bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Proteasome Gene Downregulation And Impaired Proteasomes Function Underlie Proteostasis Failure In Alzheimer’s Disease
Authors: Jiang Shan , Srikanth Malavika , Serpe Rossana , Yavari Shadi , Gaur Palavi , Collins Galen Andrew , Soni Rajesh , Menon Vilas , Myeku Natura 
Published: January 2025

AbstractAlzheimer’s disease (AD) is characterized by the accumulation of pathogenic proteins, notably amyloid-beta and hyperphosphorylated tau, which disrupt neuronal function and contribute to cognitive decline. Although proteotoxic stress is well-established in AD, the role of the ubiquitin-proteasome system (UPS) in maintaining neuronal proteostasis, and how it becomes compromised during disease progression remains incompletely understood.Here we integrated multiple approaches to characterize proteasome function, composition, and regulation in post-mortem human AD brain tissue compared to age-matched controls. These included proteasome kinetic assays, affinity purification of intact 26S proteasomes, in-gel activity assays and proteomics. According to Braak staging, we further interrogated bulk RNA-seq and single-nucleus RNA-seq (sn-RNA-seq) datasets spanning the progression of AD pathology. Finally, we examined Nrf1/NFE2L1 binding and subcellular localization to understand the transcriptional regulation of proteasome genes in AD.We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. This reduction in proteolytic capacity persisted after proteasome purification, implicating intrinsic defects within the proteasome complex. Proteomic profiling revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g., tau, α-synuclein), suggesting proteasome entrapment in pathological aggregates. Transcriptomic analyses showed progressive downregulation of constitutive proteasome subunit genes in individuals along the Braak stage axis, with downregulation apparent even at the earliest Braak stages, in tissue without overt tau aggregation. Neurons were disproportionately affected, whereas non-neuronal cells did not show substantial differences in proteasome-related gene expression, possibly through immunoproteasome induction. Despite elevated NFE2L1 expression, a key transcription factor normally driving proteasome gene transcription, AD brains exhibited impaired Nrf1 nuclear localization, preventing the expected compensatory upregulation of proteasome components.Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course. Intrinsic alterations in proteasome complexes, coupled with early transcriptional downregulation of proteasome subunits and disrupted Nrf1-mediated regulatory pathways, contribute to a vicious cycle of proteotoxic stress and neuronal vulnerability. Restoring proteasome function and enhancing Nrf1-driven transcriptional responses may represent promising therapeutic strategies to preserve proteostasis and mitigate neurodegeneration in AD.
Proteomic Analysis of Breast Cancer Subtypes Identifies Stromal Contributions that Dictate Aggressive Malignant Behavior
Authors: Burton Jordan B. , Gascard Philippe , Pan Deng , Bons Joanna , Bai Rosemary , Chen-Tanyolac Chira , Caruso Joseph A. , Hunter Christie L. , Schilling Birgit , Tlsty Thea D. 
Published: January 2025

ABSTRACTBreast cancer manifests as multiple subtypes with distinct patient outcomes and treatment strategies. Here, we optimized proteomic analysis of Formalin-Fixed Paraffin-Embedded (FFPE) specimens from patients diagnosed with five breast cancer subtypes, luminal A, luminal B, Her2, triple negative (TNBC) and metaplastic breast cancers (MBC), and from disease-free individuals undergoing reduction mammoplasty (RM). We identified and quantified ∼6,000 protein groups (with >2 peptides per protein) with significant changes in over 26% of proteins comparing each cancer subtype with control RM. Stringent statistical filters allowed us to deeply mine 576 significant conserved protein changes shared by all subtypes and protein changes unique to each subtype. The most aggressive subtype, MBC, revealed exacerbated stromal stress responses, as illustrated by a collagenolytic extracellular matrix (ECM) and immune participation biased towards neutrophils and eosinophils. Immunostaining of breast tissue sections confirmed differences across subtypes, in particular, a dramatic upregulation of SERPINH1, neutrophil-specific myeloperoxidase and eosinophil cationic protein in MBC. In summary, deep proteomic, digitalized protein abundance profiles, generated from FFPE breast cancer tissues, revealed significant changes in ECM and cellular proteins providing insight into clinically relevant states.
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

AbstractApathy 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

ABSTRACTSocial 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

AbstractInfection 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 SummaryPhage 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.
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

ABSTRACTZika 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

AbstractIn 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

ABSTRACTThe 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.IMPORTANCEBacterial 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

AbstractAmyotrophic 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

AbstractAlthough 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.