoyment.
Association of fibrinogen αE, fibrinogen γ′, and sialylated fibrinogen with development of ischemic stroke in patients with recently diagnosed type 2 diabetes
Authors: Daugaard Nicoline , Bladbjerg Else-Marie , Svane Helene Matilde Lundsgaard , Thomsen Reimar Wernich , Nielsen Jens Steen , Palarasah Yaseelan , de Maat Moniek P.M. , Münster Anna-Marie Bloch
Published: December 2024

Background

Stroke is a major cause of death globally, especially in type 2 diabetes (T2D) patients. Fibrinogen is known to predict stroke risk, but fibrinogen is a highly variable protein and we hypothesized that fibrinogen variants can improve stroke prediction.

Objectives

To investigate the association of total fibrinogen and fibrinogen variants with risk of ischemic stroke in T2D patients.

Methods

In a nested case-control study with a median follow-up of 4.1 years, we included 144 T2D patients with ischemic stroke (cases) and 144 matched T2D patients without ischemic stroke (controls). We measured total fibrinogen, absolute and relative (ratio between variant and total fibrinogen) levels of three fibrinogen variants (fibrinogen αE, fibrinogen γ′, and sialylated fibrinogen) and compared levels between cases and controls. We used logistic regression to determine the association with stroke risk.

Results

Total fibrinogen and absolute levels of fibrinogen αE, fibrinogen γ′, and sialylated fibrinogen were higher in stroke cases than controls (total fibrinogen 3.55 and 3.44 g/l; fibrinogen αE: 8.95 and 8.55 µg/ml; fibrinogen γ′: 638 and 626 µg/ml; sialylated fibrinogen: 1.32 and 1.18 arbitrary units). Absolute levels of fibrinogen positively associated with risk of stroke, both for total fibrinogen (highest vs lowest tertile; adjusted odds ratio (OR) 1.9 (95% CI 0.9-4.2)), fibrinogen γ′ (OR 1.8 (0.8-3.8)), and sialylated fibrinogen (OR 2.5 (1.1-5.8)). Relative levels of fibrinogen variants did not convincingly associate with stroke risk.

Conclusion

Patients with T2D who developed stroke had increased levels of total fibrinogen, fibrinogen αE, fibrinogen γ′, and sialylated fibrinogen compared with T2D controls. Total fibrinogen and absolute, but not relative, levels of fibrinogen γ′ and sialylated fibrinogen prospectively associated with a 2-fold increased risk of ischemic stroke.
Climacteric Women’s Perspectives on Menopause and Hormone Therapy: Knowledge Gaps, Fears, and the Role of Healthcare Advice
Authors: Rodrigues Marcio Alexandre H. , Reis Zilma Silveira Nogueira , Verona Ana Paula de Andrade , Teixeira Matheus Candido , Pappa Gisele Lobo , Soares Junior Jose Maria , da Silva Filho Agnaldo Lopes , Baracat Edmund Chada , Maciel Gustavo Arantes Rosa
Published: December 2024

Objective

This study aims to evaluate the knowledge, attitudes, and practices of Brazilian women regarding menopause, related symptoms, and the use of hormone therapy, including indications and contraindications.

Methods

A cross-sectional study was conducted between 18/07/2022 and 01/10/2023, involving women aged 40 to 65 years from various cities in Minas Gerais, São Paulo, and other regions of Brazil. A structured KAP (Knowledge, Attitudes, and Practices) Survey was used to assess sociodemographic characteristics, the prevalence of menopausal symptoms, and the participants’ knowledge and practices concerning Menopause Hormone Therapy.

Results

The median age of the women surveyed was 50 years; 55.4% were postmenopausal (median age 55), and 44.6% were premenopausal (median age 45). The data indicate limited knowledge about menopause among Brazilian women. Less than one-third (30.3%) expressed satisfaction with the information they had received regarding menopause and available treatment options. Furthermore, 92.97% of participants demonstrated little or no knowledge of hormone therapy. Nearly 27% were unaware of MHT, and 22% opposed its use. Only 29% reported current use of MHT, with common reasons for discontinuation including fear of side effects and contraindications advised by gynecologists.

Conclusion

The findings indicate that many Brazilian women have insufficient knowledge about menopause and hormone therapy. Furthermore, a lack of information and training among healthcare providers may lead to the low utilization of menopausal hormone therapy (MHT). To effectively address menopausal symptoms and empower women to make informed choices about hormone therapy, it is crucial to improve access to accurate information and enhance the training of healthcare providers.
CALIPERS: Cell cycle-aware live imaging for phenotyping experiments and regeneration studies
Authors: Di Sante Moises , Pezzotti Melissa , Zimmermann Julius , Enrico Alessandro , Deschamps Joran , Balmas Elisa , Becca Silvia , Reali Alessandro , Bertero Alessandro , Jug Florian , Pasqualini Francesco S.
Published: December 2024

Measuring cell structure and function along with cell cycle progression in live cell imaging has been challenging because Fluorescence Ubiquitin Cell Cycle Indicators (FUCCI) and most phenotypic sensors both utilize green (GFP) and red (RFP) fluorescence proteins. We introduce CALIPERS, a method for cell cycle-aware live-cell imaging for phenotyping experiments and regeneration studies. CALIPERS uses a custom FUCCI sensor called FUCCIplex that spectrally multiplexes with GFP and RFP-based sensors. To demonstrate the broad range of applications for CALIPERS, we validated it with epithelial and human induced pluripotent stem cell multi-color reporter lines in proliferation, migration, cardiac drug testing, and regenerative medicine studies.
Noninvasively real-time monitoring in-vivo immune cell and tumor cell interaction by NIR-II nanosensor
Authors: Huang Liwen , Ming Jiang , Wang Zhihua , Wu Jiaxin , Yun Baofeng , Liang Aibin , Fan Yong , Zhang Fan
Published: December 2024

Immunocytotherapy holds significant promise as a novel cancer treatment, but its effectiveness is often hindered by delayed responses, requiring evaluations every two to three weeks based on current diagnostic methods. Early assessment of immune cell-tumor cell interactions could provide more timely insights into therapeutic efficacy, enabling adjustments to treatment plans. In this study, we report a noninvasive nanosensor (C8R-DSNP) for real-time monitoring of in vivo immune cell activities in the second near-infrared long-wavelength (NIR-II-L) window (1500-1900 nm), which offers deep tissue transparency. The C8R-DSNP responds rapidly to caspase-8, a key apoptotic signaling molecule generated during interactions between natural killer (NK-92) immune cells and tumor cells. Using ratiometric NIR-II-L fluorescence imaging, we captured dynamic in vivo observations of NK-92 cell engagement with tumor cells in a mouse model. These results demonstrated cancer cell apoptosis that happens as early as 4.5 hours after NK-92 cell infusion. Additionally, in vitro urine imaging confirmed the initiation of apoptosis via cleaved fluorescent small molecules, while single-cell tracking within blood vessels and tumors further elucidated immune cell dynamics. This real-time NIR-II-L monitoring approach offers valuable insights for optimizing immunocytotherapy strategies.
Gene regulatory network integration with multi-omics data enhances survival predictions in cancer
Authors: Pop Romana T. , Hsieh Ping-Han , Belova Tatiana , Mathelier Anthony , Kuijjer Marieke L.
Published: December 2024

The emergence of high-throughput omics technologies has resulted in their wide application to cancer studies, greatly increasing our understanding of the disruptions occurring at different molecular levels. The role of gene regulation as a core driver of biological processes and its role in the development and progression of cancer has been well established. Transcriptional regulation, a crucial aspect of gene regulation, can be represented as a network of interactions between regulators (such as transcription factors) and their target genes. These networks are known as gene regulatory networks (GRNs). Several joint dimensionality reduction (JDR) methods and tools for integrating multi-modal data have been developed in recent years. This study presents a new approach to integrate multi-modal data of different dimensions to consider sample-specific GRNs with multi-omics data in ten cancer datasets from The Cancer Genome Atlas (TCGA). We compare JDR models that include GRNs with those that do not, assessing their association with patient survival. We find that including GRNs can improve associations with patient survival across several cancer types. Focusing on liver cancer, our methodology identifies potential mechanisms of gene regulatory dysregulation associated with cancer progression.
Prediction of Cell States and Key Transcription Factors of the Human Cornea through Integrated Single-Cell Omics Analyses
Authors: Arts Julian A. , Fallo Sofia , Florencio Melanie S. , Smits Jos G.A. , Cunha Dulce Lima , Roubroeks Janou A.Y. , Dickman Mor , LaPointe Vanessa L.S. , Yu Rosemary , Zhou Huiqing
Published: December 2024

The cornea, a transparent tissue composed of multiple layers, allows light to enter the eye. Several single-cell RNA-seq analyses have been performed to explore the cell states and to understand the cellular composition of the human cornea. However, the inconsistences in cell state annotations between these studies complicate the application of these findings in corneal studies. To address this, we integrated single-cell RNA-seq data from four published studies and created a human corneal cell state meta-atlas. This meta-atlas was subsequently evaluated in two applications. First, we developed a machine learning pipeline cPredictor, using the human corneal cell state meta-atlas as input, to annotate corneal cell states. We demonstrated the accuracy of cPredictor and its ability to identify novel marker genes and rare cell states in the human cornea. Furthermore, cPredictor revealed the differences of the cell states between pluripotent stem cell-derived corneal organoids and the human cornea. Second, we integrated the single-cell RNA-seq based cell state meta-atlas with chromatin accessibility data, conducting motif-focused and gene regulatory network analyses. These approaches identified distinct transcription factors driving cell states of the human cornea. The novel marker genes and transcription factors were validated by immunohistochemistry. Overall, this study offers a reliable and accessible reference for profiling corneal cell states, which facilitates future research in cornea development, disease and regeneration.

Significance statement

This study creates a human corneal cell state meta-atlas that provides a common nomenclature of cells in the human cornea, through integrating multiple single-cell RNA-seq analyses. Using this meta-atlas, we developed a machine learning pipeline, cPredictor, to accurately annotate cell states in corneal studies using single-cell RNA-seq. Additionally, we identified distinct transcription factors driving cell states through integrating the atlas with chromatin accessibility data. This meta-atlas and the computational tool cPredictor enable future research in cornea development, disease, and regeneration.
Breaking Boundaries: New locality records and a reassessment of the conservation status of the Khasi Hill Toad (Bufoides meghalayanus) endemic to Meghalaya, Northeast India
Authors: Sengupta Samrat , Chachei Esau Asakho , Boruah Bitupan , Nath Anukul , Das Abhijit
Published: December 2024

Bufoides meghalayanusis a Critically Endangered toad, endemic to East Khasi Hills, Meghalaya, Northeast India. This endemic toad was presumed to be restricted to just three locations, all within 1-2 km from one another around the type locality in Meghalaya. This article gives the first account of three previously unknown populations, extending the known geographic range of the species significantly. Additionally, we include the newly obtained molecular sequences ofB. meghalayanusin a comprehensive molecular phylogeny with a note on its genetic and morphometric variations within these new populations and its congeneric members.
OmiGA: A Toolkit for Ultra-efficient Molecular Trait Analysis in Complex Populations
Authors: Teng Jinyan , Zhang Wenjing , Gong Wentao , Chen Jiajian , Gao Yahui , Fang Lingzhao , Zhang Zhe
Published: December 2024

Molecular quantitative trait loci (molQTL) mapping is one of the most popular approaches to systematically characterize functional impacts of genomic variants, leading to advanced understanding of the regulatory mechanisms underpinning complex traits and diseases. However, when applied to high-throughput molecular phenotypes, the existing molQTL mapping tools often implement simple linear models, overlooking complex inter-individual relatedness, leading to false positives and insufficient statistical power. Here, we introduce theOmicsGeneticAnalysis toolkit (OmiGA), an ultra-efficient linear mixed model (LMM) based toolkit, for molQTL mapping in populations with complex relatedness. Both computational simulations and real data analyses demonstrated that OmiGA outperformed the existing popular tools regarding molQTL discovery power, fine mapping of causal variants, colocalization of molQTL and trait associations, and computational efficiency. In summary, we recommend OmiGA for molQTL mapping in populations with complex relatedness, for example, those in the Farm animal Genotype-Tissue Expression (FarmGTEx) project and family-based molQTL studies in humans.
Detecting mtDNA effects with an Extended Pedigree Model: An Analysis of Statistical Power and Estimation Bias
Authors: Lyu Xuanyu , Burt S. Alexandra , Hunter Michael D. , Good Rachel , Carroll Sarah L. , Garrison S. Mason
Published: December 2024

Mitochondrial DNA (mtDNA) plays a crucial role in numerous cellular processes, yet its impact on human behavior remains underexplored. The current paper proposes a novel covariance structure model with seven parameters to specifically isolate and quantify mtDNA effects on human behavior. This approach uses extended pedigrees to obtain estimates of mtDNA variance while controlling for other genetic and environmental influences. Our Monte-Carlo simulations indicate that a sample size of approximately 5,000 individuals is sufficient to detect medium mtDNA effects (mt2= 5%), while a more substantial cohort of around 30,000 is required for small effects (mt2= 1%). We show that deeper pedigrees increase power to detect the mtDNA effect while wider pedigrees decrease power, given the equal total sample size. We evaluated how missing kinship records and mtDNA mutations impact bias. Both lead to underestimation of mtDNA variance, and an overestimation of the interaction between nuclear DNA and mtDNA. In addition, the false positive rate of mtDNA effect estimation is low when fitting the model with data generated without mtDNA effects. Collectively, we demonstrate that using extended pedigrees to quantify the influence of mtDNA on human behavior is robust and powerful.
T-ALPHA: A Hierarchical Transformer-Based Deep Neural Network for Protein-Ligand Binding Affinity Prediction With Uncertainty-Aware Self-Learning for Protein-Specific Alignment
Authors: Kyro Gregory W. , Smaldone Anthony M. , Shee Yu , Xu Chuzhi , Batista Victor S.
Published: December 2024

There is significant interest in targeting disease-causing proteins with small molecule inhibitors to restore healthy cellular states. The ability to accurately predict the binding affinity of small molecules to a protein target in silico enables the rapid identification of candidate inhibitors and facilitates the optimization of on-target potency. In this work, we present T-ALPHA, a novel deep learning model that enhances protein-ligand binding affinity prediction by integrating multimodal feature representations within a hierarchical transformer framework to capture information critical to accurately predicting binding affinity. T-ALPHA outperforms all existing models reported in the literature on multiple benchmarks designed to evaluate protein-ligand binding affinity scoring functions. Remarkably, T-ALPHA maintains state-of-the-art performance when utilizing predicted structures rather than crystal structures, a powerful capability in real-world drug discovery applications where experimentally determined structures are often unavailable or incomplete. Additionally, we present an uncertainty-aware self-learning method for protein-specific alignment that does not require additional experimental data, and demonstrate that it improves T-ALPHA’s ability to rank compounds by binding affinity to biologically significant targets such as the SARS-CoV-2 main protease and the epidermal growth factor receptor. To facilitate implementation of T-ALPHA and reproducibility of all results presented in this paper, we have made all of our software available athttps://github.com/gregory-kyro/T-ALPHA.
Methods for estimating maternal, newborn, and child health and nutrition effective coverage cascades from household and health facility surveys
Authors: Munos Melinda K. , Sheffel Ashley , Carter Emily , Perin Jamie ,   IMPROVE Coverage Group
Published: December 2024

Background

Effective coverage cascades have been proposed to understand to what extent populations are able to benefit from interventions to address their health needs. Theoretical effective coverage cascades have been developed for reproductive, maternal, newborn, child, and adolescent health and nutrition (RMNCAH&N), but there is no consensus regarding the methods to estimate effective coverage cascades. We operationalized the proposed effective coverage cascades for selected RMNCAH&N services; this paper presents the overall methods, challenges, and lessons learned.

Methods

We used data from Demographic and Health Surveys, Multiple Indicator Cluster Surveys, Service Provision Assessments, and the Service Availability and Readiness Assessment to estimate effective coverage cascades in seven low- and middle- income countries for the following service areas: antenatal care, care for small and/or sick newborns, postnatal care, sick child care, and maternal and child nutrition. We developed operational definitions for each of the seven steps of the effective coverage cascade and developed readiness, and, where data allowed, process quality indices for each service area. Readiness- and process quality-adjusted coverage were estimated using ecological linking by stratum. We propose approaches for dealing with multiple observations per facility; multiple care-seeking episodes; and empty strata, as well as a jackknife approach to estimate the standard errors for readiness- and process quality-adjusted coverage.

Results

We were able to estimate effective coverage cascades through intervention coverage (step 4) for postnatal care and through process quality-adjusted coverage (step 5) for antenatal care, sick child care, and maternal and child nutrition. For small and/or sick newborn care, we did not have an appropriate denominator or measure of service contact coverage and had to modify the cascade significantly. Data gaps were the largest barrier to the estimation of effective coverage cascades for RMNCAH&N. Other challenges included accounting for community- and home-based interventions, determining whether the cascade should be nested, and interpreting the cascade.

Conclusions

To make effective coverage cascades feasible for routine use, clear guidance is needed on cascade methods and definitions, accounting for the full spectrum of RMNCAH&N interventions, and developing our understanding of how coverage cascades can be used by stakeholders to improve health systems and programs.
Protocol For a Scoping Review of Patient-Preferred Outcomes in Depressive Disorders
Authors: Boreham Megan A , Bogdanova Mariia , Bloomfield Madeleine , Cleare Anthony J , Strawbridge Rebecca
Published: December 2024

Depressive disorders remain a leading cause of health-related burden globally. Patients often suffer with symptoms throughout their lifetime, and rates of remission have been estimated to be as high as 66%. Clinicians typically favour the use of scales monitoring quantity and severity of depressive symptoms to evaluate response to treatment and determine whether patients have entered remission. However, given the complexity of the disorders and the subjective nature of mental health, research indicates that patients value outcomes beyond this narrow definition, identifying outcomes related to functioning and quality of life as important in addition to control of depressive symptoms. These studies are typically limited by relatively small sample sizes and associated lack of generalisability.

Here, we outline the protocol for a scoping review that aims to comprehensively collect and review research into patient preferred outcomes in treatment and management of depressive disorders. Our review was designed in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR) statement. Embase, Medline, PsycINFO, and CINAHL will be searched for relevant records. Qualitative and mixed-methods studies will be included, and all data will be synthesised and presented in narrative form. We anticipate that our results will provide useful insight for clinicians when caring for patients with depressive disorders and highlight potential misalignment between patient and clinician treatment goals.
Impact of wildfire smoke and diesel exhaust on inflammatory response in aging human microglia
Authors: Cuní-López Carla , Ng Mei Fong , Stewart Romal , Milton Laura A. , Etebar Fazeleh , Sun Yifan , Vivian Emily , Nguyen Tam Hong , Asare Patrick F. , Lupton Michelle K. , Roberts Tara L. , Ristovski Zoran , Hodge Sandra , Reynolds Paul N. , White Anthony R. , Quek Hazel
Published: December 2024

Background

Air pollution, particularly from Diesel Exhaust Particles (DEP) and Wildfire Smoke (WFS), is increasingly recognised as a significant driver of neuroinflammation linked to brain diseases. However, the role of microglia in mediating these neuroinflammatory responses remains poorly understood. This study aimed to investigate the effects of air pollution on monocyte-derived microglia-like cells (MDMi) from both young (< 40 years of age), and (older > 60 years of age) healthy individuals, focusing on immune response, cytokine secretion, nitrosative stress, and phagocytic activity.

Results

Our study demonstrated that DEP and WFS extract (WFSE) significantly upregulated expression of the oxidative stress marker, heme-oxygenase-1 (HO-1) in MDMi after 24 hr, with levels normalising by 96 hr, indicating a transient oxidative stress response. Both DEP and WFSE elicited distinct inflammatory cytokine profiles. DEP induced a rapid response, increasing TNF-α, IL-6, IL-23, and IL-33 within 2 hr in young MDMi and 24 hr in aged MDMi. In contrast, WFSE triggered a delayed but sustained inflammatory response, with TNF-α, IFN-γ, IL-23, and IL-33 levels persisting at 96 hr in aged MDMi, highlighting an age-related vulnerability to air pollutant-induced inflammation.

Both pollutants activated p38, ERK, and NF-κB pathways, with p38 activity resolving by 96 hours and ERK activation persisting, reflecting their distinct roles in cellular stress and inflammation. NF-κB p65 nuclear translocation, observed at 24 hours, highlighted its critical role in cytokine release and inflammation following exposure to DEP and WFSE. This is the first report of NF-κB activation in human microglia exposed to air pollutants.

Conclusions

These results highlight the distinct and potentially harmful effects of DEP and WFSE on immune and inflammatory responses in MDMi, particularly in ageing populations, with significant implications for brain health. DEP triggers acute oxidative stress and inflammatory responses, while WFSE induces more prolonged effects, especially in aged microglia. Both pollutants activate the MAPK and NF-κB pathways and exhibit unique cytokine profiles, underscoring their overlapping yet distinct mechanisms of action. These findings advance our understanding of air pollutant-induced neuroinflammation and its contribution to neurodegeneration, providing a foundation for developing targeted interventions to mitigate the neurotoxic effects of air pollution.
Mobilization of nuclear antiviral factors by Exportin XPO1 via the actin network inhibits RNA virus replication
Authors: Sun Biao , Wu Cheng-Yu , Gonzalez Paulina Alatriste , Nagy Peter D.
Published: December 2024

The intricate interplay between +RNA viruses and their hosts involves the exploitation of host resources to build virus-induced membranous replication organelles (VROs) in cytosol of infected cells. Previous genome- and proteome-wide approaches have identified numerous nuclear proteins, including restriction factors that affect replication of tomato bushy stunt virus (TBSV). However, it is currently unknown how cells mobilize nuclear antiviral proteins and how tombusviruses manipulate nuclear-cytoplasmic communication. The authors discovered that XPO1/CRM1 exportin plays a central role in TBSV replication in plants. Based on knockdown, chemical inhibition, transient expression and in vitro experiments, we show that XPO1 acts as a cellular restriction factor against TBSV. XPO1 is recruited by TBSV p33 replication protein into the cytosolic VROs via direct interaction. Blocking nucleocytoplasmic transport function of XPO1 inhibits delivery of several nuclear antiviral proteins into VROs resulting in dampened antiviral effects. The co-opted actin network is critical for XPO1 to deliver nuclear proteins to VROs for antiviral activities. We show that XPO1 and XPO1-delivered restriction factors accumulate in vir-condensates associated with membranous VROs. Altogether, the emerging theme on the role of vir-condensates is complex: we propose that vir-condensate serves as a central battleground between virus and the host for supremacy in controlling virus infection. It seems that the balance between co-opted pro-viral and antiviral factors within vir-condensates associated with membranous VROs could be a major determining factor of virus replication and host susceptibility. We conclude that XPO1 and nuclear antiviral cargos are key players in nuclear-cytoplasmic communication during cytosolic +RNA virus replication.

Significance

Tomato bushy stunt virus (TBSV), similar to other (+)RNA viruses, replicates in the cytosol and exploits organellar membrane surfaces to build viral replication organelles (VROs) that represent the sites of virus replication. The authors discovered that XPO1 exportin nuclear shuttle protein inhibited TBSV replication in plants. The conserved XPO1 is a central protein interaction nod, which propelled nucleocytoplasmic transport of several viral restriction factors into the cytosolic VROs that restricted tombusviruses replication. The delivered virus restriction factors provided inhibitory functions within virus-induced condensates associated with membranous VROs. The authors propose that the VRO-associated condensate serves as a central battleground between virus and the host for supremacy in controlling virus infection. Altogether, XPO1 is a critical protein interaction hub with major implications in viral replication. The authors conclude that XPO1 and its nuclear antiviral cargos are key players in nuclear-cytoplasmic communication during cytosolic (+)RNA virus replication.