bluuebunny/crossref_metadata_2025 huggingface dataset:
A comprehensive benchmark and guide for sequence-function interpretable deep learning models in genomics
Authors: Sun Canzhuang , Sun Yu , Xu Kang , He Zhijie , Li Hao , Li Yaru , Yu Zongyuan , Wang Yuyang , Lin Xuanwei , Xu Xiang , Hu Pengzhen , Bo Xiaochen , Liao Mingzhi , Chen Hebing
Published: January 2025

The development of sequence-based deep learning methods has greatly increased our understanding of how sequence determines function. In parallel, numerous interpretable algorithms have been developed to address complex tasks, such as elucidating sequence regulatory syntax and analyzing non-coding variants from trained models. However, few studies have systematically compared and evaluated the performance and interpretability of these algorithms. Here, we introduce a comprehensive benchmark framework for evaluating sequence-to-function models. We systematically evaluated multiple models and DNA language foundation models using 369 ATAC-seq datasets, employing diverse training strategies and evaluation metrics to uncover their critical strengths and limitations. Our benchmark study highlights that different model architectures and interpretability methods are better suited to specific scenarios. Negative samples derived from naturally inactive regions outperform synthetic sequences, whereas single-cell tasks require specialized models. Additionally, we demonstrate that interpretable sequence-function models can complement traditional sequence alignment methods in studying cross-species enhancer regulatory logic. We also provide a pipeline to help researchers select the optimal sequence-function prediction and interpretability algorithms.
Armadillo Repeat Only Proteins Are Crucial for the Function of Plant CNGC Channels
Authors: Kulich Ivan , Oulehlová Denisa , Vladimirtsev Dmitrii , Zhou Minxia , Lileikyte Edita , Janda Martin , Iakovenko Oksana , Neubergerová Michaela , Studtrucker Tanja , Pleskot Roman , Dietrich Petra , Fendrych Matyáš , Friml Jiří
Published: January 2025

Plant cells respond to a wide range of stimuli through intracellular calcium (Ca2+) signaling. Cyclic nucleotide-gated channels (CNGCs) are a major class of plant Ca2+channels, with 20 homologs inArabidopsis. These tetrameric plasma membrane (PM) proteins are activated by diverse stimuli, such as phytohormones, extracellular damage and cell wall integrity signals. Here, we identify a novel class of plant-specific proteins, Armadillo Repeat Only (ARO), as essential regulators of possibly all plant CNGC channels. Abrogation of functional sporophytic AROs results in a phenotypic pattern reminiscent of CNGC dysfunction, including defects in root gravitropism, root hair growth and morphology, stomatal movement, and responses to extracellular ATP and the phytohormone auxin.aro2/3/4mutants are fully resistant to the toxic effects caused by overexpression of CNGCs. AROs colocalize and physically interact with multiple CNGCs and modulate CNGC-dependent currents inXenopusoocytes. Structural modeling suggests that AROs form a tetramer surrounding the CNGC channel. These findings highlight AROs as key plant-specific players in plant CNGC function and Ca2+signaling.
Serum and Plasma Sphingolipids as Biomarkers of Anthracycline-Induced Cardiotoxicity
Authors: Mohammed Samia , Kalogeropoulos Andreas P. , Alvarado Victoria , Weisfelner-Bloom Michelle , Clarke Christopher J.
Published: January 2025

Although effective as a chemotherapy, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox or other anthracyclines is hampered by a lack of effective biomarkers to identify susceptible patients, and to detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from patients undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed there were substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion towards baseline following treatment. Linear mixed-effects model analysis revealed that at baseline, a number of SLs correlated with adverse cardiac outcomes with serum sphingosine-1-phosphate (S1P) and dihydroS1P, and plasma Cer performing comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dhS1P and plasma Cer levels showed correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24- Cer ratios – previously reported as predictive of adverse cardiac outcomes – showed no correlation in the context of anthracycline treatment. Taken together, this pilot study provides supporting evidence that plasma and serum SLs may have benefit as both prognostic and diagnostic biomarkers for patients undergoing anthracycline-containing therapy. This suggests that diagnostic SL measurements – recently implemented for metabolic-associated cardiac disorders – could have wider utility.
Characterization and automated classification of sentences in the biomedical literature: a case study for biocuration of gene expression and protein kinase activity
Authors: Raciti Daniela , Van Auken Kimberly M. , Arnaboldi Valerio , Tabone Christopher J. , Muller Hans-Michael , Sternberg Paul W.
Published: January 2025

Biological knowledgebases are essential resources for biomedical researchers, providing ready access to gene function and genomic data. Professional, manual curation of knowledgebases, however, is labor-intensive and thus high-performing machine learning methods that improve biocuration efficiency are needed. Here we report on sentence-level classification to identify biocuration-relevant sentences in the full text of published references for two gene function data types: gene expression and protein kinase activity. We performed a detailed characterization of sentences from references in the WormBase bibliography and used this characterization to define three tasks for classifying sentences as either 1) fully curatable, 2) fully and partially curatable, or 3) all language-related. We evaluated various machine learning (ML) models applied to these tasks and found that GPT and BioBERT achieve the highest average performance, resulting in F1 performance scores ranging from 0.89 to 0.99 depending upon the task. Our findings demonstrate the feasibility of extracting biocuration-relevant sentences from full text. Integrating these models into professional biocuration workflows, such as those used by the Alliance of Genome Resources and the ACKnowledge community curation platform, might well facilitate efficient and accurate annotation of the biomedical literature.
TheRalstonia solanacearumeffector RipAV targets Plant U-box proteins and induces proteasomal-dependent degradation of BIK1
Authors: Rufian Jose S. , Liu Xin , Wang Yaru , Rueda-Blanco Javier , Yu Gang , Ruiz-Albert Javier , Macho Alberto P.
Published: January 2025

Plants have developed a complex immune system to detect and respond to invading pathogens. A critical aspect of this defence relies on regulatory mechanisms that control the activation of immune responses, ensuring these are efficient yet do not compromise overall plant performance. Many pathogens secrete proteins called effectors to manipulate plant cellular functions, suppressing plant immunity and promoting infection. Here, we show that the bacterial effector RipAV, secreted by the soil-borne bacterial pathogenRalstonia solanacearum, hijacks a major immune signalling hub to suppress immune responses. RipAV targets members of the plant-specific ubiquitin ligase (PUB) family and calcium-dependent protein kinase 28 (CPK28), which has been shown to phosphorylate a set of PUBs to enhance their activity and regulate the stability of the key immune regulator BIK1. RipAV association enhances the CPK28-mediated phosphorylation of PUBs, inducing the proteasome-mediated degradation of BIK1 and the suppression of immunity. Importantly, we found that RipAV is required for maintaining a low accumulation of BIK1 during aR. solanacearuminfection. These findings provide new insights into the sophisticated strategies employed by pathogens to subvert plant immunity.
DNALongBench: A Benchmark Suite for Long-Range DNA Prediction Tasks
Authors: Cheng Wenduo , Song Zhenqiao , Zhang Yang , Wang Shike , Wang Danqing , Yang Muyu , Li Lei , Ma Jian
Published: January 2025

Modeling long-range DNA dependencies is crucial for understanding genome structure and function across a wide range of biological contexts. However, effectively capturing these extensive dependencies, which may span millions of base pairs in tasks such as three-dimensional (3D) chromatin folding prediction, remains a significant challenge. Furthermore, a comprehensive benchmark suite for evaluating tasks that rely on long-range dependencies is notably absent. To address this gap, we introduce DNALongBench, a benchmark dataset encompassing five important genomics tasks that consider long-range dependencies up to 1 million base pairs: enhancer-target gene interaction, expression quantitative trait loci, 3D genome organization, regulatory sequence activity, and transcription initiation signals. To comprehensively assess DNALongBench, we evaluate the performance of five methods: a task-specific expert model, a convolutional neural network (CNN)-based model, and three fine-tuned DNA foundation models – HyenaDNA, Caduceus-Ph, and Caduceus-PS. We envision DNALongBenchas a standardized resource with the potential to facilitate comprehensive comparisons and rigorous evaluations of emerging DNA sequence-based deep learning models that account for long-range dependencies.
Growth Hormone Excess Drives Liver Aging via increased Glycation stress
Authors: Singh Parminder , Gautam Anil , Trujillo Marissa , Galligan James , Hensley Lisa , Kapahi Pankaj , Bartke Andrzej
Published: January 2025

Growth hormone (GH) plays a crucial role in various physiological functions, with its secretion tightly regulated by complex endocrine mechanisms. Pathological conditions such as acromegaly or pituitary tumors result in elevated circulating GH levels, which have been implicated in a spectrum of metabolic disorders, potentially by regulating liver metabolism. In this study, we focused on the liver, a key organ in metabolic regulation and a primary target of GH, to investigate the impact of high circulating GH on liver metabolism. We used bovine GH overexpressing transgenic (bGH-Tg) mice to conduct a comprehensive transcriptomic analysis of hepatic tissues. The bGH-Tg mouse livers exhibit dysregulated fatty acid metabolism and heightened inflammatory responses. Notably, the transcriptomic profile of young bGH-Tg mouse livers resembled that of aged livers and displayed markers of increased cellular senescence. Furthermore, these mice exhibited a significant accumulation of advanced glycation end products (AGEs). Intervention with glycation-lowering compounds effectively reversed the insulin resistance and aberrant transcriptomic signatures in the liver that are associated with elevated GH levels. These findings underscore the potential therapeutic value of glycation-lowering agents in mitigating the deleterious effects of chronic GH overexpression.

Highlights

Overexpression of bovine growth hormone impacts transcriptional changes in liver fat metabolism and inflammatory response in mice.

High circulating growth hormone leads to transcriptional changes that suggest enhanced liver aging and induce cellular senescence.

Detoxification pathways in bGH-Tg mice are inhibited, leading to the accumulation of Advanced Glycation End (AGE) products.

Glycation-lowering compounds can mitigate pathologies associated with high GH levels.
Radial extracorporeal shock wave therapy is more effective than a combination of physical therapy modalities for rotator cuff injury: a randomized controlled trial
Authors: Wang Zheng , Tang Lan , Wang Ni , Huang Lihua , Schmitz Christoph , Zhou Jun , Zhao Yingjie , Chen Kang , Ma Yanhong
Published: January 2025

Objectives

This study tested the hypothesis that in treatment of rotator cuff (RC) injury, radial extracorporeal shock wave therapy (rESWT) is more effective than a combination of physical therapy modalities (PTMs; i.e., interferential current therapy, shortwave diathermy and magnetothermal therapy).

Methods

A total of 60 patients with RC injury without presence of full-thickness RC tear were randomly allocated to rESWT for 6 weeks (n=30; one session per week) or treatment with PTMs for 6 weeks (n=30; five sessions per week). The primary outcome measure was the ASES shoulder score. Secondary outcome measures were the VAS pain score, patient’s satisfaction, shoulder range of motion, thickness of the supraspinatus tendon and the acromiohumeral distance. All outcome measures were assessed by blinded assessors at baseline as well as at 6 weeks post-baseline (W6) and W12.

Results

No serious adverse events occurred during the trial. Compared to the patients in the PTMs group, the patients in the rESWT group had significantly (p<0.05) higher mean ASES total scores at W6 and W12 (power with two-sided 95% confidence interval: 65.7% at W6 and 92.8% at W12) as well as lower mean VAS pain scores, higher mean satisfaction scores and higher mean active and passive shoulder abduction values at W6 and W12. Furthermore, rESWT but not PTMs significantly reduced the mean thickness of the ST and increased the acromiohumeral distance.

Conclusion

In treatment of rotator cuff injury without presence of full-thickness rotator cuff tear, rESWT is more effective than the investigated combination of PTMs.

Registration

China Clinical Trials Registration Center (Registration number: ChiCTR2300077386; registration on 7 November 2023).
Genetic Insights from Automated Lumen Diameter Measurements in Carotid Ultrasounds of the UK Biobank
Authors: Ortín Vela Sofía , Bontempi Dennis , Mazini Bianca , Böttger Leah , Trofimova Olga , Bergmann Sven
Published: January 2025

Carotid ultrasound is routinely used in clinical practice for non-invasive vascular anatomical and functional assessment, such as measuring carotid Intima-Media Thickness (cIMT), an important marker for quantifying atherosclerotic burden in the common carotid arteries (CCAs). Recent research suggests that several risk factors associated with higher cIMT, such as high blood pressure, can induce a compensatory increase in the carotid Lumen Diameter (cLD) of the CCAs. However, the genetic architecture of cLD and its association with other cardiovascular traits are still poorly understood. To investigate these questions, we trained a Deep Learning model to segment the carotid artery from ultrasound images and developed an algorithm to measure the cLD. We compared multiple measures of cLD corresponding to lateral and central views of the left and right carotid arteries. By applying genome-wide association studies (GWAS), we investigated the genetic architecture of cLD and the relationship between cLD and cIMT in a cohort of 18 804 individuals imaged with carotid ultrasound from the UK Biobank. We found that cLD has an estimated heritability of 31%, substantially higher than that of cIMT (23%). Furthermore, these phenotypes only have a mild phenotypic (37%) but much higher genotypic (58%) correlation.
Spinal Movement Impairments in People with Acute Low Back Pain
Authors: Krueger Kayla O. , Duncan Ryan P. , van Dillen Linda R.
Published: January 2025

Objective

Identify whether people with people with acute low back pain (LBP) display spinal movement impairments during clinical tests. Compare the prevalence of impairments in people with acute LBP to that of people with chronic LBP. Examine the effect on symptoms of systematically modifying impairments.

Design

Secondary analysis of data from a cross-sectional study on LBP.

Methods

183 people with LBP were examined by a physical therapist using a standardized examination. Participants performed 9 primary tests using their preferred strategy. The clinician determined whether an impairment was present or absent. Participants reported the effect of the primary test on symptoms. If an impairment was present, it was modified during a secondary test. Participants reported the effect of the secondary test on symptoms relative to symptoms with the primary test. Chi-square tests of independence were used to test for differences in the proportion of impairments between people with acute LBP and people with chronic LBP. A McNemar-Bowker test was used to test whether there was a change in symptoms from the primary test to the secondary test.

Results

People with acute LBP displayed spinal movement impairments and the prevalence was similar to that of people with chronic LBP for 7 of the 9 primary tests. Most participants with symptomatic impairments reported their symptoms improved when the impairment was modified.

Conclusion

Spinal movement impairments are prevalent in people with acute LBP and may be modified during clinical tests to improve LBP symptoms.
Computationally optimized ctDNA surveillance for recurrence detection in HPV-positive head and neck squamous cell carcinoma
Authors: Mohammadi Narges , Rosenberg Ari J , Izumchenko Evgeny G , Pearson Alexander T , Skandari M. Reza
Published: January 2025

Importance

Early detection of Head and Neck Squamous Cell Carcinoma (HNSCC) recurrence in HPV-positive patients is crucial for improving survival rates and reducing treatment costs. Integrating circulating tumor DNA (ctDNA) testing as part of post-treatment surveillance may enhance timely cancer recurrence detection, reduce false-positive rates, and lower overall costs.

Objective

To develop and evaluate personalized, cost-effective post-treatment surveillance strategies that integrate ctDNA testing with established, computed tomography (CT) scans, with the goal of minimizing costs and treatment delays for HPV-positive HNSCC patients.

Methods

We constructed a microsimulation model that optimizes the timing of ctDNA tests and generates testing schedules designed to achieve detection delays below specified thresholds at a minimum cost. The model was fit using n= 840 training data and validated using n= 447 external data. Six sub-populations were created based on the combination of cancer stage (AJCC 8th edition stage 1, stage 2, and stage 3) and smoking status (non-smoker and ever-smoker). The study compared the proposed ctDNA-based strategy with established clinical guidelines, as well as a strategy from the literature.

Results

Our optimization model generated cost-effecive strategies for scheduling ctDNA tests for a range of detection delay tolerances (i.e., 3, 6, and 9 months) across the six subpopulations. The optimal ctDNA-based strategy demonstrated substantial cost savings, potentially reducing annual surveillance costs in the USA by at least $200 million compared to imaging-based guidelines, while matching an equal patient outcome of treatment delay. Additionally, a hypothetical scenario of monthly ctDNA testing, incurring comparable total cost to the existing guidelines’, offers a 32% reduction in treatment delay. The study also highlighted the growing importance of HPV-positive HNSCC surveillance, with the annual incidence projected to rise, further emphasizing the cost-saving potential of ctDNA integration.

Conclusion

Integrating ctDNA testing with traditional imaging methods for post-treatment surveillance of HPV-positive HNSCC patients offers a cost-effective strategy that minimizes surveillance costs and treatment delays. As the HPV-positive HNSCC population grows, the significance of the cost savings will increase. Future research should focus on the applicability of the developed strategy and their impact on patient survival and quality of life.
Evaluation of Flow Control Using PID versus Fuzzy Logic in an Electropneumatic Circuit for Pulmonary Ventilation Applications
Authors: Lescher Alfredo , González Lina , Griffith Issa , Molino Jay , Rojas Asdrúal , Quijano Damián
Published: January 2025

High-tech commercial mechanical ventilators are designed to provide a constant and accurate flow, thus ensuring the precision of ventilatory treatment. Therefore, this research aims to evaluate the flow control in a prototype electro-pneumatic unit for mechanical ventilator applications using a PID versus a Fuzzy Logic method.

Specifically, the intention is to determine if there is evidence of superior performance of fuzzy logic control over PID in this application. For this reason, the methodology is based on measurement and numerical analysis. The design of this research is quasi-experimental and conducted in a laboratory. Thus, samples of the data of the variables were taken at convenience under a pre-established scheme and conditions. In terms of the type of study, it is considered quantitative, experimental, and applied.

The main results show that according, the Bland-Altman analysis both controllers meet the accuracy limits of commercial equipment. However, the fuzzy logic controller presented better standard deviation and difference limits, demonstrating greater reliability in the accuracy of results. Additionally, the PID control demonstrated quicker response times with a shorter settling time (between 0.32 and 0.43 seconds) than in the fuzzy logic control (between 0.43 and 0.77 seconds); moreover, the fuzzy control presents an improvement in the volume of 900 mL, highlighting the efficiency of this controller in conditions of higher demand. The results show that both the PID and Fuzzy Logic controllers meet the stability conditions of the Jury Test. The system’s poles are within the unit circle of the Z plane, confirming the controllers’ stability. Also, the curve of the fuzzy control in the Nyquist analysis is farther away from the origin and from the point (−1, 0j) than the curve of the PID control, indicating better stability and a more robust system against variations or disturbances.
Investigating the Role of Vitamin D in the Prevention and Control of Dengue Virus Vectors and Related Diseases: A Systematic Review Study
Authors: Abbasi Ebrahim
Published: January 2025

Introduction

Dengue fever is one of the most common vector-borne diseases in the world, affecting many people annually and causing many deaths. Besides, treating this disease is difficult, and there is no effective vaccine for it. In recent years, attention has been paid to the role of micronutrients, including vitamin D, in the control and treatment of viral diseases, including dengue fever. Accordingly, this study aimed to investigate the role of vitamin D in the treatment and control of dengue fever worldwide using a systematic review method.

Methods

This study was conducted as a systematic review of the role of vitamin D in the prevention and control of dengue fever globally using a systematic review method. Therefore, all relevant articles were extracted and reviewed through a search in the international scientific databases, including PubMed/MEDLINE, WEB OF Science (ISI), and SCOPUS, without a time limit until the end of 2024. The quality of the articles was assessed using the STROB checklist.

Results

Six articles published between 2018 and 2023 were included in the systematic review process. According to the findings, vitamin D affects macrophages that are differentiated from monocytes and increases resistance to dengue virus. Vitamin D also reduces pro-inflammatory cytokines, transcription, and reduction of mRNA receptors, increases the production of interleukins, especially IL-10, and plays a role in reducing viral load, severity of clinical symptoms, and infection control.

Conclusion

Vitamin D3 can control the disease and decrease viral load and the severity of dengue fever in patients by inhibiting the inflammatory response and enhancing the immune response. However, given the limited number of studies, it is recommended that more studies be conducted in this field so that this can be discussed with more evidence and accuracy.
Regional Variations in Burden of Chronic Obstructive Pulmonary Disease
Authors: Mehareen Jeenat , Choy Kayly , Yin Yiwei , Sin Don D. , Sadatsafavi Mohsen
Published: January 2025

Background

Chronic Obstructive Pulmonary Disease (COPD) imposes a significant burden on individuals and communities. While differences in such burden are often studied across countries and healthcare systems, differences within jurisdictions have not been well evaluated. The aim of this study was to assess the trends of, and factors explaining, regional variability in the burden of COPD within a well-defined population with publicly funded healthcare system.

Methodology

We used population-based health records of people aged 35 years or older diagnosed with COPD across the 16 health regions of British Columbia, Canada (2010–2020). The primary outcomes were prevalence, incidence, all-cause hospital admissions, and all-cause mortality, while secondary outcomes were COPD- and cardiovascular disease (CVD)-specific hospitalization and mortality. We used generalized linear models to examine how outcomes varied by regions and changed over time, controlling for sex, age, socioeconomic status, and rural/urban residence.

Results

Over the 11-year study period, there were 312,014 individuals diagnosed with COPD (48.1% female, mean baseline age: 68.2 years). Across the province, standardized prevalence and all-cause mortality remained relatively stable during the study period, whereas incidence and all-cause hospitalization declined. There were up to a three-fold difference in standardized incidence and prevalence, and up to a two-fold difference in standardized all-cause hospitalization and mortality across regions (all p<0.05). These differences remained significant after controlling for case mix. Among COPD patients, both CVD-specific hospitalization and mortality were higher compared to COPD-specific hospitalization and mortality.

Conclusion

Despite being governed by the same universal healthcare system, difference in burden of COPD across geographic regions in this Canadian province was significant. Heterogeneity was more prominent in incidence and prevalence, compared with hospitalization and mortality, suggesting that the variation in the process of care leading to diagnosis is more substantial than variation in COPD outcomes.
Queen loss unmasks cryptic worker influence and decentralizes the bumble bee social network
Authors: Ruttenberg Dee M. , Wolf Scott W. , Webb Andrew E. , Wyman Eli S. , White Michelle L. , Melo Diogo , Traniello Ian M. , Kocher Sarah D.
Published: January 2025

Bumble bees (Bombus impatiens) undergo a radical transformation in social dynamics as a natural part of their colony life cycle. Early in the season, bumble bee societies are eusocial and contain a reproductive queen and functionally sterile workers. As the colony grows, the colony transitions to a competition phase in which reproductive division of labor breaks down and some workers activate their ovaries and lay unfertilized, male-destined eggs. This transition represents a key shift in colony organization, but its underlying social dynamics, including the relationship between individual- and colony-level behavior, are poorly understood. Using multianimal pose tracking to quantify social interactivity and related movement dynamics, we compared queenright and queenless colonies that capture these distinct cooperative and competitive phases of the colony life cycle. Queenright colonies displayed highly centralized social networks in which the queen received, rather than initiated, the majority of social interactions. In contrast, queenless colonies displayed higher worker interaction rates, and a subset of workers exhibited queen-like social behaviors and higher reproductive potential relative to nestmates. The unmasking of these “influencers” in a queenless, competitive context transformed the colony’s social network from a centralized to distributed social organization with higher overall network efficiency. Thus, the bumble bee queen masks a hidden relationship between worker influence and reproductive potential that underlies their latent social flexibility. In the absence of a queen, the colony social structure is transformed, revealing that significant modifications in information transfer can accompany shifts in colony social organization and highlighting a novel layer of resilience in this social system.
Antiproliferative Activity, Phytochemistry, Network Pharmacology, Molecular Docking and Gene Expression Analysis ofMaerua edulisExtracts against Human Cervical Cancer Cell Line
Authors: Lagu Inyani John Lino , Letoluo Rakita , Kamau Sally Wambui , Kuria James Menni , Musila Fredrick Mutie , Kungurtsev Vyacheslav , Nyamai Dorothy W. , Njeru Sospeter Ngoci
Published: January 2025

Maerua edulisexhibits significant antiproliferative activity against HeLa cells, with hexane and ethyl acetate extracts showing IC50values of 0.02% and 47.42µg/mL, respectively. Gas Chromatography-Mass Spectrometry (GC-MS) analysis identified key phytochemicals such as diisooctyl phthalate, squalene, and stigmasta-3,5-diene, which were associated with the regulation of apoptotic and cell cycle-related genes (BCL2, CDK2, TP53). Gene expression assays confirmed the modulation of these targets, suggesting the therapeutic potential ofM. edulisin cervical cancer. Further in vivo studies are recommended to validate these findings and establish its safety profile.
Ecological niche stability ofBiomphalariaintermediate hosts forSchistosoma mansoniunder extreme flooding and seasonal change
Authors: Iacovidou Melissa A. , Byaruhanga Anatol M. , Besigye Fred , Nabatte Betty , Kabatereine Narcis B. , Chami Goylette F.
Published: January 2025

Understanding spatiotemporal distributions and niches of vectors and intermedi-ate hosts for ecologically dependent pathogens is crucial for identifying endemic areas, assessing habitat suitability for transmission, and targeting interventions for both the environment and humans. This study focuses onBiomphalaria sudan-icaandB. stanleyi, intermediate hosts of intestinal schistosomes, with over 700 million people at risk in endemic areas. We identified how extreme flooding and seasonal changes influence habitat preferences and species interactions across 674 sites in 52 villages in rural Uganda between 2022–2024. A comprehensive analy-sis of ground truth data was conducted, covering spatiotemporal information, site characteristics, physicochemical parameters, ecological factors, and human activi-ties. Spatiotemporal models incorporating a new polygon-based method to account for space, bypassing limitations of administrative boundaries, with time as a fixed effect were developed to analyse snail abundance.B. sudanicawas associated with marshy sites near lake shorelines and presence of hyacinths, whileB. stanleyiwas more likely found in deeper waters withVallisneriaplants. However, both species often cohabited at the same sites. The extent of habitat suitability for each species fluctuated seasonally and more starkly with extreme flooding resulting in switch-ing of dominance between species. Our study shows that climatic variations may influence local changes in habitat suitability without necessitating an expansion of environmental areas. By providing a robust, generalisable spatiotemporal mod-elling pipeline, our study enables precise tracking of dynamic ecological niches in a changing climate that, if replicated in other areas, can be used to better target environmental and human interventions.
Integration of differential expression under drought with gene family expansion unique to drought tolerant species predicts candidate genes for drought adaptation in Brassicaceae species
Authors: Uebermuth-Feldhaus Carolin , Schoof Heiko
Published: January 2025

Background

In order to predict candidate genes for drought adaptation, we analyze genomic data of the more drought resistant Brassicaceae speciesEutrema salsugineumandArabidopsis lyratacompared to more drought sensitive speciesArabidopsis thalianaandBrassica napus.We combine gene family expansion, which is an important driver of evolution in plants, unique to the drought resistant species with differential expression under drought (DE).

Results

We show that combining trait-specific gene family expansion with differential expression predicts a concise set of candidate genes. To demonstrate that these are relevant for drought adaptation in tolerant species we show enrichment of DE conserved between both tolerant species, DE unique to the tolerant species, and up regulation. We show that specific functions are enriched, and that the set contains genes with functions such as root development in line with drought adaptation based on evidence from other species, while the background of all differentially expressed genes (DEGs) contains many general stress reaction genes. Whereas DEGs in general are rarely under diversifying selection, signatures of diversifying selection are slightly enriched in the candidate gene families, highly significantly enriched in DEGs in tolerant species-specific expanded gene families, and in contrast not enriched in DEGs in sensitive species-specific expanded gene families.

Conclusions

Our approach identifies a concise and functionally relevant set of candidate genes for drought adaptation with promising targets for functional studies and crop improvement for drought tolerance. We propose that our method can also be used to predict candidate genes for adaptation to other environmental factors.
Androgen receptor inhibition extends PARP inhibitor activity in prostate cancer models beyond BRCA mutations and defects in homologous recombination repair
Authors: Illuzzi Giuditta , Galbiati Alessandro , Staniszewska Anna D. , Hanson Robert , Michaloglou Chrysiis , Cooke Sophie , Uznańska Karolina , Białecka Maja , Solarczyk Kamil , Dev Harveer , Massie Charles E. , Albertella Mark , Leo Elisabetta , Forment Josep V. , O’Connor Mark J.
Published: January 2025

Recent phase 3 clinical trial readouts have shown benefit of the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway inhibitors (ARPi) in metastatic, castration-resistant prostate cancer (mCRPC). While benefit was particularly evident in patients with tumours harbouring mutations in homologous recombination repair (HRR) genes, improved outcomes were also observed in patients with no such defined alterations in their cancers. Although there is literature linking AR activity with DNA repair pathways, the basis of the interaction between the AR and PARP is unclear. Here, we show that benefit of the combination of ARPi and PARPi in prostate cancer in vitro and in vivo models with no HRR mutations requires ARPi-responsive cells and a PARPi with PARP1-trapping activity, and does not involve an effect of PARPi treatment in modulating the transcriptional role of the AR. Combination benefit is driven by an increase in DNA damage in the form of DNA double-strand breaks and micronuclei formation, which is not due to a direct control of HRR gene transcription by the AR. In addition, we uncover a novel role of PARP1 in modulating AR recruitment to chromatin in the presence of DNA damage. These data shed new light on the interplay between PARP1 and the AR in dealing with genotoxic insults and provide a mechanism of action consistent with the observed clinical benefit of the combination of PARPi and ARPi in patients with prostate cancer.

Statement of significance

Combination of androgen receptor pathway inhibitors and PARP inhibitors has shown efficacy in prostate cancer. We provide a mechanistic explanation through increased DNA damage accumulation observed in combination vs single-agent treatments.
Gut meta-virome reveals potential zoonotic pathogens and environmental RNA viruses carried by non-human primates
Authors: Yan Yujie , Li Yuhang , Yang Linshan , Wu Haojie , Wu Fan , Chang Hongli , Hu Zhengfeng , He Shujun , Ren Yi , Zhu Lifeng , Li Baoguo , Guo Songtao
Published: January 2025

The majority of human infectious diseases originate from mammals and are inherently zoonotic. Non-human primates (NHPs) are not only carriers of many zoonotic pathogens, but also the best intermediary for virus shift from harmless to harmful due to their similar phylogenetic relationship with humans. Knowledge of NHP viral composition and its underlying information can therefore provide an assessment of the risk of cross-species transmission and spillover of zoonotic diseases. However, studies that have successfully eliminated the effects of different natural habitat environments on viral carriage have been limited, making it difficult to identify which zoonotic viruses and potentially species-barrier-crossing viruses are carried by widely distributed NHP hosts. Here, we analyze viruses excreted in feces from NHP hosts and reveal the presence of possible zoonotic pathogens. Most of the viruses found come from plants that are eaten by them. Analysis of the evolutionary relationships of potential pathogens suggests that other clinical isolates are genetically correlated to HIV, PBV, and EV we identified. This study provides foundational data for surveillance of NHP enteroviruses that could help to be challenging to track potential human viruses carried by NHP in the absence of clinical surveillance.

Importance

As a result of internationalization and other factors, many viruses have broken through the limits of geographical units and spread into human society, causing many emerging and re-emerging infectious disease hazards. However, the virus spreads and is by no means infectious to humans overnight. There is a phenomenon of host shift, in which the virus does not necessarily cause disease in an intermediate host, but causes significant damage when transmitted to humans. We focus on captive non-human primates, close relatives of humans in cities, because the phenomenon of host shifts is related to both biological similarity and geographical proximity of the host. Primates may carry zoonotic viruses and viruses that are currently incapable of infecting humans but have evolved with pathogenic potential. In summary, comprehensive viral surveillance and screening of captive nonhuman primates is necessary.
Distribution of alternative routes for completing denitrification in microbial genomes and metagenomes of global biomes
Authors: Pold Grace , Saghai Aurelien , Jones Christopher M. , Hallin Sara
Published: January 2025

Diverse microorganisms can execute one or more steps in denitrification, during which nitrate or nitrite is successively reduced into nitric oxide, nitrous oxide, and ultimately dinitrogen. Many of the best-characterized denitrifiers are complete denitrifiers capable of executing all steps in the process, but whether they dominate in natural communities and what environmental factors drive the distribution of complete vs. partial denitrifiers remain unclear and incomplete in a global context. To address this, we conducted a comparative analysis of denitrification genes in 48,284 genomes and assessed their environmental distribution in 3,991 metagenomes covering all major biomes. We determined that the genomic potential to initiate denitrification is more common than the potential to terminate it, particularly in high nitrate or nitrite environments, and that partial denitrifiers outnumber complete denitrifiers across the majority of biomes. Our results further indicate that complete denitrifiers are more likely to be fast-growing organisms compared to partial denitrifiers, indicating the former may grow opportunistically when conditions are favorable. Together, our results indicate an environmental footprint on the gain and loss of denitrification genes which favors the genomic potential for partial over complete denitrification in most biomes, in line with the scarcity of high carbon input rates that might favor organisms encoding complete denitrification.
Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons
Authors: Strucinska Klaudia , Kneis Parker , Pennington Travis , Cizio Katarzyna , Szybowska Patrycja , Morgan Abigail , Weertman Joshua , Lewis Tommy L
Published: January 2025

Mitochondrial ATP production and calcium buffering are critical for metabolic regulation and neurotransmission making the formation and maintenance of the mitochondrial network a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously showed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Thus, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture andin vivo, and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 regulates morphological and functional mitochondrial characteristics that influence dendritic tree arborization and connectivity.
Nucleus accumbens dopamine encodes the trace period during appetitive Pavlovian conditioning
Authors: Wanat Matthew J. , Camacho Erika T. , Phillips Paul E.M.
Published: January 2025

Pavlovian conditioning tasks have been used to identify the neural systems involved with learning cue-outcome relationships. In delay conditioning, the presentation of a conditioned stimulus (CS) overlaps or co-terminates with the delivery of the unconditioned stimulus (US). Prior studies demonstrate that behavioral responding during delay conditioning is regulated by dopamine signaling in the nucleus accumbens (NAc). In particular, the dopamine response to the CS reflects the relative value of the upcoming reward in these tasks. In contrast to delay conditioning, trace conditioning involves a ‘trace’ period that separates the end of the CS and the delivery of the US. While dopamine has been implicated in trace conditioning, no studies to date have examined how NAc dopamine responds to reward-related stimuli in these tasks. To address this, we developed a within-subject trace conditioning task where distinct audio CSs signaled either a short trace period (5s) or a long trace period (55s) prior to the delivery of a food reward. Male rats exhibited higher levels of conditioned responding and a faster latency to respond to the Short Trace CS relative to the Long Trace CS. Voltammetry recordings in the NAc found that dopamine levels to the CS increased on Short Trace trials but decreased on Long Trace trials. Conversely, US-evoked dopamine responses were greater on Long Trace trials relative to Short Trace trials. We found that the CS dopamine response correlated with the latency to respond and not to the level of conditioned responding. Furthermore, the relationship between CS dopamine and latency was best explained by an exponential function. Taken together, our results illustrate how CS-evoked dopamine signals in the NAc relate to behavioral outcomes. Furthermore, we find that trace period is encoded by the bidirectional NAc dopamine response to the CS during Pavlovian conditioning.

Significance statement

Learning how to associate a given cue with an outcome is fundamental process underlying reward seeking behavior. Dopamine in the ventral striatum is important for establishing the link between cues and rewarding outcomes in Pavlovian conditioning tasks. However, it is unclear how striatal dopamine release responds to cues during trace conditioning when there is temporal gap between the cue and the rewarding outcome. To address this, we performed voltammetry recordings of dopamine release in male rats trained on trace conditioning task. We demonstrate that cue-evoked dopamine signals encode the trace period and is related to the latency to respond. While prior reports find that the relative reward value is signaled by increases in dopamine neuron activity to cues, the current study highlights the that dopamine response to reward-predictive cues can signal the relative reward value through bidirectional changes in dopamine transmission.
Maturase K forms a plastidial splicing complex with a neofunctionalized branching enzyme
Authors: Liang Yuanyuan , Gao Yang , Fontana Andrea , Abt Melanie R. , Gicgier Adam P. , Liu Chun , Sharma Mayank , Zoschke Reimo , Zeeman Samuel C. , Pfister Barbara
Published: January 2025

Chloroplast group IIA introns derive from bacterial ribozymes. Their splicing likely requires Maturase K (MatK), which has been largely inaccessible to functional analyses being itself a chloroplast intron-encoded protein. Here we show that MatK physically interacts with a conserved, essential plastid-localized homolog of starch-branching enzymes (BEs), dubbed MATURASE K INTERACTING PROTEIN1 (MKIP1). We demonstrate that MKIP1 proteins have lost BE activity and acquired an insertion enabling direct interaction with the N-terminal region of MatK. Arabidopsis MKIP1 specifically co-precipitates all known intron targets of MatK. InducedMKIP1silencing results in pale newly emerging leaves, in which the splicing of these intron targets is strongly reduced. Our data suggest that MKIP1 functionally diverged from canonical BEs to facilitate splicing in conjunction with MatK. We propose that the N-terminus of MatK, in turn, has evolved from an RNA-binding domain into a platform for protein interaction, helping its transition towards a general splicing factor.
One-point correlators of conserved and nonconserved charges in QCD
Authors: Riembau Marc , Son Minho
Published: January 2025

One-point correlators of conserved charges are argued to be perturbatively IR safe in quantum chromodynamics (QCD), which includes not only the density of energy, but also those of electric charge, isospin, and baryon number. Theoretical and phenomenological aspects of the density matrix of one-point correlators are discussed in the context of the states produced by a chiral current, as in the decay of a polarized electroweak boson. Densities of some nonconserved charges such as energy with arbitrary non-negative powers, despite their incalculability, are shown to obey an infinite set of consistency constraints. QCD is observed to live near a kink in the allowed parameter space of one-point correlators.

Published by the American Physical Society
2025
DALI sensitivity to streaming axion dark matter
Authors: De Miguel Javier , Kryemadhi Abaz , Zioutas Konstantin ,   On behalf of the DALI Collaboration
Published: January 2025

Dark matter substructures emerge naturally in axion cosmology. The DALI experiment is a next-generation interferometer for wavelike dark matter in the 25–250  μeV range, currently in its prototyping phase. Although DALI’s main objective is to explore the dark matter in our galaxy as a haloscope, to a large degree in this article we explore the prospect for detection of fine grained streams made of axions that would enter the Solar System, as suggested by previous work, which would be performed in parallel without interfering with the search for virialized axions. We find that DALI will have a sensitivity to encounters with these coherent streams that fully spans the window defined by the coupling strength to photons of representative axion models over a stacked bandwidth of two decades in mass.

Published by the American Physical Society
2025