bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal Digital Phenotyping of Behavior in a Neurology Clinic: Development of the Neurobooth Platform and the First Two Years of Data Collection
Authors: Nunes Adonay S. , Patel Siddharth , Oubre Brandon , Jas Mainak , Kulkarni Divya D. , Luddy Anna C. , Eklund Nicole M. , Yang Faye X. , Manohar Rohin , Soja Nancy N. , Burke Katherine M. , Wong Bonnie , Isaev Dmitry , Espinosa Steven , Schmahmann Jeremy D. , Stephen Christopher D. , Wills Anne-Marie , Hung Albert , Dickerson Bradford C. , Berry James D. , Arnold Steven E. , Khurana Vikram , White Lawrence , Sapiro Guillermo , Gajos Krzysztof Z. , Khan Sheraz , Gupta Anoopum S. 
Published: December 2024

AbstractQuantitative analysis of human behavior is critical for objective characterization of neurological phenotypes, early detection of neurodegenerative diseases, and development of more sensitive measures of disease progression to support clinical trials and translation of new therapies into clinical practice. Sophisticated computational modeling can support these objectives, but requires large, information-rich data sets. This work introduces Neurobooth, a customizable platform for time-synchronized multimodal capture of human behavior. Over a two year period, a Neurobooth implementation integrated into a clinical setting facilitated data collection across multiple behavioral domains from a cohort of 470 individuals (82 controls and 388 with neurologic diseases) who participated in a collective 782 sessions. Visualization of the multimodal time series data demonstrates the presence of rich phenotypic signs across a range of diseases. These data and the open-source platform offer potential for advancing our understanding of neurological diseases and facilitating therapy development, and may be a valuable resource for related fields that study human behavior.
Clear Cell Renal Cell Carcinoma: Unveiling Age-Linked Genetic Signatures, Relative Disease Aggressiveness, and Predictive Impact on Systemic Therapy
Authors: Pace-Loscos Tanguy , Dufies Maeva , Schiappa Renaud , Teisseire Manon , Chamorey Emmanuel , Kinget Lisa , Beuselinck Benoit , Borchiellini Delphine , Pagès Gilles 
Published: December 2024

SummaryBackground and objectivesAge influences the development and progression of clear cell renal cell carcinoma (ccRCC). Management of non-metastatic (M0) ccRCC involves surgery, adjuvant immune checkpoint inhibition (e.g., pembrolizumab) and surveillance. For metastatic (M1) ccRCC, treatment combines immune checkpoint inhibitors with anti-angiogenic therapies, achieving long-term remission in approximately 30% of patients. Despite these advancements, a definitive cure remains elusive for most individuals. Furthermore, predictive criteria for relapse that incorporate age-specific variations are lacking, highlighting the critical need for prognostic models to optimize outcomes across diverse age groups. This study aimed to validate tumor aggressiveness markers in ccRCC, focusing on age as a determinant factor.MethodsData from The Cancer Genome Atlas (TCGA) were analyzed to identify age-related gene expression differences, which were then validated using an independent cohort and ccRCC cell lines. Random Survival Forest models were employed to predict overall survival (OS) and disease-free survival (DFS) post nephrectomy and progression-free survival upon tyrosine kinase inhibitors and immunotherapies.Key findings and limitationsOf 110 age-differentiated genes identified, 31 were significantly correlated with OS and DFS. Poor prognostic markers included CIAO1, EIF2B1, NARF, UBE2G2, and SART3, while TMEM167B emerged as a good prognostic marker, and a potential predictive biomarker for immunotherapy efficacy. Limitations include the need for larger independent cohort validation and deeper exploration of gene mechanisms.Conclusions and clinical implicationsThe study presents age-informed prognostic models that integrate gene expression profiles, offering a foundation for personalized treatment strategies. TMEM167B stands out as a novel candidate for improving age-specific ccRCC management.Advancing PracticeWhat does the study add?This study explores age-dependent differentially expressed genes in clear cell renal cell carcinoma (ccRCC) and proposes a potential age-specific prognostic gene signature that could be applicable to both non-metastatic and metastatic patients. This signature may assist in identifying individuals at higher risk of relapse. Among the identified genes,TMEM167Bis highlighted as a candidate associated with favorable prognosis and shows promise as a potential predictive biomarker for immunotherapy efficacy.Patient SummaryAggressiveness in ccRCC varies with age and gene expression. Tailored treatments based on these factors may enhance outcomes and minimize side effects, particularly for patients over 75 years of age.
Short and Late Term Mortality and Quality of Life in Patients Requiring Continuous Veno-Venous Hemofiltration after Cardiac Surgery
Authors: Duong Minh-Thu , Shariff Masood A , Haddad Fady G , Catella Paul , Salmane Chadi , Demissie Seleshi , El-Charabaty Elie , El-Sayegh Suzanne , McGinn Joseph T , Nabagiez John P 
Published: December 2024

AbstractPurposeAcute kidney injury (AKI) is a significant cause of morbidity and mortality post cardiac surgery sometimes requiring intermittent hemodialysis (IHD) or continuous veno-venous hemofiltration (CVVH). Previous studies included only procedures utilizing cardiopulmonary bypass (CPB). We reviewed CPB and non-CPB patients who developed AKI and required CVVH versus no CVVH.Materials and Methods141 patients undergoing adult cardiac surgery developed AKI. 70 required CVVH (group1) and 71 did not (group2). We compared 30 day mortality, renal recovery, respiratory status and late mortality between both groups.Results73% of patients in group1 required CVVH compared to 51% in group2 (p=0.007). Mortality was 38% versus 25% respectively at 1year (p=0.23) and 54% versus 17% respectively at 30 days (p<0.0001). Renal recovery was found in 47% versus 85%, freedom from ventilator support in 59% versus 83%, and discharge to long term nursing facility (LTNF) in 69% versus 44% respectively.ConclusionMortality was significantly higher in CVVH group at 30 days but not at 1 year suggesting a long term benefit in those who survive the acute episode. The CVVH group demonstrated a higher rate of discharge to LTNF and lower rates of full renal recovery and freedom from ventilator support at discharge.
Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Hoheisel Friederike , Fleischer Kathrin Maria , Rubarth Kerstin , Sepúlveda Nuno , Bauer Sandra , Konietschke Frank , Kedor Claudia , Stein Annika Elisa , Wittke Kirsten , Seifert Martina , Bellmann-Strobl Judith , Mautner Josef , Behrends Uta , Scheibenbogen Carmen , Sotzny Franziska 
Published: December 2024

AbstractBackgroundEpstein-Barr virus (EBV) infection is a known trigger and risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we found enhanced IgG reactivity to EBV EBNA4 and EBNA6 arginine-rich sequences in postinfectious ME/CFS (piME/CFS).ObjectiveThis study aims to investigate IgG responses to arginine-rich (poly-R) EBNA4 and EBNA6 sequences and homologous human sequences in PCS and ME/CFS.MethodsThe IgG responses against poly-R EBNA4 and EBNA6 and corresponding homologous human 15-mer peptides and respective full-length proteins were analyzed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Sera of 45 PCS patients diagnosed according to WHO criteria, with 26 patients fulfilling the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 healthy controls (HC) were investigated.ResultsAutoantibodies to poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, angiogenic regulator TSPYL5, as well as to full-length α-adrenergic receptor (ADRA) proteins were more frequent in patients. Several autoantibodies were positively associated with key symptoms of autonomic dysfunction, fatigue, cognition, and pain.ConclusionCollectively, we identified autoantibodies with new antigen specificities with a potential role in PCS and ME/CFS.Clinical ImplicationThese finding should prompt further studies on the function of these autoantibodies, their exploitation for diagnostic use, and of drugs targeting autoantibodies.Capsule summaryOur study reveals elevated autoantibodies to EBV-related poly-R sequences and their human homologues in PCS and ME/CFS patients associated with symptom severity, suggesting a potential role in disease pathogenesis.
Cold Atmospheric Plasma Selectively Disrupts Breast Cancer Growth in a Bioprinted 3D Tumor Microenvironment Model
Authors: Bouret Laura M. , Billeau Jean-Baptiste , Weber Michael H. , Rosenzweig Derek H. , Reuter Stephan 
Published: December 2024

AbstractSpine metastases are the most common bone site for breast cancer, with evolving surgery and multidisciplinary care improving outcomes. Current treatments, including chemotherapy and invasive surgery, may damage healthy tissue and may leave residual tumors that lead to recurrence. Cold atmospheric plasma (CAP) offers a non-invasive alternative by delivering reactive oxygen and nitrogen species (RONS) locally to tumor sites, selectively targeting cancer cells while sparing healthy tissue. To assess the impact and selectivity toward tumor cells adjacent to bone-like tissue, we develop a 3D bioprinted tumor-stroma model using a 1% alginate and 7% gelatin cell-laden hydrogel to mimic a bone-like microenvironment. The model co-cultures triple-negative MDA-MB-231 human breast cancer cells with primary human bone marrow mesenchymal stromal cells to simulate tumor-stroma interactions. The effects of CAP treatments are assessed through metabolic activity and viability assays over three days. Results show significant selectivity for cancer cells in both 2D and 3D cultures. CAP minimizes damage to healthy cells, offering the potential for localized treatment over systemic chemotherapies such as doxorubicin. Our novel bioprinted model, combined with a plasma source controlling RONS composition, enables detailed studies of redox-based cancer cell inactivation and highlights CAP as a personalized, non-invasive treatment for bone metastases.
Computational Disruption of Paired Helical Filaments (PHFs) Assembly Using Milk Lactalbumin-derived Peptides Against Alzheimer’s Disease
Authors: Pourmand Saeed , Zareei Sara , Jozi Mohanna , Massahi Shokoufeh 
Published: December 2024

AbstractPeptides show great potential in diagnosing and treating Alzheimer’s disease (AD), particularly by targeting amyloid-beta plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins. This study focuses on designing peptide inhibitors from bovine milk alpha-lactalbumin to reduce tau aggregation in AD. Using computational techniques, such as docking, molecular dynamics simulations, and mutagenesis, we evaluated the binding and stability of these peptides against the paired helical filament (PHF) core. Our results identified promising inhibitors, with p136 emerging as the most effective. It significantly altered the PHF core’s structure, preventing further aggregation by blocking additional subunits. Additionally, p76 displayed strong binding against straight filaments (SFs). These findings highlight the potential of peptides derived from bovine milk alpha-lactalbumin as diagnostic and therapeutic tools for AD, with p136 standing out as a promising candidate for disrupting tau aggregation.
Analysis of mouse lens morphological and proteomic abnormalities following depletion of βB3-crystallin
Authors: Rayêe Danielle , Wilmarth Phillip A. , VanSlyke Judy K. , Zientek Keith , Reddy Ashok P. , Musil Linda S. , David Larry L. , Cvekl Ales 
Published: December 2024

ABSTRACTCrystallin proteins serve as both essential structural and as well as protective components of the ocular lens and are required for the transparency and light refraction properties of the organ. The mouse lens crystallin proteome is represented by αA-, αB-, βA1-, βA2-, βA3-, βA4-, βB1-, βB2-, βB3-, γA-, γB-, γC-, γD-, γE, γF-, γN-, and γS-crystallin proteins encoded by 16 genes. Their mutations are responsible for lens opacification and early onset cataract formation. While many cataract-causing missense and nonsense mutations are known for these proteins, including the human CRYBB3 gene, the mammalian loss-of function model of theCrybb3gene remains to be established. Herein, we generated the first mouse model via deletion of the Crybb3 promoter that abolished expression of the βB3-crystallin. Histological analysis of lens morphology using newborn βB3-crystallin-deficient lenses revealed disrupted lens morphology with early-onset phenotypic variability. In-depth lens proteomics at four time points (newborn, 3-weeks, 6-weeks, and 3-months) showed both down- and up-regulation of various proteins, with the highest divergence from control mice observed in 3-months lenses. Apart from the βB3-crystallin, another protein Smarcc1/Baf155 was down-regulated in all four samples. In addition, downregulation of Hspe1, Pdlim1, Ast/Got, Lsm7, Ddx23, and Acad11 was found in three time points. Finally, we show that the βB3-crystallin promoter region, which contains multiple binding sites for the transcription factors AP-2α, c-Jun, c-Maf, Etv5, and Pax6 is activated by FGF2 in primary lens cell culture experiments. Together, these studies establish the mouseCrybb3loss-of-function model and its disrupted crystallin and non-crystallin proteomes.
Bipolar and schizophrenia risk geneAKAP11encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission
Authors: Lee You-Kyung , Xiao Cong , Zhou Xiaoting , Wang Le , McReynolds Meghan G. , Wu Zhiping , Purisic Eric , Kim Henry , Li Xianting , Pang Zhiping , Dai Jinye , Peng Junmin , Yang Nan , Yue Zhenyu 
Published: December 2024

AbstractHuman genomic studies have identified protein-truncating variants inAKAP11associated with both bipolar disorder and schizophrenia, implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adaptor, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorted PKA activity and impaired cellular functions that significantly overlap with pathways associated with the psychiatric diseases. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impaired neurotransmission, providing key insights into the mechanism underlyingAKAP11-associated psychiatric diseases.
RNAGenesis: Foundation Model for Enhanced RNA Sequence Generation and Structural Insights
Authors: Zhang Zaixi , Chao Linlin , Jin Ruofan , Zhang Yikun , Zhou Guowei , Yang Yujie , Yang Yukang , Huang Kaixuan , Yang Qirong , Xu Ziyao , Zhang Xiaoming , Cong Le , Wang Mengdi 
Published: December 2024

ABSTRACTRNA molecule plays an essential role in a wide range of biological processes. Gaining a deeper understanding of their functions can significantly advance our knowledge of life’s mechanisms and drive the development of drugs for various diseases. Recently, advances in RNA foundation models have enabled new approaches to RNA engineering, yet existing methods fall short in generating novel sequences with specific functions. Here, we introduce RNAGenesis, a foundation model that combines RNA sequence understanding and de novo design through latent diffusion. With a Bert-like Transformer encoder with Hybrid N-Gram tokenization for encoding, a Query Transformer for latent space compression, and an autoregressive decoder for sequence generation, RNAGenesis reconstructs RNA sequences from learned representations. Specifically for the generation, a score-based denoising diffusion model is trained to capture the latent distribution of RNA sequences. RNAGenesis outperforms current methods in RNA sequence understanding, achieving the best results in 9 of 13 benchmarks (especially in RNA structure prediction), and further excels in designing natural-like aptamers and optimized CRISPR sgRNAs with desirable properties. Our work establishes RNAGenesis as a powerful tool for RNA-based therapeutics and biotechnology.
Central cholinergic degeneration in prodromal and early manifest Parkinsons disease: relation to cognition, clinical phenotype, and future conversion
Authors: Eisenstein Tamir , Groenewald Karolien , van Hillegondsberg Ludo , Al Hajraf Falah , Zerenner Tanja , Lawton Michael A , Ben-Shlomo Yoav , Griffanti Ludovica , Hu Michele T , Klein Johannes C 
Published: December 2024

AbstractThe neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders.Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation, and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD).Using structural MRI data from 393 early PD patients, 128 iRBD patients, and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β=-12.56,p=0.003) and iRBD (β=-16.41,p=0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β=0.12,p=0.012), decreased non-motor (β=-0.66,p=0.026) and motor (β=-1.44,p=0.023) symptom burden, and lower risk of future conversion to dementia (Hazard ratio (HR)<0.400,p<0.004). Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR<0.490,p<0.016). However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD.These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion.
Targeting AML Resistance with LY3009120-Sapanisertib and Ruxolitinib-Ulixertinib Combinations Demonstrate Superior Efficacy inFLT3,TP53,andMUC4mutations
Authors: Gholizadeh Elham , Zangene Ehsan , Parsons Alun , Kontro Mika , Heckman Caroline A. , Jafari Mohieddin 
Published: December 2024

AbstractAcute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal expansion of myeloid precursor cells. Advances in genomic profiling have enhanced our understanding of AML pathogenesis, leading to the identification of recurrent mutations, includingTP53, FLT3, MUC4, RAS,andIDH1/2. These mutations significantly influence treatment response and prognosis, withTP53mutations conferring poor outcomes and resistance to conventional therapies. Despite the advent of venetoclax-based regimens, resistance mechanisms persist, necessitating the development of novel therapeutic strategies. This study aims to investigate the efficacy of drug combinations for the treatment of AML using bothin vitroAML cell lines and anin vivozebrafish embryo xenograft model. Specifically, we focus on two drug combinations; the pan-RAF inhibitor LY3009120 combined with the mTOR inhibitor sapanisertib (designated as LS), and the JAK1/2 inhibitor ruxolitinib combined with the ERK inhibitor ulixertinib (designated as RU). The study integrates real-time cell viability assays, xenograft imaging, and genomic analyses to assess drug efficacy and explore correlations between treatment responses and mutational profiles, particularlyTP53, FLT3, and MUC4mutations. Both combinations, LS and RU, demonstrated superior efficacy compared to venetoclax-based treatments in reducing cell viability across AML cell lines. The LS combination showed significant reductions in cell viability in MOLM16 and SKM cells, while RU exhibited comparable efficacy with lower toxicity profiles. In zebrafish embryos, the LS combination effectively inhibited the proliferation of xenografted human AML cells, as evidenced by decreased fluorescence signals, indicating cell death. The RU combination also disrupted survival signaling pathways, showing promise as a therapeutic strategy. Furthermore, a correlation was identified between drug response and mutational profiles, withTP53, FLT3 and MUC4mutations significantly influencing sensitivity to the LS and RU combinations. These findings support the further development of LS and RU as effective alternatives to current clinical regimens, with implications for personalized AML treatment.
scRepertoire 2: Enhanced and Efficient Toolkit for Single-Cell Immune Profiling
Authors: Yang Qile , Safina Ksenia R. , Borcherding Nicholas 
Published: December 2024

AbstractSingle-cell adaptive immune receptor repertoire sequencing (scAIRR-seq) and single-cell RNA sequencing (scRNA-seq) provide a transformative approach to profiling immune responses at unprecedented resolution across diverse pathophysiologic contexts. This work presents scRepertoire 2, a substantial update to our R package for analyzing and visualizing single-cell immune receptor data. This new version introduces an array of features designed to enhance both the depth and breadth of immune receptor analysis, including improved workflows for clonotype tracking, repertoire diversity metrics, and novel visualization modules that facilitate longitudinal and comparative studies. Additionally, scRepertoire 2 offers seamless integration with contemporary single-cell analysis frameworks like Seurat and SingleCellExperiment, allowing users to conduct end-to-end immune profiling with transcriptomic data. Performance optimizations in scRepertoire 2 substantially reduce computational time and memory usage, addressing the demands of the ever-increasing size and scale of single-cell studies. This release marks an advancement in single-cell immunogenomics, equipping researchers with a robust toolset to uncover immune dynamics in health and disease.