bluuebunny/crossref_metadata_2025 huggingface dataset:
A micro-costing of latent tuberculosis infection testing and treatment in adults in secondary care in England
Authors: Snoad Laura , Vesga Juan , Lipman Marc , Dedicoat Martin , Gupta Rishi K , Abubakar Ibrahim , Dart Susan , Gorsuch Thomas , Kunst Heinke , Mungall Sarah , Noonan Ryan , White Peter J
Published: February 2025

Background

Latent TB infection (LTBI) screening and treatment of population groups at high risk for TB is part of England’s Tuberculosis Action Plan, which has succeeded in increasing testing volumes. However, analysis of the cost-effectiveness is hampered by a lack of detailed information on health service costs.

Methods

We surveyed clinics with large volumes of activity, located in the London, West Midlands, South East & South West, and North West England TB Control Board areas. These represent three-quarters of England’s TB diagnoses. We mapped clinical pathways and determined costs of staff time, testing, and drugs.

Results

The clinics use interferon gamma release assays (IGRAs) (Quantiferon-TB Gold Plus, T-SPOT.TB, or both) for LTBI testing, and the most common outcomes of the testing pathways are asymptomatic patients testing negative (costing £64.11 per patient, range: £49.08-£81.02) or positive (costing £142.86(£120.95-£174.68)). Symptomatic patients, testing positive or negative, have higher costs (£124.35(£101.29-£138.23)). The estimated cost per patient diagnosed with LTBI is £458.32(£362.49-£571.47). Treatment costs depend on the regimen and the amount of monitoring the patient requires, e.g. 3 months daily Isoniazid and Rifampicin costs £192.86(£140.43-£255.32) for most patients, and £238.62(£157.47-£346.03) for those requiring more monitoring. 6 months daily Isoniazid costs £407.71(£342.56-£474.25). 4 months daily Rifampicin costs £226.98(£190.16-£270.73). One clinic uses 3 months of weekly Isoniazid and Rifapentine for some patients, costing £559.05.

Discussion

These are the first detailed cost estimates of latent TB screening and treatment, and will enable improved assessment of cost-effectiveness, and allocation of resources.
Beyond contacts: the important role of the support region to distinguish stable and transient protein interfaces
Authors: Miclot Tom , Timr Stepan
Published: February 2025

Protein-protein interactions (PPIs) are fundamental to virtually all cellular processes; however, elucidating the principles that govern protein association into complexes remains a significant challenge. In this study, we present a comparative analysis of stable and transient protein interfaces, offering a detailed perspective on the interactions that form them. Moving beyond the traditional focus on pairs of neighboring residues, we examine interacting pairs by identifying their distinct non-bonded interactions. Additionally, we account for the contextual dependence of these interactions by analyzing the regions of the interface where they occur. Our approach quantifies the diversity of pairs in each region, considering the type of interface. Furthermore, we introduce an innovative strategy to analyze pair co-occurrence, enabling a comparison of the inner local organization of stable and transient interfaces. Our findings reveal that stable and transient interfaces differ not in overall residue composition, but in the residue- and interaction-partitioning patterns across the variably hydrated regions of the interface. These results underscore the importance of considering the contextual environment in which pairs interact and identify the support region as a key determinant for distinguishing transient and stable protein complexes. The software package developed for this analysis is available as open source.
Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation
Authors: Zhang Luojia , Gordiyenko Yuliya , Morgan Tomos , Franco Catarina , Vidaković Ana Tufegdžić , Zhang Suyang
Published: February 2025

During productive transcription elongation, the speed of RNA polymerase II (Pol II) is highly dynamic within individual genes and varies between different genes1,2. Unregulated rapid transcription elongation can lead to detrimental consequences such as transcription-replication collisions, altered alternative splicing patterns, and genome instability1–7. Therefore, elongating Pol II requires mechanisms to slow its progression, yet the molecular basis of transcription braking remains unclear. RECQL5 is a DNA helicase that functions as a general elongation factor by slowing down Pol II8–11. Here we report cryo-electron microscopy (cryo-EM) structures of human RECQL5 bound to multiple transcription elongation complexes. Combined with biochemical analysis, we identify an α-helix of RECQL5 responsible for Pol II binding and slowdown of transcription elongation. We further reveal that the transcription-coupled DNA repair (TCR) complex allows Pol II to overcome RECQL5-induced transcription braking through concerted actions of its translocase activity and competition with RECQL5 for engaging Pol II. Additionally, RECQL5 inhibits TCR-mediated Pol II ubiquitination to prevent activation of the DNA repair pathway. Our results suggest a model in which RECQL5 and the TCR complex coordinately regulate the transcription elongation rate to ensure transcription efficiency while maintaining genome stability. This work provides a framework for future studies on the regulatory role of elongation speed in gene expression.
Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance
Authors: Qi XiaoYan , Xiong Feng , Xiao Jiening , Muthukumarasamy Kalai Mangai , Altuntas Yasemin , Zhong Yuan , Abu-Taha Issam , Bruns Florian , Tekook Marcel , Kamler Markus , Villeneuve Louis , Nozza Anna , Sirois Martin , Karch Jason , Pasdois Philippe , Bers Donald M. , Dobrev Dobromir , Nattel Stanley
Published: February 2025

BACKGROUND

Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model.

METHODS AND RESULTS

Atrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca2+-concentration ([Ca2+]Mito), reactive oxygen species (mtROS) production, membrane potential (ΔΨm), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca2+]Mitoand mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca2+-current (ICaL)-downregulation in canine and human AF ACMsin vitro. Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca2+-overload, mtROS-overproduction, structural damage and abnormalities in ΔΨmand respiration. Functionally, mitoquinone reduced AF-induced Ca2+-current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability.

CONCLUSIONS

Mitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.
Hyaluronic acid hydrogels: Establishing a sustained delivery system for extracellular vesicles
Authors: Chabria Yashna , O’Dwyer Joanne , McDermott Emma , Owens Peter , Lowery Aoife J. , Duffy Garry P. , Dwyer Róisín M.
Published: February 2025

Extracellular vesicles (EVs) are versatile transporters of genetic cargo with enormous potential in the therapeutic setting. Scalable production of EVs, and routes to overcome rapid clearance are required. Biocompatible hydrogels may support precise, localized delivery of EVs to target sites. This study aimed to establish sustained production of EVs in a scalable 3D dynamic bioreactor and to fabricate hydrogels using tyramine-modified hyaluronic acid (HA-TA) to study EV integration and release patterns.

MDA-MB-231 cells transduced with lentiviral GFP fused with CD63, were cultured in a 20kD dynamic hollow fiber bioreactor and GFP-EVs harvested over five weeks. GFP-EVs were characterized by Nanoparticle Tracking Analysis(NTA), Western Blot(WB) and Transmission Electron Microscopy(TEM). Tyramine modified hyaluronic acid(HA-TA) hydrogels were formulated via enzymatic crosslinking using hydrogen peroxide and horseradish peroxidase, to investigate EV release patterns in static and dynamic conditions. Hydrogel swelling was recorded at 1-72 hrs and hydrogels were loaded with GFP-EVs to assess distribution and release by Scanning Electron Microscopy(SEM) and NTA respectively. GFP-EV uptake was assessed by confocal microscopy.

Longitudinal GFP expression was demonstrated in transduced cells and released EVs throughout bioreactor culture. TEM and NTA demonstrated successful isolation of EVs of 30-200 nm in size with intact lipid bilayers (average 4×109EVs/harvest). Initial harvests exhibited subpopulations of larger EVs, which disappeared upon serum withdrawal. WB verified the presence of EV markers CD63, TSG101, and CD81. HA-TA hydrogels were successfully formed and swelling assays revealed the requirement for higher concentrations of HA-TA and crosslinkers for scaffold stability and continued swelling. GFP-EVs were successfully incorporated into the hydrogels with variable release patterns observed over time, depending on EV concentration and hydrogel formulation. EV clusters in hydrogels were visualized by SEM. Investigation of GFP-EV release patterns under static and dynamic conditions highlighted a significant increase in release under fluid flow conditions. Efficient transfer of released EVs to recipient cells was also demonstratedin vitro.

The data demonstrate the potential for scalable production of engineered EVs in serum free conditions and subsequent incorporation into HA-TA hydrogels for sustained release. These biocompatible hydrogels hold promise for tuneable delivery of therapeutic EVs in a variety of disease settings.
Therapeutic Potential of PRMT1 as a Critical Survival Dependency Target in Multiple Myeloma
Authors: Hussain Tabish , Awasthi Sharad , Shahid Farid , Yi S. Stephen , Sahni Nidhi , Aldaz C Marcelo
Published: February 2025

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through post-translational modification. Dysregulation or overexpression of PRMT1 has been observed in various malignancies including MM and is linked to chemoresistance. Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines. This was accompanied by reduced levels of asymmetric dimethylation of arginine (ADMA) and increased arginine monomethylation (MMA) in MM cells. Cell cycle analysis revealed an accumulation of cells in the G0/G1 phase and a reduction in the S phase upon GSK3368715 treatment. Additionally, PRMT1 inhibition led to a significant downregulation of genes involved in cell proliferation, DNA replication, and DNA damage response (DDR), likely inducing genomic instability and impairing tumor growth. This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.
Benchmarking gene embeddings from sequence, expression, network, and text models for functional prediction tasks
Authors: Zhong Jeffrey , Li Lechuan , Dannenfelser Ruth , Yao Vicky
Published: February 2025

Abstract

Gene embeddings have emerged as transformative tools in computational biology, enabling the efficient translation of complex biological datasets into compact vector representations. This study presents a comprehensive benchmark by evaluating 38 classic and state-of-the-art gene embedding methods across a spectrum of functional prediction tasks. These embeddings, derived from data sources such as amino acid sequences, gene expression profiles, protein-protein interaction networks, and biomedical literature, are assessed for their performance in predicting individual gene attributes, paired gene interactions, and gene set relationships. Our analysis reveals that biomedical literature-based embeddings consistently excel in general predictive tasks, amino acid sequence embeddings outperform in functional and genetic interaction predictions, gene expression embeddings are particularly well-suited for disease-related tasks, and protein-protein interaction embeddings perform well in pairwise tasks. Importantly, we find that the type of training data has a greater influence on performance than the specific embedding construction method, with embedding dimensionality having only minimal impact. By elucidating the strengths and limitations of various gene embeddings, this work provides guidance for selecting and successfully leveraging gene embeddings for downstream biological prediction tasks. All associated code is available athttps://github.com/ylaboratory/gene-embedding-benchmarks.
Boosting Motor Cortex Plasticity through Respiratory Phase-Triggered Paired Associative Stimulation
Authors: Baker Stuart N , Zaaimi Boubker
Published: February 2025

Paired Associative Stimulation (PAS) has shown promise in promoting motor cortex plasticity by using transcranial magnetic stimulation (TMS) paired with peripheral nerve stimulation. However, the effectiveness of PAS is often limited by its short-lived potentiation effects. Recent research indicates that respiratory rhythms can influence cortical excitability, suggesting a potential method to enhance PAS efficacy. This study investigated the impact of synchronizing PAS with respiratory phase transitions - specifically, the transition from inspiration to expiration (I-E) and expiration to inspiration (E-I) - on motor cortical plasticity. We conducted experiments with 18 healthy volunteers (13 females, 5 males) aged 21-45 years, assessing motor-evoked potentials (MEPs) elicited by TMS applied to the left motor cortex. Participants underwent PAS sessions where paired stimuli were delivered either at I-E or E-I transitions, or at random intervals. MEPs were recorded at baseline, immediately post-PAS, and at 10, 20, and 30 minutes post-stimulation. Results showed that PAS triggered at the I-E transition significantly increased MEP amplitudes, with significant differences in MEP amplitudes at 20 minutes post-PAS between the I-E and the other conditions. This highlights the benefit of timing PAS with the I-E transition for enhanced motor cortical plasticity. These findings underscore the potential of integrating respiratory rhythms into neuromodulation techniques to improve therapeutic outcomes. Synchronizing PAS with natural respiratory phases may enhance motor recovery strategies and offers a refined approach for therapeutic interventions. This approach could be particularly relevant for stroke rehabilitation, where enhancing motor cortical plasticity is crucial for recovery.

Significance Statement

This study demonstrates that syncing brain stimulation with breathing patterns can enhance motor learning. By coordinating Paired Associative Stimulation (PAS)—a technique that stimulates sensory and motor inputs—with specific phases of the breathing cycle, we observed stronger responses in the motor cortex. This approach not only improves our understanding of brain adaptability but also offers a new way to fine-tune therapeutic techniques. For stroke patients, where regaining motor function is critical, integrating natural body rhythms into treatment could lead to more effective and personalized rehabilitation strategies.
Evaluating the Causal Impact of Immune Cells on Breast Cancer and the Mediating Role of Inflammatory Proteins through Mendelian Randomization
Authors: Guo Qianling , Yang Jiahao , Wen Ying , Zhuang Kai , Fahira Aamir , Yan Lin , Huang Zunnan
Published: February 2025

Breast cancer (BC) is a leading cause of mortality among women globally. Emerging evidence suggests that the immune system is involved in BC pathogenesis, with distinct subtypes showing unique immune responses. Inflammation correlates closely with these immune responses. However, the causal role of immune cell characteristics across BC subtypes and the mediating influence of inflammatory proteins remains unclear. We used bi-directional two-sample Mendelian Randomization (MR) to evaluate causal relationships between 731 immune traits and BC risk, including its subtypes, followed by a two-step mediation analysis with 91 inflammatory proteins. The Inverse Variance Weighted (IVW) method served as the primary analysis, supported by sensitivity and reverse MR analyses. Sixteen immune traits showed significant causal associations with BC and its subtypes, with 108 relationships potentially mediated by inflammatory proteins. Traits such as CD25 on CD24+ CD27+, CD25 on IgD- CD38dim, and HLA DR++ monocyte %monocyte acted as protective factors, while CD40 on CD14-CD16+ monocytes posed risks. Notably, CD40L receptor levels mediated up to 73% of the relationship between IgD- CD27-%B cells and ER+BC. Sensitivity analyses indicated no horizontal pleiotropy or reverse causality. This study underscores immune cells’ potential role in BC risk and the mediating impact of inflammatory proteins across subtypes. Targeting specific inflammatory proteins may offer novel strategies for BC risk reduction, informing clinical decision-making and therapeutic development.
Quantitative observational evidence of indirect herd benefits from COVID-19 vaccination or prior infection on SARS-CoV-2 infections and COVID-19 deaths: a population-based retrospective cohort study in Ontario, Canada
Authors: Wang Linwei , Swayze Sarah , Siddiqi Arjumand , Baral Stefan D. , Sander Beate , Sbihi Hind , Kwong Jeffrey C. , Mishra Sharmistha
Published: February 2025

Background

Empirical evidence on the indirect herd benefits of COVID-19 vaccination and/or prior infection is limited. We aimed to examine how area-level immunity interacts with individual-level immunity to affect COVID-19 diagnoses and deaths.

Methods

Ontario residents aged ≥18 years were followed from August-01-2021 to January-30-2022. Individual-level immunity was defined as received a primary series of COVID-19 vaccines or a positive SARS-CoV-2 test in the past 165 days. Area-level immunity was determined based on the proportion of immune individuals in an individual’s residing area. We used logistic regression and cause-specific hazard models to examine the relationship between immunity and COVID-19 diagnosis, and between immunity and COVID-19 death, respectively. We included an interaction term between individual-level and area-level immunity in each model.

Results

Of 11,122,816 adults, 7,518,015 (67.6%) were immune at baseline. After accounting for individual-level demographics, baseline health, and area-level social determinants of health, area-level immunity (highest vs. lowest quintiles) was associated with lower odds of COVID-19 diagnosis; the association was larger among non-immune (odds ratios [95% confidence interval]: 0.72 [0.70, 0.75]) than immune individuals (0.93 [0.90, 0.96]). Higher area-level immunity (highest vs. lowest quintiles) was also associated with lower hazard of COVID-19 death among non-immune individuals (hazard ratio: 0.77 [0.60, 1.00]).

Conclusions

Our study provides observational evidence supporting the herd benefits of vaccination or prior infection on SARS-CoV-2 infections and COVID-19 deaths. Findings reinforce the need for high vaccination coverage to protect vaccinated and unvaccinated populations, while providing insights for interpreting vaccine effectiveness estimates in the context of herd immunity.

Main points

Using area-level immunity coverage as a proxy for herd immunity, our study demonstrates observational evidence of indirect herd benefits from vaccination and/or prior infection on SARS-CoV-2 infections and COVID-19 deaths. Moreover, herd benefits are greater among non-immune individuals.
Prevalence and correlates of contraceptive use among parenting adolescents: results from a cross-sectional survey in Ouagadougou, Burkina Faso, and Blantyre, Malawi
Authors: Otukpa Emmanuel Oloche , Munthali Alister , Sawadogo Nathalie , Ushie Boniface Ayanbekongshie , Ajayi Anthony Idowu
Published: February 2025

Background

Contraceptive use among sexually active adolescent mothers can prevent repeat pregnancy with positive implications for their health, education, and economic prospects. Few studies have examined the prevalence and correlates of contraceptive uptake among adolescent mothers in sub-Saharan Africa. Our study examines contraceptive use, its correlates, and reasons for non-use of contraception among adolescent mothers (aged 12-19) in Ouagadougou, Burkina Faso and Blantyre, Malawi.

Methodology

The data analyzed for this study were part of a larger cross-sectional survey on the lived experiences of pregnant and parenting girls. For this study, we limited our analysis to 628 (Ouagadougou) and 500 (Blantyre) adolescent mothers who were neither pregnant nor trying to get pregnant. We randomly selected urban and rural enumeration areas (EAs) in the study settings, conducted household listing, and identified eligible participants whom we interviewed. We used interviewer-administered questionnaires to obtain information on contraceptive awareness, use, and reason for non-use and analyzed the data using descriptive and inferential statistics.

Results

Knowledge of contraceptive methods is nearly universal among parenting girls, and the contraceptive prevalence was higher than the national average in both study settings. Single adolescent mothers were significantly less likely to be currently using any contraceptive methods (AOR: 0.75; 95% CI: 0.61-0.93 in Burkina Faso vs. AOR: 0.60; 95% CI: 0.50-0.71 in Malawi) or any modern methods (AOR: 0.66; 95% CI: 0.49-0.90 in Burkina Faso vs. AOR: 0.55; 95% CI: 0.46-0.66 in Malawi) compared to their married counterparts in both countries. Adolescent mothers aged 19 were more likely to be current users of any contraceptives compared to those aged 16 or younger in Burkina Faso (AOR: 1.55; 95% CI: 1.07-2.26) and were also more likely to have ever used any methods in Malawi (AOR: 1.28; 95% CI: 1.07-1.53). Infrequent sex (Malawi, 64.9%; Burkina |Faso, 36.6%) was the main reason for contraceptive non-use though fear of side-effects (17.7%) and religious prohibition (16.6%) also stood out.

Conclusion

A substantial proportion of adolescent mothers, especially single and younger adolescents, are not using any contraceptive methods or relying on less effective methods. These results underscore the need for more interventions targeting adolescent mothers with accurate information on contraceptive methods. These interventions should address the religious objection to contraceptives in Burkina Faso and infrequent sex in Malawi.
Modelling exposure to aerosols from showers: implications for microbial risk assessment
Authors: Tang Lizhan , Eichelberg Antonia , Böni Franziska , Hamilton Kerry A. , Sylvestre Émile , Hammes Frederik , Julian Timothy R
Published: February 2025

Inhalation of aerosols produced during showering exposes people to chemical and microbial contaminants present in the water. To improve quantitative estimates of exposure and to inform the efficacy of potential interventions to reduce exposures, we conducted empirical measurements of aerosol concentration and size distribution during showering events. We measured aerosol count concentrations and size distributions with an aerodynamic particle sizer over the duration of mock showering events under various conditions, including different water temperatures and different showerhead types (conventional and rain showers). The empirical data were then used to fit a mass balance model to obtain aerosol generation rates and decay rates for each aerosol size class through least square fitting. We observed an initial high peak concentration of aerosols under hot water conditions relative to cold water conditions which resulted in a rapid increase in aerosol exposure during the first 1-2 minutes of showering. This suggests that people showering in hot water conditions will have a potentially increased exposure during the first 1-2 minutes. The model-fitted values suggest large inter-experiment variation in estimated aerosol generation and decay rates, even among triplicates of the same showering conditions. Current exposure assessment approaches assume constant aerosol concentrations during showers which might lead to miscalculated cumulative risk. Thus, considering aerosol dynamics is beneficial during shower exposure assessments to inform risk management interventions. The data set and associated modeling results provided can support this, as they can be readily integrated into microbial risk assessment for waterborne pathogens such asLegionellaspp., nontuberculousMycobacteria(NTM) andPseudomonas aeruginosa.
Sub-national estimation of surveillance sensitivity to inform declaration of disease elimination: A retrospective validation against the elimination of wild poliovirus in Nigeria
Authors: Nightingale Emily S , Pham-Minh Ly , Bello Isah Mohammed , Okrior Samuel , Erbeto Tesfaye Bedada , Baba Marycelin , Adeneji Adekunle , Auzenbergs Megan , Edmunds W John , O’Reilly Kathleen M
Published: February 2025

A fundamental question in the global commitment to polio eradication is how long a period of absence would be consistent with regional elimination, and the safe withdrawal of the oral polio vaccine is contingent on the answer. We present a statistical framework to estimate time-varying sensitivity of two key components of polio surveillance - environmental sampling and clinical cases of acute flaccid paralysis - for detecting infection at the local government authority level. We estimate the probability of freedom from infection (FFI) at a critical prevalence level that is consistent with interruption of transmission, given the absence of virus in collected samples. We validated this framework against two periods of poliovirus absence in Nigeria (2014-2016 and 2016-2020).

We observed substantial heterogeneity in surveillance sensitivity over time and space and, given this, concluded an 85% probability (95% uncertainty interval: 77.1-90.2%) of the country being free from WPV1 infection after 23 months without detection from July 2014. Detection of WPV1 in July 2016 demonstrated that circulation had indeed persisted during this time. In contrast, we conclude a probability of 98% (97.9-98.7%) by the time elimination of the serotype was officially declared in 2020.

The inferred probability of FFI during both time periods was found to be consistent with the retrospectively known status of regional elimination. This supports the validity of applying this framework prospectively to inform the certification of wild poliovirus elimination from remaining endemic regions, and to determine the resolution of cVDPV2 outbreaks.
Designing AI-powered healthcare assistants to effectively reach vulnerable populations with health care services: A discrete choice experiment among South African university students
Authors: Zheng A , Long L , Govathson C , Chetty-Makkan C , Morris S , Rech D , Fox MP , Pascoe S
Published: February 2025

Introduction

South African young adults are at increased risk for HIV acquisition and other non-communicable diseases and face significant barriers to accessing healthcare services. The rapid development of artificial intelligence (AI), in particular AI-powered healthcare assistants (AIPHA), presents a unique opportunity to increase access to health information and linkage to healthcare services and providers. While successful implementation and uptake of such tools require understanding user preferences, limited understanding of these preferences exist. We sought to understand what preferences are important to university students in South Africa when engaging with a hypothetical AIPHA to access health information using a discrete choice experiment.

Methods

We conducted an unlabeled, forced choice discrete choice experiment among adult South African university students through Prolific Academic, an online research platform, in 2024. Each choice option described a hypothetical AIPHA using eight attribute characteristics (cost, confidentiality, security, healthcare topics, language, persona, access, services). Participants were presented with ten choice sets each comprised of two choice options and asked to choose between the two. A conditional logit model was used to evaluate preferences.

Results

300 participants were recruited and enrolled. Most participants were Black, born in South Africa, heterosexual, working for a wage, and a mean age of 26.5 years (SD: 6.0). Results from the discrete choice experiment identified that language, security, and receiving personally tailored advice were the most important attributes for AIPHA. Participants strongly preferred the ability to communicate with the AIPHA in any South African language of their choosing instead of only English and to receive information about health topics specific to their context including information on clinics geographically near them. Results were consistent when stratified by sex and socioeconomic status.

Conclusions

Participants had strong preferences for security and language which is in line with previous studies where successful uptake and implementation of such health interventions clearly addressed these concerns. These results build the evidence base for how we might engage young adults in healthcare through technology effectively.
The Association of the Microbiome with Melanoma Tumor Response to Immune Checkpoint Inhibitor Treatment and Immune-Related Adverse Events (NCT05102773)
Authors: Dravillas Caroline , Williams Nyelia , Husain Marium , Hoyd Rebecca , Hussein Ahmed , Meara Alexa , Lynn Mari , Bibi Amna , Conrad Bailey , Lepola Noah , Gray Shannon , Bodnar Michael , Arya Namrata , Roberts Scott , Hoang Phuong , Apparicio Jessica , Merrill Deanna , Wu Richard , Verschraegen Claire , Burd Christin E. , Kendra Kari , Spakowicz Dan
Published: February 2025

Improved understanding of the factors that underlie immune checkpoint inhibitor (ICI) response and toxicity are needed as only half of patients with metastatic melanoma respond, and 10-40% experience immune-related adverse events (irAEs). Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. Here, we sought to determine if the pre-treatment gut microbiome predicts ICI response or toxicity in the setting of metastatic melanoma. Melanoma patients (n=88) over 18 years of age, planning to receive ICI therapy enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Patients taking corticosteroids for indications other than adrenal physiologic replacement were excluded. Stools were collected at baseline, within 10 days of an irAE as determined by CTCAE v 5.0 criteria, and at 12 weeks. ICI response and progression-free survival (PFS) were evaluated q12 weeks using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Metagenomic whole-genome shotgun sequencing of the microbiome was classified using MetaPhlAn4/HUMAnN3 and differential abundance analyzed with ANCOM-BC2. Of the 88 patients enrolled, 41 had metastatic disease and complete data. There were 25 participants classified as responders, defined as having complete response or partial response according to RECIST criteria, or stable disease with 6-month PFS. Grade ≥ 1 irAEs were observed in 15/41 participants. The abundance ofIntestinimonas butyriciproducens(q-value = 0.002) andLongicatena caecimuris(q-value = 0.003) were enriched in responders,Tenericutes(q-value= 0.001) andLachnospira sp. NSJ 43(q-value =0.002) in non-responders.Blautia luti, as well as several otherLachnospiraceae, were associated with response and no irAE (response q-value = 0.02, no irAE q-value = 0.02). The association of response to ICIs with several taxa in the familyLachnospiraceae, a prevalent microbial family in the gut, is consistent with prior research, which has found that this family may influence treatment outcomes through various mechanisms, such as immune regulation, metabolism, and pathogen exclusion. While no statistical relationship was observed between response and irAEs in this cohort, the microbes associated with both could serve as biomarkers. Future studies to assign causal roles for (specific microbes) in response and toxicity could identify mechanisms to improve patient outcomes.
Measuring weak effects in high dimensional mediation analysis
Authors: Li Chunlin , Chen Li , Pankow James S. , Yang Tianzhong
Published: February 2025

Existing mediation analysis methods have often fallen short in accurately quantifying the contribution of omics mediators, particularly those with weak effects. To address this issue, we propose two new variance-based causal measures for the global mediation effect. Then, we develop a flexible and computationally efficient estimation procedure based on a mixed-effects working model. Through this approach, we are able to accurately quantify the total mediation effect and discover the weak effects that are largely mis-estimated by existing methods. The proposed approach is general and complements the existing mediation analysis methodologies by offering new perspectives on the global and weak effects.
Interpretable Kolmogorov-Arnold Networks for Enzyme Commission Number Prediction
Authors: Dumontet Louis , Han So-Ra , Prouvost Axel , Lee Jun Hyuck , Oh Tae-Jin , Kang Mingon
Published: February 2025

Accurate prediction of enzyme commission (EC) numbers remains a significant challenge in bioinformatics, limiting our ability to fully understand enzyme functions and their roles in biological processes. This paper presents the integration and evaluation of the next paradigm of deep learning architecture, named Kolmogorov-Arnold network (KAN), in state-of-the-art models for predicting EC numbers. KAN modules are incorporated into current state-of-the-art models to assess their impact on predictive performance. Additionally, we introduce a novel interpretation method, specifically designed for KANs, to identify relevant input features for a given prediction, addressing a current limitation in KANs. Our evaluation demonstrates that the integration of KANs significantly enhances predictive performance compared to the state-of-the-art deep learning models, with up to a 4.35% increase in micro-averagedF1score and a 4.1% increase in macro-averagedF1score. Moreover, our novel interpretation method not only enhances the predictions’ trustworthiness but also facilitates the discovery of motif sites within enzyme sequences. This innovative approach provides deeper insights into enzyme functionality and highlights potential new targets for research. The results underscore KANs’ effectiveness in improving enzymatic classification and advancing our understanding of enzyme structures and functions. The open-source code is publicly available at:https://github.com/datax-lab/kan_ecnumber.
Comparative genomics of sex determination related genes reveals shared evolutionary patterns between bivalves and mammals, but notDrosophila
Authors: Nicolini Filippo , Nuzhdin Sergey , Ghiselli Fabrizio , Luchetti Andrea , Milani Liliana
Published: February 2025

The molecular basis of sex determination (SD), while being extensively studied in model organisms, remains poorly understood in many animal groups. Bivalves, a diverse class of molluscs with a variety of reproductive modes, represent an ideal yet challenging clade for investigating SD and the evolution of sexual systems. However, the absence of a comprehensive framework has limited progress in this field, particularly regarding the study of sex-determination related genes (SRGs). In this study, we performed a genome-wide sequence evolutionary analysis of the Dmrt, Sox, and Fox gene families in more than 40 bivalve species. For the first time, we provide an extensive and phylogenetic-aware dataset of these SRGs, and we find support to the hypothesis thatDmrt-1LandSox-Hmay act as primary sex-determining genes, by showing their high levels of sequence diversity within the bivalve genomic context. To validate our findings, we studied the same gene families in two well-characterized systems, mammals andDrosophila. In the former, we found that the male sex-determining geneSryexhibits a pattern of amino acid sequence diversity similar to that ofDmrt-1LandSox-Hin bivalves, consistent with its role of master SD regulator. In contrast, no such pattern was observed among genes of the fruit fly SD cascade, which is controlled by a chromosomic mechanism. Overall, our findings highlight similarities in the sequence evolution of some mammal and bivalve SRGs, possibly driven by a comparable architecture of SD cascades. This work underscores once again the importance of employing a comparative approach when investigating understudied and non-model systems.
Exploring the Role of PEDOT Electrodes in Electrostimulation of Vascular Endothelial Cells
Authors: Víteček Jan , Kratochvíl Matouš , Weiter Martin
Published: February 2025

The potential of electrical stimulation for cell control in tissue engineering remains largely underestimated, as does the use of organic semiconductors. The tunable physico-chemical properties of organic semiconductors offer advantages over commonly used inert metals.

This study investigates the effects of pulsed electrostimulation and electrode materials, gold and poly(3,4-ethylenedioxythiophene) (PEDOT), on the physiological functionality of human vascular endothelial cells. A novel electrostimulation platform incorporating gold or PEDOT electrodes was developed and characterized for electrical performance. Human umbilical vein endothelial cells were cultured on this platform, and the effects of electrostimulation and electrode material were assessed through morphological analysis, nitric oxide (NO) production, and expression of key endothelial marker genes.

PEDOT electrodes produced higher electrical current during electrostimulation. Interestingly, cell morphology, including elongation and alignment, showed minimal changes under electrostimulation. NO production, a key marker of vascular health, was enhanced by electrostimulation, with PEDOT electrodes showing a trend toward greater NO accumulation than gold. Gene expression analysis revealed material- and stimulation-specific trends: electrostimulation generally upregulated KLF2, KLF4, and CYP1B1 on PEDOT electrodes but suppressed their expression on gold electrodes.

These findings suggest that PEDOT electrodes, with their enhanced electrochemical properties and ability to support endothelial functionality, provide a safe and efficient platform for endothelial cell electrostimulation. This study advances understanding of the interplay between material properties and electrostimulation and highlights PEDOT as a promising candidate for vascular tissue engineering and regenerative medicine.
Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics
Authors: Kabella Nicole , Bayer Florian P. , Stamatiou Konstantinos , Abele Miriam , Sakhteman Amirhossein , Chang Yun-Chien , Wagner Vinona , Gabriel Antje , Krumm Johannes , Reinecke Maria , Holzner Melanie , Aigner Michael , The Matthew , Hahne Hannes , Bassermann Florian , Ludwig Christina , Vagnarelli Paola , Kuster Bernhard
Published: February 2025

Mutated KRAS is among the most frequent activating genetic alterations in cancer and drug discovery efforts have led to inhibitors that block its activity. To better understand oncogenic KRAS signaling and the cytostatic effects of drugs, we performed comprehensive dose-dependent proteome-wide target deconvolution, pathway engagement and protein expression characterization of KRAS, MEK, ERK, SHP2 and SOS1 inhibitors in pancreatic (KRAS G12C, G12D) and lung cancer (KRAS G12C) cells. Analysis of the resulting 687,954 dose-response curves available online revealed both common and cell line-specific signaling networks dominated by oncogenic KRAS activity. Time-dose experiments separated early KRAS-MEK-ERK from CDK-mediated signaling that cause cells to exit from the cell cycle. This transition to a quiescent state occurred without substantial proteome re-modelling but extensive changes of protein phosphorylation and ubiquitylation. The collective data highlights the complexity of KRAS signaling in cancer and places a large number of new proteins into this functional context.
A molecular switch at the yeast mitoribosomal tunnel exit controls cytochrome b synthesis
Authors: Carlstrom Andreas , Bridgers Joseph B. , Couvillion Mary , Singh Abeer Prakash , Forne Ignasi , Imhof Axel , Churchman L. Stirling , Ott Martin
Published: February 2025

Mitochondrial gene expression needs to be balanced with cytosolic translation to produce oxidative phosphorylation complexes. In yeast, translational feedback loops involving lowly expressed proteins called translational activators help to achieve this balance. Synthesis of cytochrome b (Cytb or COB), a core subunit of complex III in the respiratory chain, is controlled by three translational activators and the assembly factor Cbp3-Cbp6. However, the molecular interface between the COB translational feedback loop and complex III assembly is yet unknown. Here, using protein-proximity mapping combined with selective mitoribosome profiling, we reveal the components and dynamics of the molecular switch controlling COB translation. Specifically, we demonstrate that Mrx4, a previously uncharacterized ligand of the mitoribosomal polypeptide tunnel exit, interacts with either the assembly factor Cbp3-Cbp6 or with the translational activator Cbs2. These reciprocal interactions determine whether the translational activator complex with bound COB mRNA can interact with the mRNA channel exit on the small ribosomal subunit for translation initiation. Organization of the feedback loop at the tunnel exit therefore orchestrates mitochondrial translation with respiratory chain biogenesis.
Orthologous transcription factor replacement reveals that stable TFIIIC complexes are required for proper mitotic chromosome segregation
Authors: Gupta Akshi , Hsu Po-Chen , Litan Richard Ron R. , Leu Jun-Yi
Published: February 2025

Transcription factors are speculated to play crucial roles in adaptive evolution. Using ortholog replacement of essential transcription factors (eTFs) from other yeast species, we investigated how eTFs can change. Several orthologs could not fully complementSaccharomyces cerevisiaemutants, indicating that functions or interactions of these eTFs have changed, rendering them incompatible. We further characterized TFIIIC, a fast-evolving protein complex that assists RNA polymerase III-mediated transcription, which exhibited complete or partial incompatibility in several subunits. In the orthologous Tfc7-replacement line, binding of TFIIIC to tRNA genes was reduced, yet tRNA abundance was not severely affected. However, the chromosomes of Tfc7-replacement cells were often mis-segregated during mitosis and their fitness was further reduced in a spindle checkpoint mutant. Our chromatin-immunoprecipitation experiments uncovered that unstable TFIIIC binding results in defective cohesion loading, leading to chromosome mis-segregation. Swapping the highly divergent C-terminal domain of Tfc7 orthologs rescued its interaction with Tfc1 and cell fitness, supporting that incompatibility is caused by altered interactions between complex subunits. Our results reveal distinct essential functions of a well-studied protein complex.
AnchoRNA: Full virus genome alignments through conserved anchor regions
Authors: Eulenfeld Tom , Triebel Sandra , Marz Manja
Published: February 2025

Motivation

Multiple sequence alignment of full viral genomes can be challenging due to factors such as long sequences, large insertions/deletions (spanning several 100 nucleotides), high number of sequences, sequence divergence, and high computational complexity, as e.g., in the context of secondary structure prediction. Standard alignment methods often face these issues, especially when processing highly variable sequences or when specific phylogenetic analysis is required on selected subsequences. We presentAnchoRNA, a Python-based command line tool designed to identify conserved regions, or anchors, within coding sequences. These anchors define split positions, guiding the alignment of complex viral genomes, including those with significant secondary structures.AnchoRNAenhances the accuracy and efficiency of full-genome alignment by focusing on these crucial conserved regions. The presented approach can be particularly useful when designing primers conserved across a virus family.

Results

AnchoRNAguided alignments are systematically compared to the results of 3 alignment programs. Utilizing a dataset of 55 representativePestivirusgenomes,AnchoRNAidentified 56 anchors that are crucial for guiding the alignment process. The incorporation of these anchors led to significant improvements across all tested alignment tools, highlighting the effectiveness ofAnchoRNAin enhancing alignment quality, especially in complex viral genomes.

Availability

AnchoRNAis available to the scientific community under the MIT license on GitHub athttps://github.com/rnajena/anchorna, with releases archived on Zenodo. The package includes a tutorial featuring aPestivirusdataset and is compatible with all platforms that support Python.