bluuebunny/crossref_metadata_2025 huggingface dataset:
Apathy progression is associated with brain atrophy and white matter damage in Parkinson’s disease
Authors: Moqadam Roqaie , Azizi Houman , Brzezinski-Rittner Aliza , Ronat Lucas , Hanganu Alexandru , Zeighami Yashar , Dadar Mahsa
Published: January 2025

Apathy is a prevalent non-motor symptom that significantly impacts the quality of life in Parkinson’s disease (PD) patients. Although previous studies have investigated the neural correlates of apathy in PD, the longitudinal relationships between regional brain atrophy, white matter hyperintensities (WMHs), and apathy progression remain underexplored. Using longitudinal, multisite data ofde novoPD patients from the Parkinson’s Progression Markers Initiative (PPMI), the present study aims to investigate these relationships.

We used T1-weighted magnetic resonance imaging (MRI) and clinical data from 445 participants. Apathy was assessed as part of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I. We applied deformation-based morphometry (DBM) to quantify gray matter atrophy and used the Brain tISsue segmentatiON (BISON) algorithm to segment WMHs from T1-weighted images. Using linear regression models, we performed cross-sectional analyses to identify the associations between baseline brain measurements (DBM and WMH) and apathy severity. Longitudinal analyses utilized linear mixed-effects models to investigate whether baseline brain measurements were associated with future apathy progression over time, accounting for covariates such as age, sex, motion artifacts, Hoehn and Yahr stage, levodopa-equivalent daily dose (LEDD), Total Intracranial Volume (TIV), and baseline apathy. Hypothesis-based and exploratory analyses were conducted to confirm the results previously reported in the literature and explore potential new associations.

No cross-sectional regional associations survived multiple comparison corrections. Longitudinal hypothesis-based models confirmed that baseline atrophy in regions such as the bilateral nucleus accumbens area, superior parietal, putamen, insula, left precuneus, right precentral, and cerebellum gray matter was significantly associated with future apathy progression. Exploratory longitudinal analyses identified additional regions, including the bilateral lingual, parahippocampal, basal forebrain, ventral diencephalon, isthmus cingulate, thalamus, hippocampus, left middle temporal, right inferior temporal, pericalcarine, medial orbitofrontal, cuneus, where baseline atrophy was correlated with progression of apathy severity. Moreover, greater WMH burden, particularly in the frontal lobe, was associated with worsening apathy. These results highlight the influence of both gray matter atrophy and WMHs on apathy progression in PD.
Co-coverage of social protection programs and maternal and child nutrition interventions in Bangladesh, India and Nepal
Authors: Scott Samuel , Neupane Sumanta , Tasic Hana , Akseer Nadia , Kim Sunny S. , Alderman Harold , Carducci Bianca , Heidkamp Rebecca
Published: January 2025

Social protection programs (SPPs) are common in South Asia, a global malnutrition hotspot. Provision of SPP benefits as well as essential health/nutrition interventions to mothers and children are goals for optimal health and development outcomes, but the degree of co-coverage of SPPs and health/nutrition interventions among beneficiary households is poorly described. Using six population-based surveys from 2012 to 2019 in Bangladesh, India, and Nepal (n=253,703 women with children under five years of age), we examined data availability for SPPs (food and cash transfers) and health/nutrition interventions, and estimated their coverage and co-coverage during a woman’s last pregnancy (interventions: take-home food rations plus at least four antenatal care visits, receipt of at least 100 iron-folic acid tablets, deworming, and tetanus injections), after delivery (cash benefit plus the interventions above), and in children (take-home ration for the child plus vitamin A supplementation, deworming, iron syrup, growth monitoring, and nutrition counseling). In India, 52% and 51% of women and children, respectively, received food transfers, but only 3% and 8% received food plus all health/nutrition interventions. In India and Nepal, respectively, cash after delivery was received by 41% and 86% of women, but only 2% and 21% received cash after delivery plus all health/nutrition interventions. There was insufficient data to estimate coverage of both SPPs and health/nutrition interventions in Bangladesh. Our findings highlight the need for data on both SPP and health/nutrition intervention coverage in household surveys. There are missed opportunities to reach women and children with interventions across multiple sectors.
ATrypanosoma cruziTrans-Sialidase Peptide Demonstrates High Serological Prevalence Among Infected Populations Across Endemic Regions of Latin America
Authors: Kortbawi Hannah M. , Marczak Ryan J. , Rajan Jayant V. , Bulaong Nash L. , Pak John E. , Wu Wesley , Wang Grace , Mitchell Anthea , Saxena Aditi , Maheshwari Aditi , Fleischmann Charles J. , Kelly Emily A. , Teal Evan , Townsend Rebecca L. , Stramer Susan L. , Okamoto Emi E. , Sherbuk Jacqueline E. , Clark Eva H. , Gilman Robert H. , Colanzi Rony , Gennatas Efstathios D. , Bern Caryn , DeRisi Joseph L. , Whitman Jeffrey D.
Published: January 2025

Infection byTrypanosoma cruzi, the agent of Chagas disease, can irreparably damage the cardiac and gastrointestinal systems during decades of parasite persistence and related inflammation in these tissues. Diagnosis of chronic disease requires confirmation by multiple serological assays due to the imperfect performance of existing clinical tests. Current serology tests utilize antigens discovered over three decades ago with small specimen sets predominantly from South America, and lower test performance has been observed in patients who acquiredT. cruziinfection in Central America and Mexico. Here, we attempt to address this gap by evaluating antibody responses against the entireT. cruziproteome with phage display immunoprecipitation sequencing comprised of 228,127 47-amino acid peptides. We utilized diverse specimen sets from Mexico, Central America and South America, as well as different stages of cardiac disease severity, from 185 cases and 143 controls. We identified over 1,300 antigenicT. cruzipeptides derived from 961 proteins between specimen sets. A total of 67 peptides were reactive in 70% of samples across all regions, and 3 peptide epitopes were enriched in ≥90% of seropositive samples. Of these three, only one antigen, belonging to the trans-sialidase family, has not previously been described as a diagnostic target. Orthogonal validation of this peptide demonstrated increased antibody reactivity for infections originating from Central America. Overall, this study provides proteome-wide identification of seroreactiveT. cruzipeptides across a large cohort spanning multiple endemic areas and identified a novel trans-sialidase peptide antigen (TS-2.23) with significant potential for translation into diagnostic serological assays.

One Sentence Summary

Phage display immunoprecipitation sequencing (PhIP-seq) designed with aT. cruziwhole proteome library reveals a trans-sialidase peptide antigen (TS-2.23) with antibody responses highly prevalent across endemic regions of Latin America.
HERITABLE TISSUE-SPECIFIC GENE EXPRESSION ASSOCIATES WITH CHRONIC WOUND MICROBIAL SPECIES
Authors: Omeir Khalid , Ancira Jacob , Gabrilska Rebecca , Tipton Craig , Miller Clint , Noe Ashley , Subasinghe Kumudu , Rowe Megan , Phillips Nicole , Wolcott Joseph , Phillips Caleb D
Published: January 2025

The reasons for interpatient variability in chronic wound microbiome composition are thought to be complex but are poorly known. To investigate how patients' genetically regulated tissue expression may influence chronic wound bacterial composition, we performed a microbiome-transcriptome-wide association study. This approach involved estimating for 509 patients their tissue-specific gene expression from DNA genotypes, followed by associating gene expression to the relative abundances of species detected in their wounds as provided on clinical reports to the physician. Comparisons to artery, blood, fibroblast, skeletal muscle, skin, subcutaneous fat, and nerve tissue resulted in 251 transcriptional differences at 109 genes significantly explaining abundances of 39 different species. Overall, these species were detected in ~63% of wounds. A similar number of associations per tissue was observed (range 31-39), and many genes were associated at multiple tissues in distinct ways. The cumulative variance across loci for species relative abundance explained ranged from ~3-36%, depending on species. Although the same gene was almost never associated with more than one species, ~14% of enriched pathways were independently enriched for multiple species, which may reflect the diversity of ways microbes interact with partially overlapping attributes of the wound bed. Commonly enriched pathways pertained to collagen formation and modification, cell signaling, cytoskeletal dynamics, interactions with extracellular matrix, transmembrane proteins, among others. This work expands the new perspective that individual genetics may partially determine microbial colonization and infection.
Tailoring Glioblastoma Treatment for Frail Populations: Insights from Genomic and Clinical Data
Authors: Mansoor Masab A , Ibrahim Andrew F , Ansari Kashif
Published: January 2025

Abstract: Background/Objectives: Glioblastoma is the most common primary malignant brain tumor in adults, with a particularly high incidence among individuals aged 65 and older. Older patients often experience worse outcomes due to limited treatment options, comorbidities, and frailty. This study investigates the impact of radiation therapy and genomic factors on survival outcomes in older glioblastoma patients, aiming to inform treatment strategies for this vulnerable population. Methods: We analyzed clinical and genomic data from 109 glioblastoma patients aged 65 and older, obtained from The Cancer Genome Atlas (TCGA). Kaplan-Meier survival analysis was performed to assess the impact of radiation therapy on survival. Correlations be-tween genomic features, including mutation count, tumor mutational burden, and aneuploidy score, and overall survival were examined. Descriptive statistics were used to summarize patient demographics and treatment patterns. Results: Radiation therapy was associated with a higher mean survival (10.3 months) compared to patients who did not receive radiation (6.2 months). Genomic factors, such as mutation count and tumor mutational burden, showed weak negative correlations with survival. Despite the overall poor prognosis, radiation therapy appeared to modestly improve survival in this cohort. Conclusions: Our findings highlight the potential ben-efits of radiation therapy for older glioblastoma patients, even in the context of frailty and comorbidities. Further research is needed to explore how genomic markers can inform personal-ized treatment strategies and improve outcomes in this population.
Can Electronic care planning using AI Summarization Yield equal Documentation Quality? (EASY eDocQ)
Authors: Dorr David A , Weiskopf Nicole G , Sabile Jean M , Young Emma , Mathis Dylan , Weller Samantha , Alex Jacob , Doerr Kimberly , Bedrick Steven
Published: January 2025

Importance. Data, information and knowledge in health care has expanded exponentially over the last 50 years, leading to significant challenges with information overload and complex, fragmented care plans. Generative AI has the potential to facilitate summarization and integration of knowledge and wisdom to through rapid integration of data and information to enable efficient care planning. Objective. Our objective was to understand the value of AI generated summarization through short synopses at the care transition from hospital to first outpatient visit. Design. Using a de-identified data set of recently hospitalized patients with multiple chronic illnesses, we used the data-information-knowledge-wisdom framework to train clinicians and an open-source generative AI Large Language Model system to produce summarized patient assessments after hospitalizations. Both sets of synopses were judged blinded in random order by clinician judges. Participants. De-identified patients had multiple chronic conditions and a recent hospitalization. Raters were physicians at various levels of training. Main outcome. Accuracy, succinctness, synthesis and usefulness of synopses using a standardized scale with scores > 80% indicating success. Results. AI and clinicians summarized 80 patients with 10% overlap. In blinded trials, AI synopses were rated as useful 75% of the time versus 76% for human generated ones. AI had lower succinctness ratings for the Data synopsis task (55-67%) versus human (84-86%). For accuracy and synthesis, AI had near equal or better scores in other domains (AI: 72%-79%, humans: 68%-84%), with best scores from AI in Wisdom. Interrater agreement was moderate, indicating different preferences for synopsis content, and did not vary between AI and human-created synopses. Discussion. AI-created synopses that were nearly equivalent to human-created ones; they were slightly longer and did not always synthesize individual data elements compared to humans. Given their rapid introduction into clinical care, our framework and protocol for evaluation of these tools provides strong benchmarking capabilities for developers and implementers.
Using wastewater for population colorectal cancer screening and future research needs
Authors: Wurtzler Elizabeth , Barnell Erica , Morrison Catherine , Grass Clayton , DuPre Natalie C. , Biddle Donald J. , Jin Allie , Kavalukas Sandy , Holm Rochelle H. , Smith Ted R
Published: January 2025

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Individual screening is typically done with either a clinical stool-based test or direct clinical examination such as a colonoscopy. Given the low compliance with current screening recommendations and the high morbidity and mortality observed in areas with health disparities, we consider whether population-based testing using human RNA biomarkers in wastewater might effectively track the presence of CRC at the neighborhood level might be feasible. Wastewater samples were collected from four clusters in Louisville, KY: three representing cancer hotspots and one serving as a control neighborhood for feasibility data. Three wastewater replicates were obtained from each cluster. Human RNA biomarkers were isolated, quantified, and their RNA concentration levels were compared to clinical correlates. All replicates showed detectable levels of human cancer-associated RNA, including CDH1, which is a colorectal neoplasia-associated biomarker. Among CRC cluster sewershed samples, 8 of 9 replicate samples (89%) had a ratio of CDH1/GAPDH >=1 while the control sewershed sample showed ratio <1 for 2 of 3 samples. These preliminary data indicate that human RNA biomarkers can be detected in pooled community wastewater samples. While we have successfully identified the presence of these markers, further investigation with additional samples and closer alignment with documented case activity is necessary.
Palmitoleate Protects against Zika virus infection-induced Endoplasmic Reticulum Stress and Apoptosis in Neurons
Authors: Krishnamoorthy Chandan , Delaney Anthony , Shukla Devanshi , Hahka Taija , Anderson-Berry Ann , Natarajan Sathish Kumar
Published: January 2025

Zika virus (ZIKV) infection during pregnancy is associated with the development of fetal complications such as microcephaly. We have recently demonstrated that palmitoleate protects against ZIKV-induced apoptosis in placental trophoblasts. In the present study, we hypothesize that palmitoleate prevents ZIKV infection-induced endoplasmic reticulum (ER) stress and apoptosis in neurons. Neurons were infected with 0.1-1 multiplicity of infection of recombinant MR766 or PRVABC59 strains of ZIKV for an hour followed by treatment of palmitoleate (100 µM-200 µM) for different post-infection time points. Apoptosis was measured by nuclear morphological changes, caspase 3/7 activity, and immunoblot analysis of pro-apoptotic mediators. Activation of ER stress markers and viral envelope levels were detected using qRT-PCR and immunoblot analysis. Infectious virus particles were measured by using plaque assay. ZIKV infection to neuronal cells showed increased levels of pro-apoptotic markers like cleaved-PARP, cleaved caspase-3, Bim, and Puma, whereas decreased levels of anti-apoptotic markers such as Mcl-1, Bcl-1, and Bcl-xL. Further, we observed activation of three arms of ER stress namely: inositol requiring enzyme 1 alpha (IRE1), protein kinase-like ER kinase (PERK), and activating transcription factor (ATF6) pathways with ZIKV infection. Treatment of palmitoleate dramatically decreased ZIKV infection-induced increase in percent apoptotic nuclei and caspase 3/7 activity. Further, treatment of palmitoleate decreased cleaved PARP and PUMA protein expressions. Treatment of palmitoleate reduced ZIKV-induced ER stress activation as evidenced by decreased levels of phosphorylated forms of IRE1 and eukaryotic initiation factor 2 alpha; decreased expressions of cleaved ATF6, spliced X-box associated protein 1 and C/EBP homologous protein compared to ZIKV infection alone. Further, treatment of palmitoleate attenuated ZIKV envelope levels and infectious titer in SH-SY5Y and primary fetal cortical neurons isolated from humanized STAT2 knockin mice. These data suggest that palmitoleate supplementation protects against ZIKV-induced neuronal ER stress, apoptosis and decreases Zika viral load thereby mitigates neuronal damage.
The hyper-attenuated RVFV 40Fp8 strain can be safely administered to pregnant ewes to protect them from a virulent challenge
Authors: Borrego Belen , Alonso Celia , Moreno Sandra , Calvo-Pinilla Eva , Lorenzo Gema , Sánchez-Cordón Pedro J. , Brun Alejandro
Published: January 2025

In the present study, we evaluated the immunogenicity, safety and protective efficacy of the attenuated RVFV-40Fp8 strain in natural hosts (non-pregnant ewes) and in a highly susceptible host infection model such as pregnant ewes in the first third of pregnancy. Our results confirm the immunogenicity of 40Fp8 administration in non-pregnant and pregnant ewes, as well as the absence of foetal damage even after a high-dose vaccination regime in pregnant ewes. In addition, the ewes and their foetuses were protected against a virulent RVFV-56/74 strain challenge, as shown by comparative histopathological evaluation of tissue samples from vaccinated and non-vaccinated pregnant ewes. These results confirm the potential use of 40Fp8 as a RVF live-attenuated vaccine candidate and pave the way for further clinical developments.
Unlocking the biosynthetic potential ofPaenibacillithrough a genus-wide exploration of gene clusters for secondary metabolite production
Authors: Song Lijie , Nuhamunada Matin , Weber Tilmann , Kovács Ákos T.
Published: January 2025

The genusPaenibacillusis a prolific producer of secondary metabolites with diverse ecological and industrial applications. However, a comprehensive overview of the biosynthetic gene cluster (BGC) diversity and distribution throughout the genus has been limited. Here, we performed large-scale genome mining on 284 high-quality genomes and generated a non-redundant dataset of 126 representative genomes to explore the biosynthetic potential of this genus. A total of 3,273 BGCs were identified from the 284 genomes that clustered into 1,013 gene cluster families (GCFs), with 98.7% classified as unknown, indicating vast potential for novel secondary metabolite discovery in thePaenibacillusgenus. Comparative analysis revealed significant phylogenetic and clade-specific distribution patterns of GCFs, with certain clades enriched in unique biosynthetic pathways while others exhibited low similarity to known BGCs, suggesting evolutionary adaptation to diverse ecological niches. This study uncovers the rich and largely untapped biosynthetic potential of the genusPaenibacillus, providing a foundation for future exploration of its natural products and their applications in biotechnology and medicine.

IMPORTANCE

Bacterial secondary metabolites have been instrumental in the development of antibiotics, antifungals, and other bioactive compounds. The genusPaenibacillusis an underexplored source of such metabolites, with significant potential for novel discoveries. By integrating genome mining and phylogenetic analysis, this study systematically characterizes the diversity, distribution, and novelty of biosynthetic gene cluster across the genus. The identification of clade-specific biosynthetic patterns and numerous unknown gene cluster families highlightsPaenibacillusas a promising target for uncovering novel compounds with ecological and therapeutic relevance. These findings not only expand our understanding of bacterial secondary metabolite biosynthesis but also offer new opportunities for the development of sustainable biotechnological applications.
AAV-Delivered Anti-PC-OxPL Antibody Fragments: A Novel Therapeutic Approach to Target ALS
Authors: Gomes-Duarte Andreia , Wong Jamie K. , Pasteuning-Vuhman Svetlana , Pos Wouter , Haselberg Rob , Sogorb-Gonzalez Marina , Pascoal Sofia , van Dijk Roland , Sharifi Farangis , Giera Martin , Konstantinova Pavlina S. , Tsimikas Sotirios , Sadiq Saud A. , van Deventer Sander
Published: January 2025

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons and premature death. The limited understanding of the mechanisms underlying selective motor neuron death has significantly hindered the development of disease-modifying treatments. Ferroptosis, a form of cell death dependent on iron accumulation, has been implicated in the selective degeneration of motor neurons in ALS. Oxidized phosphatidylcholines (PC-OxPL) have been identified as key effectors in the pathophysiological processes associated with this pathway. Preclinical observations revealed a distinct PC-OxPL profile in the cerebrospinal fluid (CSF) of sporadic ALS (sALS) patients and identified apolipoprotein E (APOE) particles as the primary carriers of PC-OxPL in the CSF. Furthermore, in ALS brain and spinal cord tissue sections, PC-OxPL was found to be predominantly associated with motor neurons. Exposure of iPSC-derived motor neurons to PC-OxPL led to transcriptomic changes in genes known to be linked to ALS, as well as the induction of significant TDP-43 pathology and motor neuron death. To counter this, we developed a single-chain antibody fragment (scFv) encoded by an AAV-delivered DNA construct that specifically targets PC-OxPL neoepitopes (PC-OxPL-VecTab®). PC-OxPL-VecTab® effectively neutralized PC-OxPL-induced neurotoxicity and TDP-43 aggregation in motor neurons, while preventing motor neuron death and deficits in a sALS CSF mouse model. When administered intrathecally to minipigs, PC-OxPL-VecTab® was distributed to both upper and lower motor neurons and expressed at levels predicted to be therapeutically effective. Our work identifies PC- OxPL as a critical pathological factor and a key inducer of TDP-43 pathology in ALS, providing the foundation for a novel therapeutic intervention modality for patients with sALS. Furthermore, it offers the exciting potential to be expanded to diseases characterized by PC-OxPL neurotoxicity.
Deficient Executive Control in Transformer Attention
Authors: Patel Suketu , Wang Hongbin , Fan Jin
Published: January 2025

Although transformers in the large language models (LLMs) effectively implement a self-attention mechanism that has revolutionized natural language processing, they lack an explicit implementation of executive control of attention found in humans which is essential for resolving conflicts and selecting relevant information in the presence of competing stimuli, and is critical for adaptive behavior. To investigate this limitation in LLMs, we employed the classic color Stroop task that is widely regarded as the gold standard for testing executive control of attention. Our results revealed a typical conflict effect of better performance in terms of accuracy in the congruent condition (e.g., naming the ink color of the word RED in red) compared to incongruent condition (e.g., naming the ink color of the word RED in blue), which is similar to human performance, in short sequences. However, as sequence length increased, the performance degraded toward chance levels on the incongruent trials despite maintaining excellent performance on congruent trials and near-perfect word reading ability. These findings demonstrate that while transformer attention mechanisms can achieve human-comparable performance in smaller contexts, they are fundamentally limited in their capacity for conflict resolution across extended contexts. This study suggests that incorporating executive control mechanisms akin to those in biological attention could be crucial for achieving more general reasoning and reliable performance toward artificial general intelligence.
Infectious Complications in Philadelphia-Negative Adolescent and Young Adult Acute Lymphoblastic Leukemia Patients in the Era of Pediatric-Inspired Regimen
Authors: Vongngakesone Phoutthasin , Niprapan Piangrawee , Srichairatanakool Sirichai , Hantrakun Nonthakorn , Punnachet Teerachat , Hantrakool Sasinee , Piriyakhuntorn Pokpong , Chai-Adisaksopha Chatree , Rattarittamrong Ekarat , Tantiworawit Adisak , Norasetthada Lalita , Rattanathammethee Thanawat
Published: January 2025

Introduction: Pediatric acute lymphoblastic leukemia (ALL) has cure rates exceeding 90%, while adult ALL has a 3-year survival rate of only 40–50%. Adolescents and young adults (AYAs) face unique challenges due to age-related factors and high-risk disease features. Although pediatric-inspired regimens improve survival, intensive chemotherapy increases susceptibility to severe infections. Methods: A retrospective analysis was conducted on AYA-ALL patients treated at Chiang Mai University Hospital from 1 January 2007 to 31 December 2023. Patients were classified into pediatric-inspired (TPOG) or adult regimens (Hyper-CVAD or GMALL). Infections were categorized as clinically documented infections (CDI) or microbiologically documented infections (MDI). Multivariate logistic regression was used to identify infection risk factors. Results: Among 94 patients (62.8% male; median age 22.9 years), 56.4% received TPOG and 43.6% received adult regimens. Infectious complications occurred in 79.8% of patients, with higher rates in the adult regimen group (90.2% vs. 71.7%, p = 0.03). CDI was more frequent in the adult group (73.4% vs. 52.8%, p = 0.04), while fungal infections were more common in the TPOG group (26.4% vs. 9.8%, p = 0.04). Adult regimens significantly increased infection risk (OR 3.55; 95% CI 1.02–12.36, p = 0.04). Infection rates peaked during induction (47.8%) and consolidation (51.8%). During induction, MDI was lower in the adult group (21% vs. 79%, p = 0.01), while CDI was higher during consolidation (69% vs. 30%, p  < 0.01). Gram-negative bacteria were the most common pathogens (85%), particularly E. coli (27%) and Salmonella spp. (21%). Fungal infections affected 19.1% of patients, with invasive pulmonary aspergillosis being the most common (11.7%). Conclusion: AYA-ALL patients are highly susceptible to infections, especially those receiving adult regimens. Fungal infections were notably more common in patients on the TPOG regimen. Strengthening infection prevention and providing early treatment are vital for improving patient outcomes.
fCUT&Tag-seq: An Optimized CUT&Tag-based Method for High-Resolution Histone Modification and Chromatin-Binding Protein Profiling in both Model and Plant Pathogenic Fungi
Authors: Wang Haiting , Tan Yongjunlin , Ma Jiayue , Yang Jie , Liu Mengran , Lu Shan , Xia Haoxue , Tang Guangfei , Liu Wende , Guo Hui-Shan , Shan Chun-Min
Published: January 2025

Histone modifications and chromatin-binding proteins are important regulators of gene expression in eukaryotes and have pivotal roles in fungal pathogenicity and development. However, profiling these modifications or proteins across the genome in fungi is still challenging, due to the technical limitations of the traditional widely-used ChIP-Seq method. Here, we present an optimized CUT&Tag-Seq protocol (fCUT&Tag-Seq) specifically designed for filamentous fungi and dimorphic fungi. Our approach involves the preparation of protoplasts and nuclear extraction to enhance antibody accessibility, along with formaldehyde crosslinking to improve protein-DNA binding efficiency. We then successfully applied fCUT&Tag-Seq to accurately profile multiple histone modifications like H3K9me3, H3K27me3, H3K4me3, and H3K18ac, across different plant pathogenic or model fungal species includingVerticillium dahliae,Neurospora crassa,Fusarium graminearum, andSporisorium scitamineum. Compared to the traditional ChIP-Seq, our method showed superior signal-to-noise ratios, higher reproducibility, and enhanced detection sensitivity. Furthermore, we extended this method to profile chromatin-binding proteins, such as the histone acetyltransferase Gcn5. This study establishes fCUT&Tag-Seq as a robust and useful tool for fungal epigenetic research, enabling detailed exploration of chromatin dynamics and advancing our understanding of fungal gene regulation, development, and pathogenicity.
Connexin50 hemichannels are opened by CO2: implications for lens physiology
Authors: Lovatt Alexandra , Wijayapala Ashvini , Mui Macy , Butler Jack , Dale Nicholas
Published: January 2025

Connexin50 (Cx50) is expressed in lens fibre cells. As mutations of Cx50 cause cataracts its physiological role in the lens must be important. We have used recent cryoEM structures of Cx50 and the predictive power of alphafold3 to identify the presence of a carbamylation motif, originally described in Cx26, that suggests that Cx50 might be CO2sensitive. By expressing the naturally truncated version of Cx50 in HeLa cells and utilising coexpression of genetically encoded sensors iGluSnFr or eLACCO1.1, we have demonstrated the CO2sensitivity of Cx50 hemichannels, and their permeability to lactate and glutamate. Importantly, the properties of Cx50 predict that it will be partially open at the levels of PCO2characteristic of aqueous humour. By mutating the two key residues of the carbamylation motif, K105 and K140, we have shown that the motif is required for CO2sensitivity. Mutations of the residue V44 cause cataracts and these mutations abolish the CO2sensitivity of Cx50. We hypothesize that CO2-dependent gating of Cx50, and consequent alterations in transmembrane Na+fluxes, might provide homeostatic control of the microcirculation system that is critical for lens health.
Co-opting MBNL-dependent alternative splicing cassette exons to control gene therapy in myotonic dystrophy
Authors: Carrell ST , Carrell EM , Giovenco RC , Davidson BL
Published: January 2025

Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG repeat expansion that accumulate as toxic CUG repeat RNA. Functional sequestration of muscleblind-like (MBNL) proteins by CUG repeat RNA leads to deleterious, yet predictable changes in alternative splicing in DM. Genetic medicines for DM that reduce CUG repeat RNA or increase MBNL are advancing, but application of a viral-based approach must contend with high phenotypic and molecular variability. To address this, we have repurposed well-described cassette exons that are excluded by MBNL action to tune translational output of a therapeutic protein. We show that these splicing events can be taken out of genetic context and respond to changes in MBNL concentration or accumulation of toxic CUG repeat RNA, can deliver therapeutic MBNL1 protein to improve skeletal muscle myotonia or prevent cardiac toxicity associated with MBNL1 overexpression in mice, and distinguish DM patient-derived skeletal muscle myotubes from isogenic controls. Further work to fine-tune events to specific tissue targets and therapeutic cargos is needed, but these events can increase the therapeutic window for viral-based approaches for DM1.
Functional impact of rare variants and sex across the X-chromosome and autosomes
Authors: Ungar Rachel A. , Li Taibo , Vetr Nikolai G. , Ersaro Nicole , Battle Alexis , Montgomery Stephen B.
Published: January 2025

The human X-chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X-chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X-chromosome is understudied. To investigate functional rare variants on the X-chromosome, we use observations of outlier gene expression from GTEx consortium data. We show outlier genes are enriched for having nearby rare variants on the X-chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 753 rare variants in 449 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Combined, our study investigates functional rare variants on the X-chromosome, and further details how sex-stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.
Data-driven denoising in spinal cord fMRI with principal component analysis
Authors: Hemmerling Kimberly J. , Vigotsky Andrew D. , Glanville Charlotte , Barry Robert L. , Bright Molly G.
Published: January 2025

Numerous approaches have been used to denoise spinal cord functional magnetic resonance imaging (fMRI) data. Principal component analysis (PCA)-based techniques, which derive regressors from a noise region of interest (ROI), have been used in both brain (e.g., CompCor) and spinal cord fMRI. However, spinal cord fMRI denoising methods have yet to be systematically evaluated. Here, we formalize and evaluate a PCA-based technique for deriving nuisance regressors for spinal cord fMRI analysis (SpinalCompCor). In this method, regressors are derived with PCA from a noise ROI, an area defined outside of the spinal cord and cerebrospinal fluid. A parallel analysis is used to systematically determine how many components to retain as regressors for modeling; this designated a median of 11 regressors across three fMRI datasets: motor task (n=26), breathing task (n=27), and resting state (n=10). First-level fMRI modeling demonstrated that principal component regressors did fit noise (e.g., physiological noise from blood vessels), particularly in the resting state fMRI dataset. However, group-level motor task activation maps themselves did not show a clear benefit from including SpinalCompCor regressors over our original denoising model. The potential for collinearity of principal component regressors with the task may be a concern, and this should be considered in future implementations for which task-correlated noise is anticipated.
A single dimer of the SARS-CoV-2 N protein can associate with multiple fragments of single-stranded and stem-loop RNAs
Authors: Kaneda Naoya , Suzuki Leo , Endo Shun , Husna Syamil Muharror Ahsanul , Ishikawa Shion , Takahashi Hiroto , Oikawa Hiroyuki , Itoh Yuji , Takahashi Satoshi
Published: January 2025

The nucleocapsid (N) protein of SARS-CoV-2 associates with the viral genomic RNA (gRNA) and forms the ribonucleoprotein (RNP) granules. However, the detailed molecular structures of RNP and their formation mechanism are largely unknown. We used circular dichroism (CD) spectroscopy, fluorescence correlation spectroscopy (FCS) and single-molecule Förster resonance energy transfer (sm-FRET) spectroscopy to understand the interaction between the N protein and different structural units of RNA. We chose polyadenylate chains with 40, 30 and 20 bases possessing a single-stranded structure and three stem loops with 50, 41 and 29 bases selected from gRNA, and labeled their 5’ and 3’ ends by Alexa488 and Alexa647, respectively, for the FCS and sm-FRET measurements. We found that the N protein started to bind to the single-stranded RNAs at the concentrations between 10 and 100 nM. The binding of the N protein to one of the stem loops occurred at the concentration less than 10 nM without melting the stem loop. For all the samples, the binding of multiple molecules of the RNA fragments to a single dimer of the N protein was observed. These results demonstrate that the N protein acts as a non-specific binder to both single-stranded and stem-loop structures of RNA, and that the N protein might contract a long RNA chain by bridging its multiple segments. We propose that the RNP granules might be folded by the association of the numerous stem loops of gRNA triggered by the assembly of the N protein.
Patching up the nucleus: a novel role for PMLII in nuclear envelope rupture repair
Authors: Janssen Anne F.J. , Knowles Oliver , Britton Sébastien , Deane Janet E. , Spruijt Evan , Larrieu Delphine
Published: January 2025

The nuclear envelope (NE) is important for cellular health as it protects and organizes the genome. NE dynamics is important for various cellular processes including cell growth, migration and removal of defective NE components. In extreme cases, the NE can rupture leading to exchange of material between the nuclear interior and the cytoplasm. Rapid repair of the NE is initiated to minimize the effect on the genome. While our understanding of the machinery involved in this repair process is increasing, a lot is still unknown about this process including events leading up to NE rupture. Interestingly, biomolecular condensates have recently been found to play important roles in membrane repair and remodelling in cells. Here, we found that promyelocytic leukemia protein isoform II (PMLII), a protein involved in nuclear PML body formation, forms condensates at the NE. These condensates specifically form at sites where the lamina is disrupted. We show that NE rupture often occurs at these sites and that PMLII stays present until rupture repair is initiated suggesting a role in stabilization of the site for effective repair.
Equivalent-circuit modeling of electron-hole recombination in semiconductors and mixed ionic-electronic conductors
Authors: Moia Davide
Published: January 2025

The analysis and optimization of solar energy conversion and light-emitting devices can greatly benefit from equivalent circuit models describing their response. However, a general model of electron-hole recombination in semiconductors is currently missing. This study presents equivalent circuit models of radiative and nonradiative electron-hole recombination processes in the small-signal regime based on their linearized analytical treatment. While resistors accurately describe radiative recombination, bipolar transistors represent the general model of nonradiative recombination, and they can be replaced by resistive elements only in special cases. The proposed recombination model is integrated into a transmission-line circuit representation of complete devices that is equivalent to the linearized drift-diffusion equations in one dimension. For mixed conducting devices, such as halide perovskite solar cells, appropriate simplifications of the complete model provide analytical solutions describing the bulk and interfacial polarization effects that influence the small-signal electrostatics, recombination currents, and overall impedance. The resulting analysis facilitates data interpretation and is relevant to a wide range of materials and devices used for solar energy conversion as well as other optoelectronic and photoelectrochemical applications.

Published by the American Physical Society
2025
Hunting for a charged Higgs boson pair in proton-proton collisions
Authors: Arroyo-Ureña M. A. , Herrera-Chacón E. A. , Rosado-Navarro S. , Salazar Humberto
Published: January 2025

We explore the production and possible detection of a charged scalar Higgs pair H−H+ decaying into the final state μνμcb in proton-proton collisions at the LHC and its next step, the high luminosity LHC (HL-LHC). The charged scalars are predicted within the theoretical framework of the two-Higgs doublet model of type III (2HDM-III). As a test and validation of the model, we identify regions of the 2HDM-III parameter space that accommodate the current excess of events at 3σ in the process BR(t→H±b)×BR(H±→cb) for MH±=130  GeV, as reported by ATLAS Collaboration. Theoretical and additional experimental constraints are also included. Based on this, we propose realistic scenarios that could be brought under experimental scrutiny at the HL-LHC. Assuming the most favorable scenario, we predict a signal significance at the level of 5σ for a charged scalar boson mass MH± in the 100–350 GeV range.

Published by the American Physical Society
2025
Domain wall constraints on the doublet left-right symmetric model from pulsar timing array data
Authors: Ringe Dhruv
Published: January 2025

Recent evidence of a stochastic gravitational wave (GW) background found by NANOGrav and other pulsar timing array (PTA) collaborations has inspired many studies looking for possible sources. We consider the hypothesis that the GW signature is produced by domain walls (DWs) arising in the doublet left-right symmetric model (DLRSM) due to the spontaneous breaking of the discrete parity symmetry. We show that the DW network consists of two types of DWs, namely Z2 and LR DWs, and solve the kink equations to obtain the parametric dependence of the surface tension in the two cases. We argue that the Z2 DWs are unstable due to higher surface tension, leading to a stable network consisting only of LR DWs. Considering the GW signal from the DLRSM DW model with and without the contribution from supermassive black hole binaries, we perform a Bayesian analysis using the PTA data to estimate the posterior distribution and identify best-fit parameter ranges. The PTA data favors a parity-breaking scale of O(105)  GeV, and a biased potential Vbias∼(O(100)  MeV)4. The model with only DLRSM DWs is slightly favored over the model where additional supermassive black hole binaries contribution is considered.

Published by the American Physical Society
2025
Efficient GPU-accelerated multisource global fit pipeline for LISA data analysis
Authors: Katz Michael L. , Karnesis Nikolaos , Korsakova Natalia , Gair Jonathan R. , Stergioulas Nikolaos
Published: January 2025

The large-scale analysis task of deciphering gravitational-wave signals in the LISA data stream will be difficult, requiring a large amount of computational resources and extensive development of computational methods. Its high dimensionality, multiple model types, and complicated noise profile require a global fit to all parameters and input models simultaneously. In this work, we detail our global fit algorithm, called “Erebor,” designed to accomplish this challenging task. It is capable of analyzing current state-of-the-art datasets and then growing into the future as more pieces of the pipeline are completed and added. We describe our pipeline strategy, the algorithmic setup, and the results from our analysis of the LDC2A Sangria dataset, which contains massive black hole binaries, compact galactic binaries, and a parametrized noise spectrum whose parameters are unknown to the user. The Erebor algorithm includes three unique and very useful contributions: GPU acceleration for enhanced computational efficiency; ensemble Markov Chain Monte Carlo (MCMC) sampling with multiple MCMC walkers per temperature for better mixing and parallelized sample creation; and special online updates to reversible-jump (or transdimensional) sampling distributions to ensure sampler mixing and accurate initial estimates for detectable sources in the data. We recover posterior distributions for all 15 (6) of the injected massive black hole binaries (MBHB) in the LDC2A training (hidden) dataset. We catalog ∼12000 galactic binaries (∼8000 as high confidence detections) for both the training and hidden datasets. All of the sources and their posterior distributions are provided in publicly available catalogs.

Published by the American Physical Society
2025
Application of signal separation to diffraction image compression and serial crystallography
Authors: Kieffer Jérôme , Orlans Julien , Coquelle Nicolas , Debionne Samuel , Basu Shibom , Homs Alejandro , Santoni Gianluca , De Sanctis Daniele
Published: January 2025

We present here a methodology for real-time analysis of diffraction images acquired at a high frame rate (925 Hz) and its application to macromolecular serial crystallography at ESRF. We introduce a new signal-separation algorithm, able to distinguish the amorphous (or powder diffraction) component from the diffraction signal originating from single crystals. It relies on the ability to work efficiently in azimuthal space and is implemented in pyFAI, the fast azimuthal integration library. Two applications are built upon this separation algorithm: a lossy compression algorithm and a peak-picking algorithm. The performances of both are assessed by comparing data quality after reduction with XDS and CrystFEL.
Simulation of bent Laue crystals for a high-energy X-ray monochromator with heat load consideration
Authors: Wang Jiayi , Gao Lidan , Li Ming , Yang Yiming , Li Yanchun , Cheng Hu , Fan Longlong , Wang Youkang , Guo Huilong , Jia Quanjie
Published: January 2025

The performance of a double-crystal Laue-case monochromator has been evaluated for the Engineering Material beamline at the High Energy Photon Source. Expanding on the xrt framework, the crystal simulation incorporates the Penning–Polder and multilamellar models to determine the crystal diffraction profiles and utilizes two approaches, analytical expression and discrete point, for crystal depiction. The simulation accounts for the heat load by treating it as both face distortion and bulk distortion. Three scenarios are discussed: an ideally bent crystal without heat load, a bent crystal with thermally induced face distortion and a bent crystal with thermally induced bulk distortion. The mutual consistency in tracing confirms the validity of the crystal simulation. Two thermal distortion assessment tools are available: one for the rapid evaluation of the impact of significant distortions, and the other for the refined reflection of interior lattice plane distortions, which constitutes a key innovation of the simulation. The tracing outcomes offer valuable guidance for decision making and risk mitigation in the optical design process.
Top dusted adhesive tape sample preparation method for the X-ray diffraction analysis of small powder sample volumes with the Bragg–Brentano setup
Authors: Dickes Daniel , Glatzel Uwe
Published: January 2025

When performing X-ray diffraction (XRD) analysis of small powder sample volumes with the Bragg–Brentano setup, choosing an appropriate sample preparation method is important. This work provides practical information on the conventional top dusted sample preparation method and the top dusted adhesive tape sample preparation method. In the latter, the powder of interest is dusted onto an adhesive tape. Because adhesive tapes contribute to the measured XRD signal as background noise, care must be taken when using a particular adhesive tape. This work assists XRD users in selecting the most suitable adhesive tape for their purpose by providing the diffractograms (Cu Kα1 radiation) of 13 commercially available adhesive tapes used for office and packing applications. In general, tapes with a matte acetate or polyvinyl chloride backing are recommended as they cause a comparatively low background signal without high-intensity reflections.