bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methanol Crude Extract ofLitsea MonopetalaLeaves combats oxidative stress, clot formation, inflammation and stool frequency in Animal Model
Authors: Labu Zubair Khalid , Karim Samira , Arifuzzaman Sarder 
Published: November 2024

AbstractLitsea monopetala(LM) leaves are used in traditional medicine systems in the South Asian region for treating ailments such as digestive issues, respiratory problems, and skin disorders. In this study, we first investigated the possible antioxidant, thrombolytic characteristics, analgesic, and antidiarrheal activity of the methanolic crude extract of LM leaves. To assess the antioxidant, thrombolytic, analgesic, and antidiarrheal activity of the crude extract we used DPPH free radical scavenging, clot lysis, acetic acid, and castor oil-induced animal model, respectively. Before applying the extract to the animal model, phytochemical screening was performed to estimate the bioactive compounds (e.g.- phenol, flavonoid, alkaloids, tannins, and others) present. The extract exhibited DPPH free radical scavenging features with an IC50of 8.99 µg/mL compared to ascorbic acid, an IC50of 13.38 µg/ml. At 500 mg/kg dose, the extract produced a significant decrease (67.05%) in the frequency of writhings while diclofenac sodium decreased by 74.15%. The extract also significantly (P<0.01) decreased the frequency of diarrhea when compared to the standard drug of loperamide (3mg/kg). Finally, we assessed the clot lysis function as representative of the thrombolytic activity of extracts in comparison to streptokinase and demonstrated clot lysis action (74.15% decrease). From a therapeutic implication, we suggest that crude extract of LM’s leaves may contribute to the alternative or additive strategy to modulate conditions such as oxidative stress, clot formation, inflammation and diarrhea.
Loss of KDM6A-mediated genomic instability and metabolic reprogramming differentially regulates responses to immune checkpoint therapy and chemotherapy in bladder cancer
Authors: Singh Pratishtha , Raychaudhuri Deblina , Chakraborty Bidisha , Meher Swadhin , Tannir Aminah J. , Majumdar Anurag , Hawkins Jessalyn , Xiong Yun , Lorenzi Philip , Sharma Padmanee , Pilié Patrick , Goswami Sangeeta 
Published: November 2024

AbstractMutations in genes encoding critical epigenetic regulators are frequently noted in bladder cancer, however, the impact of these mutations on therapeutic efficacy is unclear. One of the most common driver mutations in bladder cancer occurs in theKDM6Agene, which encodes a histone demethylase that promotes gene transcription. Retrospective analyses of patients with bladder cancer demonstrated thatKDM6Amutations correlate with improved overall survival (OS) with immune checkpoint therapy (ICT), while they are associated with lower OS in patients undergoing cisplatin-based chemotherapy. Mechanistic studies utilizing CRISPR-Cas9 mediated deletion ofKdm6ashowed reduced expression of DNA mismatch repair (MMR) and DNA double-stranded base repair (DSBR) genes in tumor cells with improved response to anti-PD-1 therapy and attenuated sensitivity to cisplatin-based chemotherapy in preclinical models of bladder cancer. Additionally, the loss ofKdm6a-mediated reduction in glycolysis and intratumoral lactate accumulation impaired histone 3 lysine 9 lactylation (H3K9la) and histone 3 lysine 18 lactylation (H3K18la) in Tregs with concurrent decrease in the expression of key genes includingFoxp3, TgfbandPdcd1and their immune-suppressive function. Further, reduced expansion of PD-1hiTregs improved the ratio of cytotoxic T cells to Tregs and response to anti-PD-1 therapy inKdm6adeficient tumor-bearing mice. Collectively, this study provided key insights into the role of KDM6A-mediated epigenetic regulation of DNA repair and metabolic reprogramming which potentially govern response to chemotherapy and ICT thus highlighting the utility ofKDM6Amutation status for patient stratification and development of personalized treatment algorithms.
Species Diversity and Mitochondrial DNA Analysis of Sponges (Porifera, Demospongiae) in an Anchialine Cave on the Yucatan Peninsula
Authors: Suárez-Moo Pablo , Rivera-Domínguez Adán J. , Márquez-Velázquez Norma A. , Prieto-Davó Alejandra 
Published: November 2024

AbstractThe anchialine ecosystem in the southeastern Gulf of Mexico has an unexplored fauna, among the most understudied groups is Porifera, molecular approaches to investigate their biology and evolution remain largely short. To broaden these studies, sponge individuals collected in the anchialine cave “Xcalac” in the Mexican state of Quintana-Roo were analyzed using 18S rRNA sequences from sponge metagenomes. The three individuals studied belong to theCinachyrella, Xestospongia, and Suberitesgenera. The mitochondrial (mt) genomes ofCinachyrellasp. n. andXestospongiasp. n. were 18,493 bp to 19,604 bp in length, containing 14 protein-coding genes, 2 rRNA genes (rrnS and rrnL), and 23–25 tRNA genes, respectively. The phylogenomic analysis showed thatCinachyrellasp. n. had the same gene arrangement as the members of its subclade, including sponge species of theCinachyrellaandGeodiagenera. The mt genome ofXestospongiasp. n. contained the same gene arrangement as found in other sponges of the same genus and differed from other genera such asPetrosiaandHaliclonaby an tRNA (tyrosine, Y1). Variation in mitochondrial genomes (size, gene content, and gene order) was observed when comparing sampled sponge species from the class Demospongiae to the class Homoscleromorpha. This is the first record ofCinachyrellasp. n andSuberites sp. n.in an anchialine cave on the southeastern Yucatan peninsula, and the first report of the mitochondrial genome analysis ofCinachyrellasp. n. andXestospongiasp. n., contributing to a better understanding of the diversity and phylogeny of sponges in this ecosystem.
StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds
Authors: Wang Nicholas K. , Wiltsie Nicholas , Winata Helena K. , Fitz-Gibbon Sorel , Gonzalez Alfredo E. , Zeltser Nicole , Agrawal Raag , Oh Jieun , Arbet Jaron , Patel Yash , Yamaguchi Takafumi N. , Boutros Paul C. 
Published: November 2024

AbstractReference genomes are foundational to modern genomics. Our growing understanding of genome structure leads to continual improvements in reference genomes and new genome “builds” with incompatible coordinate systems. We quantified the impact of genome build on germline and somatic variant calling by analyzing tumour-normal whole-genome pairs against the two most widely used human genome builds. The average individual had a build-discordance of 3.8% for germline SNPs, 8.6% for germline SVs, 25.9% for somatic SNVs and 49.6% for somatic SVs. Build-discordant variants are not simply false-positives: 47% were verified by targeted resequencing. Build-discordant variants were associated with specific genomic and technical features in variant- and algorithm-specific patterns. We leveraged these patterns to create StableLift, an algorithm that predicts cross-build stability with AUROCs of 0.934 ± 0.029. These results call for significant caution in cross-build analyses and for use of StableLift as a computationally efficient solution to mitigate inter-build artifacts.
SpaMTP: Integrative Statistical Analysis and Visualisation of Spatial Metabolomics and Transcriptomics data
Authors: Causer Andrew , Lu Tianyao , Fitzgerald Christopher , Newman Andrew , Vu Hani , Tan Xiao , Vo Tuan , Cui Cedric , Narayana Vinod K. , Whittle James R. , Best Sarah A. , Freytag Saskia , Nguyen Quan 
Published: November 2024

AbstractThe ability to spatially measure multi-modal data provides an unprecedented opportunity to comprehensively explore molecular regulation at transcriptional, translational and metabolic levels to acquire insights on cellular activities underpinning health and disease. However, there is currently a lack of analytical tools to integrate complementary information across different spatial-omics data modalities, particularly with respect to spatial metabolomics data, which is becoming increasingly invaluable. We introduceSpaMTP, a versatile software that implements an end-to-end integrative analysis of spatial metabolomics and transcriptomics data. Based inR, SpaMTPbridges processing functionalities for metabolomics data fromCardinalwith user-friendly cell-centric analyses implemented in Seurat. Furthermore,SpaMTP’scomprehensive analysis pipeline covers (1) automated mass-to-charge ratio (m/z) metabolite annotation; (2) a wide range of metabolite-gene based downstream statistical analyses including differential expression, pathway analysis, and correlation analysis; (3) integrative spatial-omics analysis; and (4) a suite of visualisation functions. For flexibility and interoperability,SpaMTPincludes various functions for data import/export and object conversion, enabling seamless integration with otherRandPythonpackages. We demonstrated the utility ofSpaMTPto draw new biological understandings through analysing two biological system. We believe this software and implemented methods will be broadly utilised in spatial multi-omics and spatial metabolomics analyses.
Discovery of a Novel Missense Mutation in the RIMS1 Gene Potentially Enhances the Severity of Retinitis Pigmentosa (RP) Caused by RP1 Mutation in Humans
Authors: Lazaro-Guevara José M. , Garrido-Lopez Karen M. , Soberanis Laura Sofía Reyna , Sandoval-Vargas Maria A. , Flores-Robles Bryan-Josué , Téllez-Arreola José Luis 
Published: November 2024

AbstractRetinitis pigmentosa (RP) is a genetically diverse disorder characterized by the progressive degeneration of photoreceptors, ultimately leading to vision impairment and potential blindness. Understanding the disease progression and developing effective therapies is challenging due to its complex genetic landscape. This study unveils a di-genic complexity in RP involving a novel missense mutation in the RIMS1 and RP1 genes, traditionally associated with Cone-Rod Dystrophy. This mutation potentially enhances the RP phenotype, particularly in cases caused by RP1 mutations. We conducted a comprehensive genetic analysis on a family with a severe form of RP, focusing on the combined effects of RIMS1 and RP1. Using a targeted gene panel of 322 inherited retinal dystrophy (IRD) genes, we discovered a significant interaction between the RIMS1 variant and RP1 mutation within the cohort. Interestingly, patients with identical mutations exhibited substantial disease severity and progression differences. This discrepancy was particularly apparent in Patient E_1, who experienced rapid vision decline, emphasizing the impact of the mutation when combined with RP1. Biological network analysis shed light on the intricate genetic interplay, indicating a complex mechanism of disease modulation. Our findings contribute to a more nuanced understanding of RP’s genetic heterogeneity. The RIMS1 variant may serve as a modifier of the disease phenotype. This discovery expands our comprehension of the genetic factors influencing RP and underscores the importance of considering digenic interactions in future research and therapy development for retinal dystrophies.
In Holistic Admissions, a Combination of Non-Academic Explanatory Variables Has Significant Predictive Value for Applicant Ranking
Authors: Bergemann Andrew D. , Smith Stephen R. , Daboub Joel A. 
Published: November 2024

AbstractA medical school with a focus on community engagement has innovated its admissions process to include three different interview formats and one novel task format. Each component is designed to assess specific attributes of applicants, including teamwork skills, cultural competence, and service orientation. Correlations between these components are low, consistent with the original purpose that each should assess different attributes. To understand the use of the data by the members of the committee that ranks applicants, the authors created a model of seven explanatory variables, comprised of the three interview ratings and one task rating, a review of the written applications, and two measures of past academic performance. With regression analysis, the model significantly predicted applicant rankings, with most of the predictive capacity retained after omission of academic metrics. The results display that the school has developed innovations that allow for a reduced dependence upon academic history, and instead uses a truly holistic approach that is tailored to its mission. Most importantly, the work establishes that the admissions committee uses all the diverse forms of data provided to make decisions, which until this point has been an open question in holistic admissions.
Alzheimer’s-associated inflammatory alterations mediate tau-associated neurodegeneration in limbic and temporal regions across clinical variants of Alzheimer’s disease
Authors: Lao Patrick , Lee Seonjoo , Talmasov Daniel , Dass Dina , Chikwem Nbdusi , Johnson Aubrey , Smith Anna , Guzman Diana , Okafor Amarachukwu , Houlihan Hannah , Heuer Lauren , Sanchez Thairi , Rossano Samantha , Kreisl William , Noble James , Qureshi Yasir , Small Scott 
Published: November 2024

AbstractObjectivesMicroglia monitor and respond to the brain’s microenvironment to maintain homeostasis. However, in Alzheimer’s disease and related dementias (ADRD), microglia may contribute to pathology. We hypothesized that AD-related inflammatory changes, measured with TSPO PET, would be locally associated with amyloid, tau, and neurodegeneration, and influence key pathways among them.MethodsParticipants (21 controls, 25 with ADRD) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer’s Disease study underwent baseline amyloid PET (Florbetaben SUVR), tau PET (MK6240 SUVR), TSPO PET (ER176 SUVR), and structural MRI (gray matter volume). Cognitive assessments and consensus diagnoses (e.g., MCI, AD, PCA, FTD, LATE) were performed at the CUIMC ADRC with biomarker information when available. We evaluated regional colocalization of biomarker elevation in ADRD compared to controls, TSPO associations with ATN biomarkers, and TSPO mediations along key ATN pathways. Sensitivity analyses were stratified by amyloid positivity.ResultsElevated TSPO was spatially colocalized with elevated tau (8 regions), amyloid (7 regions), and neurodegeneration (4 regions). Higher TSPO in limbic, temporal, and parietal regions was associated with higher tau (0.8 to 2.3, p<0.03), which remained significant after adjusting for amyloid and neurodegeneration in the inferior parietal cortex. TSPO mediated the association between tau and neurodegeneration in limbic and temporal regions (−0.27 to -0.39,p<0.02; 43%to89%of the total effect), while tau did not mediate the association between TSPO and neurodegeneration. TSPO also mediated the association between amyloid and tau, as well as tau across progressive Braak stages, but only in amyloid-positive ADRD.ConclusionAcross ADRD diagnoses with different underlying brain microenvironments (e.g., pathology/copathology) to which microglia are sensitive, higher microglia density was associated with greater tau burden and mediated tau-associated neurodegeneration. Glia may represent a promising target for intervention strategies in ADRD-associated tau and neurodegeneration.
Using Genetics, Genomics, and Transcriptomics to Identify Therapeutic Targets in Juvenile Idiopathic Arthritis
Authors: Tarbell Evan , Jarvis James N. 
Published: November 2024

AbstractDespite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who had JIA continue to have active disease and have developed functional limitations. Medication side-effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA patients (when compared to healthy controls). Of the 28 candidates, the strongest new target to emerge was homeodomain interacting kinase (HIPK1), which suppresses T cell activation and is within thePTPN22locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls and PML, a known co-regulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.
Association of Hippocampus volume with normal serum Natrium levels and predictive analyses of cognitive adversities in non-demented middle-aged and older adults
Authors: Hallab Asma ,   Alzheimer’s Disease Neuroimaging Initiative
Published: November 2024

AbstractIntroductionSerum Natrium abnormalities are largely observed in older adults and are associated with higher risks. Less is known about the association between serum Natrium variations and medial temporal brain structures, mainly involved in cognition and memory. The study’s objective was to explore the association between serum Natrium and Hippocampus volume and to assess associated cognitive risks.MethodsNon-demented ADNI3 participants (healthy controls (HC) and with mild cognitive impairment (MCI)) with complete serum Natrium, ADAS13score, and Hippocampus volume at baseline were included. Linear and non-linear associations were evaluated. To assess the odds of MCI, logistic regression adjusted was performed. Holm method was used to adjust for Family-wise error rate in the main analysis and reported as aq-value.ResultsA total of 469 cases with a median age of 70 years (IQR: 66, 76) were included. The median serum Natrium level was 141 (IQR: 139, 142). Serum Natrium levels showed a significant association with Hippocampus volume in the total study population and MCI subgroup (Adj.ßMCI=-95 (−162, −28),p=0.006,q=0.036). Serum Natrium levels did not show a significant association neither with the ADAS13 total score (Adj.ßTotal=-0.04(−0.28, 0.21),p=0.8) nor with the odds of being diagnosed with MCI at baseline (ORMCI= 1.00(0.88, 1.13),p= 0.935).ConclusionsNormal Serum Natrium variations were significantly associated with Hippocampus volumes depending on the underlying neurodegenerative pathology, thus, without predicting clinically relevant cognitive adversity. Further studies are needed to better understand the mechanisms and assess protective factors.Key findingsSerum Natrium levels within normal ranges were significantly associated with Hippocampus volume.The association between Serum Natrium levels and Hippocampus volume was particularly significant in participants with mild cognitive impairment.There was no significant association between serum Natrium and ADAS13total score.Serum Natrium levels within normal ranges did not predict concomitant risk of mild cognitive impairment.
Personalized Single-cell Transcriptomics Reveals Molecular Diversity in Alzheimer’s Disease
Authors: Chandrashekar Pramod Bharadwaj , Alatkar Sayali Anil , Kalafut Noah Cohen , Jin Ting , Gupta Chirag , Burzak Ryan , Huang Xiang , Liu Shuang , Li Athan Z. ,   PsychAD Consortium, Girdhar Kiran , Voloudakis Georgios , Hoffman Gabriel E. , Bendl Jaroslav , Fullard John F. , Lee Donghoon , Roussos Panos , Wang Daifeng 
Published: November 2024

AbstractPrecision medicine for brain diseases faces many challenges, including understanding the heterogeneity of disease phenotypes. Such heterogeneity can be attributed to the variations in cellular and molecular mechanisms across individuals. However, personalized mechanisms remain elusive, especially at the single-cell level. To address this, the PsychAD project generated population-level single-nucleus RNA-seq data for 1,494 human brains with over 6.3 million nuclei covering diverse clinical phenotypes and neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD). Leveraging this data, we analyzed personalized single-cell functional genomics involving cell type interactions and gene regulatory networks. In particular, we developed a knowledge-guided graph neural network model to learn latent representations of functional genomics (embeddings) and quantify importance scores of cell types, genes, and their interactions for each individual. Our embeddings improved phenotype classifications and revealed potentially novel subtypes and population trajectories for AD progression, cognitive impairment, and NPSs. Our importance scores prioritized personalized functional genomic information and showed significant differences in regulatory mechanisms at cell type level across various phenotypes. Such information also allowed us to further identify subpopulation-level biological pathways, including ancestry for AD. Finally, we associated genetic variants with cell type-gene regulatory network changes across individuals, i.e., gene regulatory QTLs (grQTLs), providing novel functional genomic insights compared to existing QTLs. We further validated our results using external cohorts. Our analyses are available through iBrainMap, an open-source computational framework, and as a personalized functional genomic atlas for Alzheimer’s Disease.
Visualizing Geospatial and Temporal Phenotype Prevalences
Authors: Murray Michael , Ho Yuk-Lam , Panickan Vidul A. , Heise David , Connatser Keith , Muralidhar Sumitra , Honerlaw Jacqueline , Cho Kelly 
Published: November 2024

ABSTRACTHigh-throughput phenotyping strategies are capable of classifying large volumes of patients. However, translating this data to real world applications is challenging. We have developed GeoPheno, a tool which displays the geospatial prevalences of EHR-based phenotypes in the Veteran population over time. Our flexible tool can display data from a wide array of phenotypes and is integrated with the CIPHER phenotype library, allowing users to view the definitions of the conditions being visualized.
Non-invasive imaging of cell-based therapies using acoustic reporter genes
Authors: Shivaei Shirin , Liu Ann , Abedi Mohamad H. , Revilla Julio , Hurvitz Isabella U. , Swift Margaret B. , Shapiro Mikhail G. 
Published: November 2024

ABSTRACTCell-based therapies are a major emerging category of medicine. The ability of engineered cells to traffic to and function at specific anatomical locations is a major aspect of their performance. However, there is a lack of non-invasive, non-ionizing, cost-accessible methods to track these therapies inside the body and ensure proper function. Here, we establish a platform forin vivoimaging of primary cell therapies using ultrasound – a ubiquitously accessible technology for high-resolution non-invasive imaging. We introduce and optimize a lentiviral delivery system to express acoustic reporter genes based on gas vesicles in primary mammalian cells such as T cells, showing that this results in robust ultrasound contrast. Additionally, we develop genetic circuits making it possible to monitor T cell activation via activity-dependent promoters. We apply this technology to primary human T cells, using it to non-invasively track their accumulation and proliferation as a targeted therapy in a mouse tumor xenograft model and compare it to invasive, terminal measures such as immunohistology. By making it possible to visualize cell-based therapies and their function inside opaque living organs with unprecedented resolution and accessibility, this technology has the potential to significantly accelerate their development and effective use.