bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Genetically Encoded Live-Cell Iron Mapping System
Authors: Akyol Ali , Çimen Şeyma , Gottschalk Benjamin , Alston Amy Barton , Digigow Reinaldo , Flüehmann Beat , Eroğlu Emrah , Graier Wolfgang F. , Malli Roland
Published: February 2025

Any disturbances in cellular iron regulation can lead to dysfunctions and various diseases. However, our current understanding of iron dynamics in living cells is hampered by the lack of high-resolution iron reporter systems capable of monitoring the iron status of individual cells dynamically. To address this challenge, we have developed the Live-Cell Iron Mapping System (LIMS), which consists of two distinct genetically encoded fluorescent iron reporter systems: the rFeRepS and IronFist. The rFeRepS (ratiometric Iron Reporter Systems) code for two genetically encoded constructs that translate the iron status of individual cells into a ratiometric fluorescent signal. The ratio signal reflects the cellular iron status, based on endogenous iron-responsive proteins. A high rFeRepS ratio indicates ferritin-based cellular iron storage, while a low ratio implies transferrin receptor (TfR)-based active cellular iron uptake. The IronFist (Iron Fluorescent Indicators based on Stability and Translation) is derived from the hemerythrin-like domain (Hr) of the F-box and leucine-rich protein 5 (FXBL5), which undergoes a structural rearrangement upon binding to ferrous iron, preventing its ubiquitination and subsequent degradation. In the IronFist design, we fused either the blue or green fluorescent protein (FP) variant, mTagBFP2 or mNeonGreen, to the C-terminus of Hr and co-expressed mCherry via a ribosomal skipping sequence as a reference protein for normalization. Thus, IronFist dynamically translates fluctuations of the labile iron pool into a ratiometric fluorescent signal. We demonstrated the functionality of both iron reporter systems by treating cells with different iron formulations including iron carbohydrate nanoparticles. Our results show clear cell-to-cell variations in the response to high iron treatments.
Candida albicansColonization Modulates Murine Ethanol Consumption and Behavioral Responses Through Elevation of Serum Prostaglandin E2and Impact on the Striatal Dopamine System
Authors: Day Andrew , Perez-Lozada Jeyra , DiLeo Alyssa , Blandino Katrina , Maguire Jamie , Kumamoto Carol A.
Published: February 2025

Candida albicansis a commensal yeast that is a common component of the gastrointestinal (GI) microbiome of humans.C. albicanshas been shown to bloom in the GI tract of individuals with alcohol use disorder (AUD) and can promote and increase the severity of alcoholic liver disease (ALD). However, the effects ofC. albicansblooms on the host in the context of AUD or AUD-related phenotypes, such as ethanol preference, have been unstudied. In this work, we report a reduction in ethanol consumption and preference in mice colonized withC. albicans.C. albicans-colonized mice exhibited elevated levels of serum PGE2and reduced ethanol preference was reversed by injection with antagonists of PGE2receptors. Further, injection of mice with a PGE2derivative decreased their ethanol preference. These results show that PGE2acting on its receptors EP1 and EP2 drives reduced ethanol preference inC. albicans-colonized mice. We also showed altered transcription of dopamine receptors in the dorsal striatum ofC. albicans- colonized mice and more rapid acquisition of ethanol conditioned taste aversion, suggesting alterations to reinforcement or aversion learning. Finally,C. albicans-colonized mice were more susceptible to ethanol-induced motor coordination impairment showing significant alterations to the behavioral effects of ethanol. This study identifies a member of the fungal microbiome that alters ethanol preference and demonstrates a role for PGE2signaling in these phenotypes.
Characterizing trajectory-like chromatin architectures with Fun2
Authors: Zhangding Zhengrong , Liu Xuhao , Hu Jiazhi
Published: February 2025

Chromatin is intricately folded into dynamic 3D structures, orchestrating key DNA metabolic processes. DNA replication, a core chromatin metabolic event, is tightly linked to these chromatin architectures. Recently, a replication-associated chromatin interaction structure was discovered as fountains via Replication-associated in situ Hi-C (Repli-HiC), supporting that replication forks remain spatially coupled from initiation to termination. Chromatin fountains are pivotal for understanding DNA replication within the complex chromatin landscape. However, the characteristics of these fountains can vary due to factors such as origin firing efficiency and local chromatin organization. In this study, we introduce a reinforcement learning-based computational framework, integrated with Monte Carlo Tree Search (MCTS) and value gradient optimization, to develop the Fun2 algorithm. Fun2 enables a comprehensive characterization of trajectory-like chromatin architectures, including both chromatin fountains and stripes, with enhanced adaptability and accuracy. This tool facilitates systematic investigation of the spatiotemporal dynamics of DNA replication and extends to other chromatin remodeling processes, such as Cohesin-mediated loop extrusion. The Fun2 algorithm provides a versatile computational tool for deciphering dynamic chromatin architectures, offering new insights into genome organization and its regulatory mechanisms.
Coalescent-based branch length estimation improves dating of species trees
Authors: Tabatabaee Yasamin , Claramunt Santiago , Mirarab Siavash
Published: February 2025

Species trees need to be dated for many downstream applications. Typical molecular dating methods take a phylogenetic tree with branch lengths in substitution units as well as a set of calibrations as input and convert the branch lengths of the species tree to the unit of time while being consistent with the pre-specified calibrations. When dating species trees from multi-locus genome-scale datasets, the branch lengths and sometimes the topology of the species tree are estimated using concatenation. However, concatenation does not address gene tree heterogeneity across the genome. While Bayesian dating methods can address some forms of gene tree heterogeneity, such as incomplete lineage sorting, they are not scalable to large datasets. In this paper, we introduce a new scalable pipeline for dating species trees that addresses gene tree discordance for both topology and branch length estimation. The pipeline uses discordance-aware methods that account for incomplete lineage sorting for estimating the topology and branch lengths and maximum likelihood-based methods for the dating step. Our simulation study on datasets with gene tree discordance shows that this pipeline produces more accurate and less biased dates than pipelines that use concatenation or unpartitioned Bayesian methods. Furthermore, it is substantially more scalable and can handle datasets with thousands of species and genes. Our results on two biological datasets show that this new pipeline improves the inference of node ages and branch lengths for some nodes, in particular extant taxa, and improves the downstream diversification analysis.
The Role of the BMPR2 pathway in Group-II Pulmonary Hypertension Secondary to Valve Heart Disease
Authors: Martinez-Solano Jorge , Bermejo-Fernandez Jaime , Gonzalez-Mansilla Ana , GARCIA ORTA ROCIO , Sanchez Pedro , Castano Mario , Sgura-Cubero Javier , Escribano-Subias Pilar , Bayes-Genis Antoni , Martinez-Legazpi Pablo , Mombiela Teresa , Ortiz-Bautista Carlos , Gonzalez Arantxa , Bermejo Javier , Fernandez-Avila Ana I
Published: February 2025

BMPR2 is widely known to be key in the pathobiology of pulmonary arterial hypertension. Recently, data regarding pulmonary hypertension (PH) secondary to left-heart disease (LHD) have focused on inflammatory and proliferative pathways rather than classic hemodynamic scope but BMPR2 role is yet to be determined. In the current study, we assessed BMPR2 and its regulatory factor, SRSF2, in patients with PH due to valvular heart disease (VHD). Blood samples from patients included in the Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) clinical trial were analysed. The study involved PH-VHD patients with combined pre-and postcapillary PH, isolated postcapillary PH, control patients without PH and healthy subjects. We sequenced the BMPR2 exons, measured BMPR2 A-isoform expression and analysed SRSF2 gene expression levels in blood samples. Our results demonstrate that BMPR2 A-isoform levels are reduced in patients with PH-VHD compared to controls and, even more, healthy subjects. Furthermore, BMPR2 A-isoform expression showed meaningful prognostic value among PH-VHD patients. Notably, whereas pathogenic gene variants were ruled out, SRSF2 was indeed associated with BMPR2 A-isoform differential expression. To the best of our knowledge, this is the first study demonstrating the involvement of BMPR2 gene expression in PH-LHD patients, supports BMPR2 A-isoform as a potential prognosis biomarker and this pathway as a therapeutic target.
Metronidazole and Giardia: in vitro viability assay under microaerophilic conditions indicates a multifactorial basis for metronidazole treatment failure
Authors: Nohynkova Eva , Perglerova Aneta , Tumova Pavla
Published: February 2025

We developed a simple 24-hour viability assay to evaluate the tolerance of the parasite Giardia intestinalis to metronidazole (MTZ) in vitro. Our findings emphasize the importance of test conditions and evaluation parameters. Using this assay with minimum lethal concentration (MLC) as an evaluation parameter, we identified two isolates that are naturally tolerant to MTZ. Natural MTZ tolerance was detected only under microaerophilic conditions, as both isolates were susceptible to MTZ under anaerobic conditions. These isolates were derived from stool samples of patients with MTZ-refractory giardiasis, suggesting that the parasite tolerance was responsible for the failure of MTZ treatment. However, two other isolates from patients with MTZ-refractory giardiasis were susceptible under both test conditions, indicating that MTZ-refractory giardiasis likely has a multifactorial cause.
“The injection gives freedom” - An exploration of long-acting injectable HIV treatment acceptance among patients seeking care in two Nairobi tertiary hospitals
Authors: Nyukuri Duncan , Shah Reena Chhotalal , Mbithi Annastacia , Abongo Melanie , Kundu Christine , Mutai Keneth
Published: February 2025

Background Long-acting injectable antiretroviral therapy offers an alternative to daily oral HIV treatment, potentially improving adherence and reducing stigma. While its adoption has been successful in some settings, little is known about its acceptability among people living with HIV in Kenya. This study evaluates the acceptability, barriers, and facilitators of long-acting injectable antiretroviral therapy among people living with HIV in Nairobi, Kenya. Methods We conducted a mixed-methods study involving 356 people living with HIV receiving care at Kenyatta National Hospital and Aga Khan University Hospital. Quantitative data were collected through structured surveys, while qualitative insights were obtained from three focus group discussions. Descriptive and inferential statistical analyses were performed on survey data, and thematic analysis was applied to focus group discussions transcripts. Results Overall, 72.2% of participants expressed willingness to switch to long-acting injectable antiretroviral therapy Interest in long-acting injectable antiretroviral therapy was significantly associated with prior knowledge (93.9% vs 80.2%, p < 0.001) and more likely among women ((93.5% vs. 83.9%, p = 0.009). Key facilitators included the opportunity to stop taking daily pills (71.3%), improved adherence (50.3%) and reduced daily focus on HIV (44.7%).  The most frequently cited barriers were fear of side effects (69.7%), needle phobia (32.3%), and distrust in new treatments (20.2%). focus group discussions revealed interest about long-acting injectable antiretroviral therapy’s potential to reduce stigma and improve adherence, but also concerns about side effects, access, and the need for robust support systems. Conclusion People living with HIV in the participating hospitals in Nairobi showed strong interest in long-acting injectable antiretroviral therapy, driven by its potential to improve adherence and reduce stigma. However, concerns about side effects, injections, and access must be addressed. Targeted education, provider training, and healthcare support are crucial for successful implementation.
Genetic Regulation of the Metabolome Differs by Sex, Alzheimer’s Disease Stage, and Plasma Biomarker Status
Authors: Eissman Jaclyn M. , Qiao Min , Kalia Vrinda , Zerlin-Esteves Marielba , Reyes-Dumeyer Dolly , Piriz Angel , Dubey Saurabh , Nandakumar Renu , Lee Annie J. , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Honig Lawrence S. , Dalgard Clifton L. , Miller Gary W , Mayeux Richard , Vardarajan Badri N.
Published: February 2025

We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer’s disease (AD). We computed metabolite quantitative trait loci by using whole genome sequencing and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6,881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. We identified 72 novel and known SNP-metabolite associations spanning 66 genes and 12 metabolite classes, includingPYROXD2and N6-methyllysine,FAAHand myristoylglycine, as well asFADS2and arachidonic acid. In addition, we found differences in genetic regulation of metabolites among individuals with clinically defined AD compared to AD defined by a published plasma P-tau181 level cut-off. We also found more SNP-metabolite associations among males compared to females. In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites and unique biological mechanisms of genetic perturbations in AD.
A Novel Method to Disentangle Tightly Linked Risk and Resilience Genes for Brain Disorders: Application to Alzheimer’s Disease
Authors: Barnett Eric J , Hess Jonathan L , Hou Jiahui , Escott-Price Valentina , Fennema-Notestine Christine , Kremen William , Lin Shu-Ju , Zhang Chunling , Gaiteri Chris , Elman Jeremy , Holmans Peter , Faraone Stephen V , Glatt Stephen J
Published: February 2025

Background

Genetic risk factors for psychiatric and neurodegenerative disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly for brain disorders, where genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk.

Methods

We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while “unlearning” patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer’s disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS).

Results

In simulations, our model had high specificity and moderate sensitivity in identifying resilience markers, outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in risk/resilience interactions.

Conclusions

Our methods of modeling and evaluation of feature-importance successfully identified resilience markers that were obscured in previous work. The high specificity of our model provides high confidence that these markers reflect resilience and not simply low risk. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other complex brain disorders.
Contemporary Resource Utilization and Costs among Patients with Medically Managed Severe Aortic Stenosis: Results from a US National Claims Database
Authors: Vohra Adam S , Murphy Shannon M. E. , Thompson Christin Ann , Cohen David J.
Published: February 2025

Background: Patients with severe aortic stenosis (AS) who are managed medically have a poor prognosis. No contemporary studies have examined the costs and resource utilization associated with medical management for severe AS. Methods: We used data from the Optum Market Clarity Database, which links electronic health records (EHR) with claims cost and utilization data, to identify patients with documented severe AS between 2016 and 2020 who did not undergo aortic valve replacement (AVR) within one year following diagnosis. To adjust for comorbidities that may have influenced treatment decisions, medically managed patients were matched 1:1 with similar patients who underwent AVR. Outcomes included healthcare resource utilization and costs during the 4-year period following the initial diagnosis of severe AS. Unadjusted Fine and Gray competing risk models were used to estimate resource utilization, and the Bang/Tsiatis method was used to quantify utilization and cost outcomes while accounting for censoring. Results: Over the study period, 6,892 patients presented with newly diagnosed severe AS, of which 3334 (48%) were managed medically and 2812 (41%) were able to be propensity matched with patients who underwent AVR. Over 4 years of follow-up, these patients experienced an average of 1.99 hospitalizations—1.33 of which were related to a cardiovascular condition. Total healthcare-related costs (including hospitalizations, outpatient care, and pharmacy services) were $126,638/patient, of which $56,032 were related to inpatient care, $31,603 were related to outpatient care, and $21,160 were for pharmacy services. Conclusions: In contemporary practice, despite the availability of effective treatment, many patients with documented severe AS do not undergo AVR within the first year after diagnosis. These patients with severe AS who are managed medically experience high health-care related resource utilization and costs. Further research is needed to identify factors associated with lack of timely valve replacement and to address barriers to care for these patients.
Theoretical Analysis of Power-Law Stress Relaxation and Calcium-Dependent Passive Mechanics in Cardiac Muscle
Authors: Ježek Filip , Baker Anthony J , Nordsletten David A , Beard Daniel A
Published: February 2025

This study investigates the passive viscoelastic mechanical properties of cardiac muscle by introducing a theoretical model that explains the power-law kinetics of passive stress decay. The model accounts for two parallel processes contributing to passive mechanics: an elastic component and a viscoelastic component designed to simulate stress/strain-mediated unfolding of serial domains in the titin molecule. Under stress, serial globular domains within the elastic region of the titin molecule reversibly unfold. This unfolding phenomenon contributes to both hysteresis (a lag in stress between loading and unloading) and preconditioning effects in simulated striated muscle mechanics. Moreover, experimental evidence indicates that stress relaxation in cardiac muscle follows a power law, and that the muscle's nonlinear stress-strain relationship and hysteresis behavior are calcium-dependent. To analyze these mechanical phenomena, we simulate the apparent viscous element as a mesoscopic-scale ensemble of chains, each composed of serial globular domains that unfold in a stress-dependent manner. Although the model was developed to represent the behavior of titin, it equivalently represents any contributing process involving a linked series of domains that undergo stress-mediated unfolding. By providing a unified basis for the observed viscoelastic and preconditioning effects, calcium dependency, and power-law stress relaxation phenomena, this study offers a novel theoretical basis for understanding and simulating the role of titin in striated muscle mechanics.
Sexual conflict over mating duration and frequency in Zygogramma bicolorata
Authors: Pal Rabi Sankar , Bhowmick Anirban , Nandy Bodhisatta
Published: February 2025

Duration and frequency of mating are the most prominent aspects of mating behaviour over which sexual conflict can occur. Parthenium beetle (Zygogramma bicolorata) exhibits an extremely high mating rate, with each mating typically lasting several hours. We investigated mating behaviour in this beetle to assess if there is sexual conflict. Theories of sexual conflict predict that such mating behaviour, while being beneficial to the males, should be detrimental to the females with regard to reproduction and/or survival. We experimentally manipulated the length and number of matings, and examined the effect on fecundity and survivorship of the females. While long mating has previously been identified as a mate-guarding strategy that benefits the males, our data reveal that it is detrimental to female fitness, supporting the sexual conflict hypothesis. Further, we checked natural variation in mating duration and its correlation with key fitness components. Our results show that female longevity is negatively correlated to reproductive rate, but positively correlated to lifetime reproduction. We argue that such a pattern is consistent with sexual conflict. While being the first clear demonstration of sexual conflict in this species, we discuss its significance, including a potential role in reducing its efficacy as a biocontrol.
Accuracy of preferred language data in a multi-hospital electronic health record in Toronto, Canada
Authors: Ford Camron D , Bodley Thomas , Betts Martin , Fowler Rob A , Gordon Alexis , James Michele , Rawal Shail , Reppas-Rindlisbacher Christina , Tam Paul , Tomlinson George , Yarnell Christopher J
Published: February 2025

Background: Accurate preferred language data is a prerequisite for providing high-quality care. We investigated the accuracy of preferred language data in the electronic health record (EHR) of a large community hospital network in Toronto, Canada. Methods: We conducted a point-prevalence audit of patients admitted to intensive care, internal medicine, and nephrology services at three hospitals. We asked each patient 'What is your preferred language for health care communication?' and reported on agreement (with 95% confidence intervals [CI]) between interview-based and EHR-based preferred language. We used Bayesian multilevel logistic regression to analyze the association between patient factors and the accuracy of the EHR for patients who preferred a non-English language. Results: Between June 17, 2024, and July 19, 2024, we interviewed 323 patients, of whom 124 (38%) preferred a non-English language. Median age was 77 years and 46% were female. EHR accuracy was 86% for all patients. The probability of the EHR correctly identifying a patient with non-English preferred language (sensitivity) was 69% (CI 60 to 77), specificity was 97% (CI 94 to 99), positive predictive value was 95% (CI 88 to 98), and negative predictive value was 83% (CI 79 to 87). There were 26 different non-English preferred languages, most commonly Cantonese (27%) and Tamil (14%). Accuracy was better for patients who were female or older, and varied by hospital and medical service. Conclusions: In this multi-hospital point-prevalence audit, the EHR accurately captured language preference for 86% of all patients and 69% of patients who preferred a non-English language.
Livestock-related deaths in Great Britain (2010-2023)
Authors: Chartres Anna , Oultram Jo WH , Royden Alex , Shanks Sarah , Tulloch John S P
Published: February 2025

Objectives: This study aimed to describe the incidence, demographics, and context of livestock related deaths 2010 to 2023. Study design: A descriptive analysis of the Health and Safety Executives Fatal injuries in agriculture, forestry and fishing in Great Britain annual reports. Methods: Annual incidence of death was calculated. Demographic and contextual information were extracted, and data stratified by whether the victim was a farmer or member of the public. Statistical comparisons were made using Chi2 tests, Fishers exact test, and Mann Witney U Tests, where appropriate. Results: Out of 78 livestock-related fatalities, 97% were caused by domestic cattle and 74.3% were farmers. Median age of all fatalities was 67 (range:29-87), and 63.4% were alone at the point of injury. Farmers were predominantly male and tended to be working with individual animals, often in a contained space. All members of the public were killed in fields and 84.2% had a dog present with them. They were 250 times more likely to have a dog present than farmers (OR=250, p<0.001). A calf or per-parturient cow was more likely to be present when a member of the public was killed (OR=4.3, p<0.01). Conclusions: Cattle-related incidents are a concern and further research is required to enable the development and implementation of effective safety interventions. We recommend that a database of livestock-related injuries is created, measures are introduced so farmers can easily temporarily divert public rights of way, and educational programmes for farmers and the public are developed.
Understanding the Utility of State-Based Haptic Feedback in Tendon-driven Anthropomorphic Prostheses
Authors: Velasquez Lorena Isabel , Brown Jeremy Delaine
Published: February 2025

Haptic feedback has demonstrated utility in traditional prosthetic devices, however, it is unclear to what extent haptic feedback improves functionality in an anthropomorphic agonist/antagonist tendon-actuated design. We investigate the impact of state-based haptic feedback in an agonist/antagonist tendon-driven anthropomorphic prosthesis by proportionally mapping haptic sensations of the tension in the tendons during actuation. N=24 participants without limb loss were recruited to perform a grasp and transfer task using a mock prosthesis across three conditions: no haptic feedback, skin stretch feedback, and vibrotactile feedback. We hypothesized that haptic feedback of tendon tension would improve task performance and that skin-stretch feedback would outperform the vibrotactile condition due to the modality-matched similarities of tension and stretch. Results highlight that vibrotactile feedback resulted in significantly more object transfers than skin stretch feedback or no feedback. However, skin stretch feedback had a significantly higher transfer efficiency than vibrotactile feedback, demonstrating that different haptic modalities uniquely affect task performance. This study is the first to demonstrate that feedback of tendon tension in a tendon-driven prosthesis has significant utility and improves task performance. It establishes a need for further exploration of haptic integration in tendon-actuated systems given their support for limb impedance modulation.
Ecological relationships between human gut bacteria predicted from analysis of dense microbiome time series data from US travelers in Bangladesh
Authors: Martin Casey G , Lyon Laurie M , Gonzalez Antonio , Knight Rob , Lozupone Catherine
Published: February 2025

Gut microbiomes provide critical host homeostatic functions, resulting from a complex web of ecological interactions among community members. We studied these interactions using a time-lagged correlational strategy of dense longitudinal sequence data from Western individuals traveling abroad to Bangladesh who experienced diarrhea. We identified both negative (140) and positive (78) relationships between bacterial pairs. Positive relationships occurred in pairs that were significantly more phylogenetically distant, such as inter-order associations between Clostridiales and Bacteroidales, while negative relationships were more between more phylogenetically related pairs. Further analysis of computationally predicted genome content and metabolic pathways revealed that cooperative bacterial pairs overlapped less in function and offered each other metabolic support, while competitive pairs were more likely to compete for the same resources. Predicted levels of B vitamins (B5 and B3), enoyl acyl-carrier protein (acp) reductase II (FabK) and its metabolites, and nucleotide/nucleoside derivatives were able to differentiate negatively and positively associated microbe pairs. Ultimately, our findings show that combining time-series analysis with metabolic/genomic network analysis can identify relationships between bacteria with plausible causal mechanisms that are consistent with existing ecological and biochemical observations.
Substantial contribution of in-situ produced bacterial lipids to the sedimentary lipidome
Authors: Ding Su , Bale Nicole J , Cutmore Anna , von Meijenfeldt F. A. Bastiaan , Schouten Stefan , Sinninghe Damste Jaap
Published: February 2025

The sedimentary lipid pool is comprised of a myriad of individual components. Due to their importance for organic carbon sequestration and their application in paleoclimatic and geobiological reconstructions, its composition has been studied for many decades with targeted approaches but an overall view on its composition is still lacking. In part this uncertainty relates to the different sources of sedimentary lipids, they can be both delivered from the overlying water column by sedimentation, but also produced in-situ by sediment dwelling organisms. Another uncertainty relates to the differing degree of preservation, both between lipid groups and relative to other organic matters. Here we conduct an untargeted analysis of the sedimentary lipidome in the Black Sea using high resolution mass spectrometry. Besides commonly reported phytoplankton derived fossil lipids, a diverse and abundant set of sphingolipids was discovered, accounting for 20% of the sedimentary lipidome. These sphingolipids are produced in situ by sedimentary anaerobic bacteria, which probably used sphingolipids instead of phospholipids, likely because of the deficiency of phosphate in the anoxic sediments. Our results suggest that while phytoplankton derived lipids contribute 50 to 60% of the sedimentary lipidome, the importance of bacterial lipids, particularly in situ produced sphingolipids, may have been overlooked.
Genomic factors limiting the diversity of Saccharomycotina plant pathogens
Authors: Lee Sun Kyu , West Caroline , Opulente Dana A , Harrison Marie-Claire , Wolters John F , Shen Xing-xing , Zhou Xiaofan , Groenewald Marizeth , Hittinger Chris Todd , Rokas Antonis , LaBella Abigail Leavitt
Published: February 2025

The Saccharomycotina fungi have evolved to inhabit a vast diversity of habitats over their 400-million-year evolution. There are, however, only a few known fungal pathogens of plants in this subphylum, primarily belonging to the genera Eremothecium and Geotrichum. We compared the genomes of 12 plant-pathogenic Saccharomycotina strains to 360 plant-associated strains to identify features unique to the phytopathogens. Characterization of the oxylipin synthesis genes, a compound believed to be involved in Eremothecium pathogenicity, did not reveal any differences in gene presence within or between the plant-pathogenic and plant-associated strains. A reverse-ecological approach, however, revealed that plant pathogens lack several metabolic enzymes known to assist other phytopathogens in overcoming plant defenses. This includes L-rhamnose metabolism, formamidase and nitrilase genes. This result suggests that the Saccharomycotina plant pathogens are limited to infecting ripening fruits as they are without the necessary enzymes to degrade common phytohormones and secondary metabolites produced by plants.
Nutritional regulation of cellular quiescence depth and cell cycle re-entry in Vasa2+/Piwi1+ cells in a sea anemone
Authors: Pascual-Carreras Eudald , Garschall Kathrin , Steinmetz Patrick R.H.
Published: February 2025

Animals with lifelong growth adjust their growth rates to nutrient availability, yet the underlying cellular and molecular mechanisms remain poorly understood. Here, we studied how food supply and TOR signalling regulate the cell cycle in a multipotent, Vasa2-/Piwi1-expressing cell population in the sea anemoneNematostella vectensis. We discovered that starvation induces a reversible G1/G0cell cycle arrest in Vasa2+/Piwi1+ cells and that cell cycle re-entry upon refeeding is dependent on TOR signalling. In addition, the length of the refeeding stimulus after starvation determines the proportion of cells that re-enter S-phase. Remarkably, prolonged starvation delayed both refeeding-induced TOR signalling activation and S-phase re-entry. This strongly suggests thatNematostellaVasa2+/Piwi1+ cells undergo starvation-controlled quiescence deepening, previously described only in unicellular eukaryotes and mammalian cell culture. The nutritional control of quiescence and cell proliferation may thus be a fundamental, evolutionarily conserved strategy underlying the environmental regulation of indeterminate growth in animals.
From genetic disposition to academic achievement: The mediating role of non-cognitive skills across development
Authors: Zhou Quan , Liao Wangjingyi , Allegrini Andrea , Rimfeld Kaili , Wertz Jasmin , Morris Tim , Raffington Laurel , Plomin Robert , Malanchini Margherita
Published: February 2025

Genetic effects on academic achievement are likely to capture environmental, developmental, and psychological processes. How these processes contribute to translating genetic dispositions into observed academic achievement remains critically under-investigated. Here, we examined the role of non-cognitive skills (e.g., motivation, attitudes and self-regulation) in mediating education-associated genetic effects on academic achievement across development. Data were collected from 5,016 children enrolled in the Twins Early Development Study at ages 7, 9, 12, and 16, as well as their parents and teachers. We found that non-cognitive skills mediated polygenic score effects on academic achievement across development, and longitudinally, accounting for up to 64% of the total effects. Within-family analyses highlighted the contribution of non-cognitive skills beyond genetic, environmental and demographic factors that are shared between siblings, accounting for up to 83% of the total mediation effect, likely reflecting evocative/active gene-environment correlation. Our results underscore the role of non-cognitive skills in academic development in how children evoke and select experiences that align with their genetic propensity.
The response of ETV6-NTRK3 condensates to TRK inhibitors elucidates their precise phase separation mechanism
Authors: Li Huan , Zhu Tianxin , Zhu Guangya , Xie Jingjing
Published: February 2025

NTRK fusion oncoproteins are considered to mediate oncogenesis in multiple rare cancers. These fusion oncoproteins form cytoplasmic kinase condensates to hyper-activate downstream signaling pathways. However, their responses to TRK inhibitors have not been investigated. Here we show that TRK inhibitors induce a quantity increasement and liquid-to-solid transition of ETV6-NTRK3 condensates. During this process, the ETV6-NTRK3 condensates undergo rapid dissolution and subsequent reemergence, with entirely altered components. We proposed a novel phase separation model for ETV6-NTRK3 that both ETV6 and NTRK3 fragments contribute to the condensate's formation. These findings refresh the understanding of the phase separation mechanism of NTRK fusion proteins and provide basis for phenotype-based TRK inhibitor screening strategy.
Microelectrode array scaled for recording human hippocampal slices
Authors: Pelkonen Anssi , Lezhneva Vera , Ryynanen Tomi , Kreutzer Joose , Sitnikova Valeriia , Gomez-Budia Mireia , Della Pietra Adriana , Dougalis Antonios , Kyyriainen Jenni , Torkamani-Azar Mastaneh , Eronen Henri , Rauramaa Tuomas , Immonen Arto , Leinonen Ville , Sierra Alejandra , Kalviainen Reetta , Malm Tarja
Published: February 2025

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder characterized by recurrent seizures originating from the cortex, amygdala and especially hippocampus. While two-thirds of TLE patients achieve seizure control through medication, approximately one-third remain refractory to pharmacological interventions. For these individuals, surgical resection offers a potential curative option, with approximately 70% achieving seizure freedom. However, the pathogenesis of TLE remains incompletely understood, necessitating further investigation. Therefore, resected brain tissue obtained during the surgery provides a valuable resource for ex vivo study of pathological neuronal activity. Currently, microelectrode array (MEA) technology is widely used for electrophysiological studies. However, commercially available MEAs are limited in their ability to record from large tissue samples, such as an entire hippocampal section. To address this limitation, we have developed a custom MEA and sample chamber compatible with commercially available headstages. This system enables recording of extracellular action potentials (EAPs) and local field potentials (LFPs) across human hippocampal tissue, providing a valuable tool for investigating the neurophysiological mechanisms underlying TLE.
Predictive Coding Explains Asymmetric Connectivity in the Brain: A Neural Network Study
Authors: Niemeier Matthias , Khan Romesa , Zhong Hongsheng , Das Shuvam , Cai Jack
Published: February 2025

Seminal frameworks of predictive coding propose a hierarchy of generative modules, each attempting to infer the neural representation of the module one level below; the predictions are carried by top-down feedback projections, while the predictive error is propagated by reciprocal forward pathways. Such symmetric feedback connections support visual processing of noisy stimuli in computational models. However, neurophysiological studies have yielded evidence of asymmetric cortical feedback connections. We investigated the contribution of neural feedback during sensorimotor processes, in particular visual processing during grasp planning, by utilizing convolutional neural network models that had been augmented with predictive feedback and were trained to compute grasp positions for real-world objects. After establishing an ameliorative effect of symmetric feedback on grasp detection performance when evaluated on noisy stimuli, we characterized the performance effects of asymmetric feedback, similar to that observed in the cortex. Specifically, we tested model variants extended with short-, medium- and long-range feedback connections (i) originating at the same source layer or (ii) terminating at the same target layer. We found that the performance-enhancing effect of predictive coding under adverse conditions was optimal for medium-range asymmetric feedback. Moreover, this effect was most prominent when medium-range feedback originated at a level of representational abstraction that was proximal to the input layer, in contrast to more distal layers. To conclude, our simulations show that introducing biologically realistic asymmetric predictive feedback improves model robustness to noisy visual stimuli in a neural network model optimized for grasp detection.
Secreting salt glands constrain cuticle fracture to enhance desalination efficiency
Authors: Mai Melissa H , Rockwell Fulton E , Losada Juan M , Nicholson Nya , Suo Zhigang , Holbrook N. Michele
Published: February 2025

Plants responding to excessive soil salinity by discharging brine onto their leaf surface risk dehydration through the osmotic continuity between the living tissue and the surface brine, which further enriches with evaporation. Cuticle cracks have long been identified as essential for salt to reach the leaf surface but provide the potentially desiccating continuity between the brine and the gland interior. Using the secreting salt gland ofNolana mollisas a model system, we integrate mathematical modeling, imaging, and physiological measurements to examine the mechanical and biochemical processes required for efficient desalination. We find that the subcuticular space between the concentrated surface brine and the more dilute secreting cell eases the energetic limits of active desalination by reducing the concentration gradient of salt across the cell membrane. We show that crack size plays a critical role in balancing the osmotic and pressure gradients required for salt removal without runaway foliar desiccation.
Identification of chemical features that influence mycomembrane permeation and antitubercular activity
Authors: Lepori Irene , Liu Zichen , Evbarunegbe Nelson , Feng Shasha , Brown Turner P. , Mane Kishor , Shivangi fnu , Wong Mitchell , George Amir , Guo Taijie , Dong Jiajia , Freundlich Joel S. , Im Wonpil , Green Anna G. , Pires Marcos M. , Siegrist M. Sloan
Published: February 2025

Tuberculosis (TB), caused byMycobacterium tuberculosis(Mtb), is the deadliest single-agent infection worldwide. Current antibiotic treatment for TB takes a minimum of four months, underscoring the need for better therapeutics. The unique mycobacterial cell envelope, particularly the outermost mycomembrane, has long been thought to promote intrinsic antibiotic resistance by limiting compound entry into Mtb. Understanding chemical features that influence permeation across the mycomembrane may enable more accurate predictions of whole cell anti-Mtb activity, leading to development of more effective antibacterials. Here we query the mycomembrane permeation of over 1500 azide-tagged compounds in live Mtb with the bioorthogonal click chemistry-based assay PAC-MAN. We use cheminformatics and machine learning to identify chemical features associated with mycomembrane permeation and show that they have predictive value via systematic modification of two small molecule series. Additionally, we find that chemical features that influence mycomembrane permeation correlate with anti-Mtb activity in large compound libraries. These findings suggest that the mycomembrane is indeed a significant barrier to whole cell activity in Mtb and provide a rational framework for designing or modifying compounds to overcome this barrier.
Limited diversity of bat-associated RNA viruses in endangered and geographically isolated Christmas Island flying foxes
Authors: Ortiz-Baez Ayda Susana , Rose Karrie , Lang Bethan J , Hall Jane , Holmes Edward C
Published: February 2025

Bats are commonly thought to harbour a high diversity and abundance of RNA viruses, some of which are able to jump species boundaries to emerge in new hosts. However, gaps remain in our understanding of the ecological factors that shape the bat virome and influence the diversity, circulation and persistence of viral infections. Flying foxes (Pteropodidae) are representative of the chiropteran fauna in Australia, holding significant ecological, cultural, and social importance. However, some species have also been linked to the circulation of mammalian pathogens such as Hendra virus and Australian bat lyssavirus. Here, we characterised the virome of the Christmas Island flying fox (Pteropus melanotus natalis), an endemic and endangered species only found on the remote Australian territory of Christmas Island. Through metatranscriptomic sequencing of 46 samples, including faeces, blood, urine and tissue lesions, we found that these bats exhibit limited RNA virus diversity dominated by dietary viruses. The paucity of RNA viruses likely results from their small population size (between 1500 and 2600 individuals) and the virtual geographic isolation from other bat and mammalian species, except for pests and humans. However, we identified a novel alphacoronavirus in urine, related to viruses circulating in microbats in mainland Australia, and a picorna-like virus related to picornaviruses found in invertebrates. Although this novel picorna-like virus may be of a dietary origin, these flying foxes predominantly eat nectar, pollen and fruit, and viral RNA was also present in blood, urine and wing lesion samples, such that a broader tropism cannot be excluded. Overall, these data reveal how ecological factors have a profound impact on RNA virome diversity, highlighting risks to bat conservation, and showing that bats are not always persistent reservoirs for zoonotic viruses.
Fluoride triggers lysis in Streptococcus mutans by inhibition of Clp protease complex leading to an unabated competence cascade
Authors: Banerjee Aditya , Pickelner Sophie , Smith Faith , Tenuta Livia M.A. , Stockbridge Randy B
Published: February 2025

Fluoride has long been known to possess antimicrobial properties, triggering extensive lysis in diverse bacterial species. Surprisingly, given the ubiquity of fluoride in oral healthcare, the underlying mechanisms by which fluoride kills bacteria remain unknown. Using dental pathogen Streptococcus mutans as a model, we show that fluoride elicits an uncontrolled stress response characterized by upregulation of competence pathways and extensive cell wall degradation. While limited autolysis is adaptive, we show that fluoride subverts the typical tight temporal control of the competence-associated alternative sigma factor ComX by specifically inhibiting assembly and activity of Clp ATPases, thus disrupting proteolytic degradation of ComX. Phenylalanine partially restores Clp protease activity, explaining the frequent presence of a gene encoding chorismate mutase in fluoride-responsive operons. Together, these findings reveal the molecular mechanism that underlie fluoride-dependent lysis in bacteria, and identify new pathways that could be exploited to potentiate the antimicrobial effects of oral fluoride.
Long-range translational order and hyperuniformity in two-dimensional chiral active crystal
Authors: Kuroda Yuta , Kawasaki Takeshi , Miyazaki Kunimasa
Published: February 2025

We numerically study two-dimensional athermal chiral active particles at high densities. The particles in this system perform the circular motion with frequency Ω. We show that the system crystallizes at high densities even in two dimensions, accompanied by the true long-range translational order. This is due to the anomalous suppression of displacement fluctuations associated with hyperuniformity. These findings can be explained using an active elastic theory quantitatively. Surprisingly, the crystals become unstable and melt in the limit of Ω=0, for the spatial dimension of four or less. This result can be explained by a mechanism akin to quenched random systems for which the lower critical dimension is four.

Published by the American Physical Society
2025