bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning predicts tissue outcomes in retinal organoids
Authors: Afting Cassian , Bhatti Norin , Schlagheck Christina , Salvador Encarnación Sánchez , Herrera-Astorga Laura , Agarwal Rashi , Suzuki Risa , Hackert Nicolaj , Lorenz Hanns-Martin , Zilova Lucie , Wittbrodt Joachim , Exner Tarik 
Published: February 2025

AbstractRetinal organoids have become important models for studying development and disease, yet stochastic heterogeneity in the formation of cell types, tissues, and phenotypes remains a major challenge. This limits our ability to precisely experimentally address the early developmental trajectories towards these outcomes. Here, we utilize deep learning to predict the differentiation path and resulting tissues in retinal organoids well before they become visually discernible. Our approach effectively bypasses the challenge of organoid-related heterogeneity in tissue formation. For this, we acquired a high-resolution time-lapse imaging dataset comprising about 1,000 organoids and over 100,000 images enabling precise temporal tracking of organoid development. By combining expert annotations with advanced image analysis of organoid morphology, we characterized the heterogeneity of the retinal pigmented epithelium (RPE) and lens tissues, as well as global organoid morphologies over time. Using this training set, our deep learning approach accurately predicts the emergence and size of RPE and lens tissue formation on an organoid-by-organoid basis at early developmental stages, refining our understanding of when early lineage decisions are made. This approach advances knowledge of tissue and phenotype decision-making in organoid development and can inform the design of similar predictive platforms for other organoid systems, paving the way for more standardized and reproducible organoid research. Finally, it provides a direct focus on early developmental time points for in-depth molecular analyses, alleviated from confounding effects of heterogeneity.
Inhibition of methylthioadenosine phosphorylase provides protection from experimental acute kidney injury
Authors: Saliba Afaf , Chen Yidong , Nelson Jonathan W. , Vetcha Abhinav , Wang Wei Wei , Kang Li , Ragi Nagarjunachary , Maity Soumya , Rabb Hamid , Reeves W. Brian , Sharma Kumar 
Published: February 2025

ABSTRACTAcute kidney injury (AKI) increases mortality risk and predisposes individuals to chronic kidney disease. Metabolic pathways play a crucial role in AKI pathophysiology. Here, we investigate the potential of methylthioadenosine phosphorylase (MTAP) inhibition as a novel renoprotective strategy in AKI. Using AKI mouse models, we demonstrate that a small molecule MTAP inhibitor significantly reduces kidney injury markers and improves renal histology. RNA sequencing reveals that MTAP inhibition modulates pathways associated with inflammation, oxidative phosphorylation, and cell survival. Additionally, analysis of human single-cell RNA sequencing data links MTAP expression to kidney injury marker in AKI. This study provides evidence of MTAP inhibition as a potential therapeutic strategy for AKI, highlighting metabolic dysregulation as a target for future clinical interventions.
NEDD4 promotes Sertoli cell proliferation and adult Leydig cell differentiation in the murine testis
Authors: Windley Simon P. , Neirijnck Yasmine , Vidovic Diana , Schwarz Quenten , Kumar Sharad , Nef Serge , Wilhelm Dagmar 
Published: February 2025

AbstractSuccessful testis development relies on the coordinated differentiation and assembly of various cell types to establish both endocrine and reproductive functions. The ubiquitin ligase NEDD4 has emerged as a key player in murine testis development, with this enzyme being implicated in gonadal sex determination and spermatogonial stem cell differentiation. Here, we report hitherto uncharacterized roles of NEDD4 in postnatal testis development. UtilizingNr5a1-andAmh-Cre drivers to conditionally ablateNedd4in testicular somatic cells, we show that NEDD4 promotes Sertoli cell proliferation through the modulation of the PI3K-AKT signaling pathway. This ubiquitin ligase also ensures proper differentiation of adult Leydig cells and may contribute to murine steroidogenesis. Furthermore, NEDD4 is essential for adrenal gland differentiation, as its loss results in adrenal dysgenesis. These findings highlight NEDD4 as a crucial factor in testis development, emphasizing the importance of ubiquitination and post-translational modifications in reproductive biology.
Inferring Latent Behavioral Strategy from the Representational Geometry of Prefrontal Cortex Activity
Authors: Qian Yichen , Herikstad Roger , Libedinsky Camilo 
Published: February 2025

AbstractBehavioral tasks can be solved employing various strategies. Sometimes, different strategies result in the same observable behavior, making them latent. In this study, we infer the latent behavioral strategy used by monkeys in a working memory updating task by comparing the representational geometry of two prefrontal regions —the lateral prefrontal cortex (LPFC) and the prearcuate cortex (PAC)—with that of recurrent neural network (RNN) models trained to solve the task using different strategies. We found that neural activity patterns in both LPFC and PAC align with only one of the proposed strategies, suggesting that monkeys employ this latent strategy to perform the task. These findings open avenues for investigating the processes that lead to strategy learning and the decision-making mechanisms that determine which strategies are chosen when multiple options are available.
Dynamic Monomer-Dimer Transition in Ligand-induced Apelin Receptor Activation
Authors: Ji Su-Yu , Wang Wei-Wei , Yang Yixin , Xu Ping , Zhang Jiangrong , Zhao Xinyue , Xi Kun , Zang Shao-Kun , Shen Dan-Dan , Mao Chunyou , Shen Qingya , Zhang Yan 
Published: February 2025

AbstractG-protein-coupled receptors (GPCRs) are significant signal transducers that exist as monomers and in multiple oligomeric forms. However, molecular mechanism driving their dynamic interconversion to regulate intricate signaling in class A GPCRs remains elusive, compounding our understanding of their related pathophysiological functions. Here, we present a set of 12 assemblies of the apelin receptor (APLNR), including dimeric apo state, monomeric and dimeric intermediate states and fully active state stimulated by small molecule or nanobody, providing a detailed dynamic view of the monomer-dimer transition. High-resolution cryo-EM structures reveal that different ligands induce varying degrees of pre-dissociation in intermediate-state dimers, with G-protein coupling facilitating the transition from dimeric to monomeric receptor. Functional studies further highlight the critical role of cholesterol clusters in stabilizing the APLNR dimers. These insights enhance our understanding of the dynamic regulation of class A GPCRs across different aggregated forms and advance the rational drug design strategies aimed at selectively modulating of APLNR signaling.
Changes in oral risk habits and influencing factors among participants in an oral cancer screening program
Authors: Munpolsri Pattaranan , Su Chiu-Wen , Yang Hsu-Fei , Hsu Tsui-Hsia , Chou Yen-Yu , Lin Li-Ju , Wu Chao-Chun , Chen Sam Li-Sheng , Yen Amy Ming-Fang 
Published: February 2025

AbstractThis study examines changes in oral risk habits and identifies factors influencing these changes among participants in a population-based oral cancer screening program to support effective public health interventions. The study included 2,569,920 individuals aged 30 and older who participated in Taiwan’s Oral Cancer Screening Program at least twice between 2010 and 2021. Changes in cigarette smoking and betel quid chewing were assessed between the first and last screenings and categorized as improved, unchanged, or worsened. A logistic regression model evaluated factors associated with habit improvement, including baseline oral habits, sex, age, education, screening adherence, and oral potentially malignant disorder (OPMD) findings.Among participants, 25.3% improved their oral habits. Baseline habits influenced how OPMD screening results affected behavior change. Among smokers, a positive screening result increased the likelihood of quitting or reducing smoking (adjusted odds ratio [aOR] = 1.18, 95% CI 1.16–1.20). However, among betel quid chewers, whether or not they smoked, a positive screening result was negatively associated with improved habits (aOR 0.79–0.88). Being female, older, college-educated, and regularly attending screenings were positively linked to behavior improvement.The program led to habit improvements in about one-quarter of participants, particularly older individuals, those with higher education, and frequent attendees. However, a diagnosis of OPMD motivated change only among smokers, not those engaging in both smoking and betel quid chewing, highlighting a lack of awareness in high-risk groups. Strengthening collaboration between health organizations and the screening program could enhance public awareness, improve program effectiveness, reduce oral cancer incidence, and lower long-term healthcare costs.
Comparative assessment of combined concentration and extraction methods for Influenza A and B virus detection in wastewater
Authors: Fretschner Till , Zeisler Edgar Elon , Scheller Steffi , Aurenz Andreas , Schneider Beate , Lukas Marcus , Braun Ulrike , Greiner Timo , Schumacher Jakob , Selinka Hans-Christoph , Walther Birgit , Kallies René 
Published: February 2025

AbstractInfluenza, caused by Influenza A and B viruses, represents a significant global health burden due to recurrent seasonal epidemics and the risk of pandemics. To gauge the large volume of seasonal influenza cases, it may be helpful to complement classical surveillance systems with additional approaches such as wastewater-based epidemiology (WBE), which can aid in the early trend assessment of seasonal epidemics. WBE has emerged as a promising tool for population-level surveillance, enabling the detection of viral nucleic acids in wastewater and offering unique advantages over individual-based surveillance. This study evaluates the performance of six different combinations of virus concentration and RNA extraction methods for the detection of Influenza A and B viruses in wastewater. Composite samples from four wastewater treatment plants in North Germany were analyzed using precipitation, filtration and automated extraction protocols. Method performance was evaluated by quantitative recovery of viral RNA and a spike-and-recovery experiment. The combination of PureYield™ filtration and Maxwell® RSC extraction (PYC_EX1) consistently demonstrated the highest recovery rates for both Influenza virus A and B, achieving recovery efficiencies of up to 80.4% and 72.3%, respectively. This method also enabled reliable detection of low viral loads, which is critical for an early detection of rising incidence. Our findings underscore the importance of rigorous method evaluation to optimize WBE for influenza surveillance. By providing robust, sensitive and reproducible protocols, this study highlights the potential of WBE to improve public health preparedness, enables timely interventions and reduces the spread of influenza viruses within communities.
Somato-cognitive action network in laryngeal and focal hand dystonia sensorimotor dysfunction
Authors: Wang Yuchao , Huynh Baothy , Ren Jianxun , Chen Mo , Zhang Wei , Hu Dan , Li Shasha , Liu Hesheng , Kimberley Teresa J. 
Published: February 2025

AbstractThe central pathology causing idiopathic focal dystonia remains unclear, limiting effective treatment targets. The recently identified somato-cognitive action network (SCAN) with its role in coordinating physiologic processes and coarse movements has been implicated in dystonia dysfunction. SCAN is thought to interface between the phylogenetically newer primary motor regions that control fine movements and the cingulo-opercular network (CON) that putatively conveys cognitive intentions for action. We hypothesized that the effector-agnostic nature of SCAN may constitute a central pathology shared across focal dystonia subtypes affecting different body parts. Additionally, the effector-specific areas in the primary sensorimotor cortex may show distinct functional changes depending on the dystonic body region.We collected functional MRI from people with either of two subtypes of idiopathic focal dystonia (laryngeal dystonia or LD,N=24, and focal hand dystonia or FHD,N=18) and healthy control participants (N=21). Regions of interest were selected based on prior work that suggested dystonia-related abnormality within the basal-ganglia-thalamo-cortical and cerebello-thalamo-cortical sensorimotor pathways. We investigated if focal dystonia is associated with resting-state functional connectivity changes 1) between SCAN and other cortical regions (effector-specific areas and CON), 2) between cortical and non-cortical regions, or 3) between non-cortical (subcortical and cerebellar) regions. Cortical regions of interest were individualized based on resting-state data. Separately, individualized hand and mouth/larynx regions were also generated from task-based MRI (finger-tapping and phonation, respectively) for comparison.Results showed a significant interaction effect in both focal dystonia subtypes (p=0.048 for LD,p=0.017 for FHD) compared to controls, which was driven by SCAN’s higher functional connectivity to task-derived mouth/larynx region and concomitantly lower connectivity to CON. This dystonia-dependent interaction was not observed with the resting-state mouth/larynx region. No significant resting-state functional changes were observed involving subcortical and cerebellar regions when LD and FHD were modeled as independent groups. However, exploratory analysis combining LD and FHD as a single group suggested a dystonia-dependent asynchronization between SCAN and sensorimotor cerebellum (p=0.051) that may suggest a pathological rather than compensatory process.For the first time, our study systematically tested key functional connectivity changes in two focal dystonias. Our results show that SCAN is uniquely associated with dystonia dysfunction beyond the dystonic effector regions, potentially offering insights on pathophysiology and future treatments.
Surgery-induced reduction in inflammation relates to improved neural inhibitory control in obesity
Authors: Kaufmann Lisa-Katrin , Custers Emma , Vreeken Debby , Snabel Jessica , Morrison Martine C. , Kleemann Robert , Wiesmann Maximilian , Hazebroek Eric J. , Aarts Esther , Kiliaan Amanda J. 
Published: February 2025

AbstractObesity is associated with impaired inhibitory control and low-grade systemic inflammation. Systemic inflammation adversely affects neurocognitive performance. Here, we investigate the effects of metabolic bariatric surgery on systemic inflammation and its influence on neural mechanisms underlying inhibitory control. In a sample of 47 individuals with obesity, we assessed inhibitory control processing pre- and 2 years post-bariatric surgery by probing neural activation and connectivity during an fMRI Stroop task. We investigated whether surgery-induced changes in plasma markers of systemic inflammation were related to changes in altered neural responses. Data were collected as part of the BARICO (Bariatric surgery Rijnstate and Radboudumc neuroimaging and Cognition in Obesity) study. Longitudinal analyses revealed decreased Stroop-related activation in the caudate nucleus and the left insula following surgery. These activation changes were accompanied by inflammation-related changes in functional coupling with medial superior frontal regions. Specifically, greater post-surgery decreases in leptin (pro-inflammatory) were associated with decreased connectivity between the anterior insula and the medial superior frontal regions, while increases in macrophage migration inhibitory factor (MIF, potentially neuroprotective) were linked to enhanced connectivity between the caudate nucleus and the medial superior frontal gyrus. Importantly, improved functional coupling between the caudate nucleus and the medial superior frontal gyrus was predictive of better task performance. Our findings suggest that surgery-induced reductions in systemic inflammation may improve inhibitory control in individuals with obesity by promoting neural changes in inflammation-sensitive brain regions and their functional interactions.This protocol was prospectively registered with the Dutch Trial Register Onderzoekmetmensen.nl, with trial number NTR29050.
Impact assessment of vaccine-related negative news and incentive measures on vaccine hesitancy in Hong Kong
Authors: Chen Yifan , Ye Yang , Yuan Hsiang-Yu , Zhang Qingpeng 
Published: February 2025

AbstractVaccine hesitancy underscores the critical need to quantify the influence of diverse factors on vaccine uptake. In this study, we develop a social-epidemiological transmission model with an imitation mechanism to characterize the interactions between social and epidemiological dynamics. We introduce a risk score to the payoff function to assess vaccine-related negative news and incentive measures’ impacts on COVID-19 vaccine uptake during the pandemic. By fitting our model with the real data in Hong Kong, we reveal that the vaccine-related negative news drastically impeded vaccination efforts. Scenario analyses suggest that, without incentive measures, the projected fifth wave of COVID-19 in Hong Kong would have infected 98% of the population, resulting in an estimated 51,752 deaths. Both the model simulation and the real data demonstrate that the incentive measures have successfully encouraged vaccine uptake and saved approximately 38,419 lives. However, we found that the willingness to take vaccines quickly declined after the incentive measures were finished, implying limited benefits in mitigating the effect of negative news in the long run. This study also highlights the need for booster doses in the face of the immune escape of the Omicron variants. Our model offers data-driven insights into the interplay between negative news, vaccine hesitancy, and incentive measures, shedding light on the effective preparation for emerging infectious disease outbreaks.
Integrative Multi-omics of Gynecological Tumors Identifies Novel Singular Biomarkers of Disease Progression
Authors: Muthamilsevan Sangeetha , Palaniappan Ashok 
Published: February 2025

ABSTRACTGynecological cancers represent a cluster of largely preventable and treatable diseases afflicting women, but with persistent substantial global burden of disease complicated by extant social factors especially in developing countries. Cervical, ovarian and endometrial cancers comprise the major gynecological cancers that might benefit from early-stage diagnosis and personalized treatment strategies. In this work, we performed integrative multi-omics analysis of public-domain omics datasets from The Cancer Genome Atlas consortium and coupled it with custom protocols to identify consensus candidate biomarkers of each of the major gynecological cancers. Such consensus biomarkers were individually evaluated for their ability to classify ‘cancer’ and ‘normal’ samples and those with AUROC > 0.9 were identified as singular biomarkers. Our study yielded the following singular biomarkers: (i) endometrial cancer: MYOZ2, CYP1B1, PPP1R3C, DNASE1L3, ADAMTSL1, LRCH2, RBM20, LOC284276, FAM78B, COL14A1, and PDZRN3; (ii) ovarian cancer: C7 and LONRF2; and (iii) cervical cancer: HAND2, C1QTNF7, JAM3 (with AUROC > 0.99) as well as HSPB7, ACTA2 and DACT7. We demonstrated that factors from multi-omics analysis of endometrial cancer enabled a geometric separation of the ‘cancer’ and ‘normal’ samples. Our results could encourage further research into the multi-omics – based subtypes of these cancers. Our methods could be extended to the analysis of datasets of other cancer types and our studies could pave the way for the development of integrated screening models for the major gynecological cancers.
Time to Medication in School-Age Children with ADHD: Assessing the Effect of Sociodemographic and Clinical Factors
Authors: Kasinathan Sushma , Huffman Lynne C. , Luo Ingrid , Bannett Yair 
Published: February 2025

ABSTRACTObjectiveTo assess the timing of attention-deficit/hyperactivity disorder (ADHD) medication prescriptions in relation to the ADHD diagnostic visit in school-aged children seen in developmental-behavioral pediatrics (DBP) clinics and to investigate which sociodemographic and clinical factors affect the timing of medication prescription.MethodWe retrospectively analyzed electronic health records from Stanford’s DBP clinics of children 6-12-years-old seen between 2016 and 2024. ADHD cohort included patients with an ICD-10 ADHD diagnosis and with ≥1 month follow-up. Andersen Health Care Utilization model informed selection of predisposing (age, sex, race/ethnicity), enabling (insurance, clinician type), and need (ADHD subtype, comorbidities) factors. Primary outcome: Time from first ADHD diagnosis to first ADHD medication prescription within 1 year of diagnosis. Cox regression model assessed associations between sociodemographic and clinical factors and study outcome.ResultsOf 823 patients with ADHD, 623 (75.7%) were male; average age at first ADHD diagnosis was 8.2 years (SD=1.5). Of 823 patients, 484 (58.8%) were prescribed medications within 1 year of diagnosis. The average number of days from ADHD diagnosis to first prescription was 51 days (median=4). Longer time to medication prescription was associated with Asian race/ethnicity (predisposing), psychologist clinician (enabling), 1-2 or ≥3 comorbidities (need). Shorter time to prescription was associated with older patient age (predisposing), ADHD combined and hyperactive/impulsive subtypes (need).ConclusionAsian race/ethnicity and, unexpectedly, multiple comorbidities, were associated with later ADHD medication prescription by DBPs in school-age children. Further investigation is necessary to understand patient, family, and clinician factors that influence medication initiation in these patient subgroups.
Cancer and Post-therapy Cardiotoxicity Risk in Adolescents, Young Adults, and Adults with Down Syndrome
Authors: Buckman Michelle A. , Vasileva Anastasiia , Jedlicka Charles R. , Kalra Hardik , Vasilyev Mikhail , Dickens David S. , Tomasson Michael H. , Bates Melissa L. 
Published: February 2025

ABSTRACTThe median life expectancy of people with Down syndrome has increased substantially over the past several decades, from 4 years in 1970 to 53 years in 2010. Despite the recent improvement in survival, there is little data about the prevalence of age-related diseases, including age-related malignancies, and the impact of standard cancer treatments on cardiovascular health. We retrospectively reviewed medical records for age- and sex-matched patients ≥15 years old with and without Down syndrome using the TriNetX platform to identify the prevalence of malignancies and explore cardiovascular outcomes after treatment with anthracyclines. We further stratified the populations into adolescent and young adult (AYA, ages 15-39 years old) and adult (≥40 years old) cohorts, given that treatment recommendations can be different. Down syndrome patients in the AYA cohort were more likely to be diagnosed with acute myeloid (OR 8.9, CI 4.99-15.89, p<0.001) and lymphoid (OR 7.33, CI 4.82-11.15, p<0.001) leukemia. The adult cohort with Down syndrome was more likely to be diagnosed with myelodysplastic syndromes (OR 12.25, CI 6.41-23.42, p<0.001), multiple myeloma (OR 1.66, CI 1.06-2.6, p=0.026), and testicular cancer (OR 2.73, CI 1.32-5.65, p=0.005). Overall, Down syndrome patients (≥15 years old) treated with anthracyclines were more likely to be diagnosed with heart failure (OR 2.14, CI 1.07-4.27, p=0.042). Our study demonstrates adolescents and adults with Down syndrome have a higher predisposition to several malignancies and an increased risk of cardiovascular disease after anthracycline treatment and may require specific screening guidelines to address their unique health risks.