bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dynamic microRNA profile that tracks a chemotherapy resistance phenotype in osteosarcoma. Implications for novel therapeutics
Authors: Lietz Christopher E. , Newman Erik T. , Kelly Andrew D. , Xiang David H. , Zhang Ziying , Ramavenkat Nikhil , Bowers Joshua J. , Lozano-Calderon Santiago A. , Ebb David H. , Raskin Kevin A. , Cote Gregory M. , Choy Edwin , Nielsen G. Petur , Vlachos Ioannis S. , Haibe-Kains Benjamin , Spentzos Dimitrios 
Published: June 2024

ABSTRACTOsteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980s despite ongoing efforts. Overall, the five-year survival rate remains about 65%, and is much lower in patients with tumors unresponsive to methotrexate, doxorubicin, and cisplatin therapy. Genetic studies have not revealed actionable drug targets, but our group, and others, have reported that epigenomic biomarkers, including regulatory RNAs, may be useful prognostic tools for osteosarcoma. We tested if microRNA (miRNA) transcriptional patterns mark the transition from a chemotherapy sensitive to resistant tumor phenotype. Small RNA sequencing was performed using 14 patient matched pre-chemotherapy biopsy and post-chemotherapy resection high-grade osteosarcoma frozen tumor samples. Independently, small RNA sequencing was performed using 14 patient matched biopsy and resection samples from untreated tumors. Separately, miRNA specific Illumina DASL arrays were used to assay an independent cohort of 65 pre-chemotherapy biopsy and 26 patient matched post-chemotherapy resection formalin fixed paraffin embedded (FFPE) tumor samples. mRNA specific Illumina DASL arrays were used to profile 37 pre-chemotherapy biopsy and five post-chemotherapy resection FFPE samples, all of which were also used for Illumina DASL miRNA profiling. The National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments dataset, including PCR based miRNA profiling and RNA-seq data for 86 and 93 pre-chemotherapy tumor samples, respectively, was also used. Paired differential expression testing revealed a profile of 17 miRNAs with significantly different transcriptional levels following chemotherapy. Genes targeted by the miRNAs were differentially expressed following chemotherapy, suggesting the miRNAs may regulate transcriptional networks. Finally, anin vitropharmacogenomic screen using miRNAs and their target transcripts predicted response to a set of candidate small molecule therapeutics which potentially reverse the chemotherapy resistance phenotype and synergize with chemotherapy in otherwise treatment resistant tumors. Importantly, these novel therapeutic targets are distinct from targets identified by a similar pharmacogenomic analysis of previously published prognostic miRNA profiles from pre chemotherapy biopsy specimens.
Directed exploration is reduced by an aversive interoceptive state induction in healthy individuals but not in those with affective disorders
Authors: Li Ning , Lavalley Claire A. , Chou Ko-Ping , Chuning Anne E. , Taylor Samuel , Goldman Carter M. , Torres Taylor , Hodson Rowan , Wilson Robert C. , Stewart Jennifer L. , Khalsa Sahib S. , Paulus Martin P. , Smith Ryan 
Published: June 2024

AbstractElevated anxiety and uncertainty avoidance are known to exacerbate maladaptive choice in individuals with affective disorders. However, the differential roles of state vs. trait anxiety remain unclear, and underlying computational mechanisms have not been thoroughly characterized. In the present study, we investigated how a somatic (interoceptive) state anxiety induction influences learning and decision-making under uncertainty in individuals with clinically significant levels of trait anxiety. A sample of 58 healthy comparisons (HCs) and 61 individuals with affective disorders displaying elevated anxiety symptoms (iADs; i.e., anxiety and/or depression) completed a previously validated explore-exploit decision task, with and without an added breathing resistance manipulation designed to induce state anxiety. Computational modeling revealed a significant group-by-condition interaction, such that information-seeking (i.e., directed exploration) in HCs was reduced by the anxiety induction (Cohen’sd=.47,p=.013), while no change was observed in iADs. The iADs also showed slower learning rates than HCs across conditions (Cohen’sd=.52,p=.003), suggesting more persistent uncertainty. These findings highlight a complex interplay between trait anxiety and state anxiety. Specifically, state anxiety may attenuate reflection on uncertainty in healthy individuals, while familiarity with anxious states in those with high trait anxiety may create an insensitivity to this effect.
Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation
Authors: Singh Madhurbain , Dolan Conor V. , Lapato Dana M. , Hottenga Jouke-Jan , Pool René , Verhulst Brad , Boomsma Dorret I. , Breeze Charles E. , de Geus Eco J. C. , Hemani Gibran , Min Josine L. , Peterson Roseann E. , Maes Hermine H. M. , van Dongen Jenny , Neale Michael C. 
Published: June 2024

AbstractCigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects. Here, we apply an integrated approach combining MR with twin causal models to examine causality between smoking and blood DNAm in the Netherlands Twin Register (N=2577). Analyses revealed potential causal effects of current smoking on DNAm at >500 sites in/near genes enriched for functional pathways relevant to known biological effects of smoking (e.g., hemopoiesis, cell- and neuro-development, and immune regulation). Notably, we also found evidence of reverse and bidirectional causation at several DNAm sites, suggesting that variation in DNAm at these sites may influence smoking liability. Seventeen of the loci with putative effects of DNAm on smoking showed highly specific enrichment for gene-regulatory functional elements in the brain, while the top three sites annotated to genes involved in G protein-coupled receptor signalling and innate immune response. These novel findings are partly attributable to the analyses ofcurrentsmoking in twin models, rather thanlifetimesmoking typically examined in MR studies, as well as the increased statistical power achieved using multiallelic/polygenic scores as instrumental variables while controlling for potential horizontal pleiotropy. This study highlights the value of twin studies with genotypic and DNAm data for investigating causal relationships of DNAm with health and disease.
High mortality and complications in patients admitted with Takotsubo cardiomyopathy without improvement in outcomes over the years
Authors: Movahed Mohammad Reza , Javanmardi Elimira , Hashemzadeh Mehrtash 
Published: June 2024

AbstractIntroductionTakotsubo cardiomyopathy continues to be a major cause of mortality and morbidity. The goal of this study was to evaluate the outcome data of patients with Takotsubo cardiomyopathy using a large inpatient database.MethodsWe used the Nationwide inpatient sample (NIS) database for our study. We evaluated trends, mortality, and complications of patients admitted with Takotsubo cardiomyopathy from available 2016-2020 years in adults over the age of 18.ResultsA total of 199,890 patients with Takotsubo were found in our database with 83% being female and higher prevalence with age, Caucasian race, and highest income. Mortality was high at 6.5 % with no significant improvement over the years studied. Furthermore, major complications were substantial. Cardiogenic shock occurred in 6.6%, atrial fibrillation in 20.7%, Cardiac arrest in 3.4%, congestive heart failure in 35.9% and stroke in 5.3%.ConclusionTakotsubo cardiomyopathy is associated with high mortality and complications with no improvement in outcome over the 5 years study. Further improvement in care is needed to improve outcomes.
Stress-induced hyperglycemia predicts poor outcomes in primary ICH patients
Authors: Gilotra Kevin , Basem Jade , Janssen Melissa , Swarna Sujith , Mani Racheed , Ren Benny , Dashti Reza 
Published: June 2024

AbstractIntroductionThe current literature suggests hyperglycemia can predict poor outcomes in patients with primary intracerebral hemorrhage (ICH). Chronic hyperglycemia is seen in patients with pre-existing diabetes (DM), however, acute hyperglycemia in non-diabetic patients is defined as stress-induced hyperglycemia (SIH). This study explored the influence of hyperglycemia on outcomes of primary ICH patients both in the presence and absence of pre-existing DM.MethodsData regarding admission glucose, pre-existing DM, inpatient mortality, and modified Rankin scale (mRS) scores at discharge were available for 636 patients admitted to Stony Brook Hospital from January 2011 to December 2022 with a primary diagnosis of ICH. Regression models were used to compare outcomes between patients with admission hyperglycemia and/or pre-existing DM to a control group of normoglycemic and non-diabetic ICH patients.ResultsPatients with SIH had higher inpatient mortality rates and worse mRS scores at discharge (p<0.001). An association with higher mortality and worse mRS scores at discharge was also seen in patients with hyperglycemia secondary to DM, although the strength of this association was weaker when compared to patients with SIH.ConclusionIn conclusion, our study’s findings suggest that SIH may play a greater role in predicting poor outcomes at discharge rather than a history of poorly controlled DM with chronic hyperglycemia. To develop a more thorough understanding of this topic, prospective studies evaluating the effect of changes in serum glucose during hospital stay on short and long-term outcomes is needed.
α-Synuclein acts as a cholesteryl-ester sensor on lipid droplets regulating organelle size and abundance
Authors: Jacob Reeba Susan , Dema Alessandro , Chérot Hélène , Dumesnil Calvin , Cohen Shira , Shalom Hadas Sar , Rimon Nitzan , Sibony-Nevo Odelia , Beck Gilad , Ainbinder Elena , Wolinski Heimo , Athenstaedt Karin , Theillet Francois-Xavier , Thiam Abdou Rachid , Selenko Philipp 
Published: June 2024

AbstractWhile aggregated alpha-Synuclein (αSyn) is commonly associated with Parkinson’s disease, its physiological function as a membrane-binding protein is poorly understood. Here, we show that endogenous αSyn binds lipid droplets (LDs) in multiple human cell lines and in stem cell-derived dopaminergic neurons. LD-binding encompasses αSyn residues 1-100, which masks their detection by immunofluorescence microscopy, probably explaining the scarcity of similar observations in earlier studies. αSyn-LD interactions are highly temperature-sensitive and selective for cholesteryl-ester-rich LDs. They promote the formation of αSyn multimers that dissociate from LDs at non-permissive temperatures. αSyn remains LD-bound throughout starvation-induced lipolysis, whereas siRNA-knockdown diminishes LD abundance and compromises cell viability upon nutrient depletion, without affecting LD biosynthesis. Reciprocally, excess αSyn stimulates LD accumulation in dependence of lipid availability, restricts organelle size and ensures intracellular LD organization, which strictly depends on functional membrane-binding. Supporting a general role of αSyn in cellular lipid and cholesterol metabolism, our results point to additional loss-of-function similarities between Parkinson’s, Alzheimer’s and Gaucher’s disease.
A comparative study of the cryo-EM structures ofS. cerevisiaeand human anaphase-promoting complex/cyclosome (APC/C)
Authors: Vazquez-Fernandez Ester , Yang Jing , Zhang Ziguo , Andreeva Antonina E. , Emsley Paul , Barford David 
Published: June 2024

AbstractThe anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that controls progression through the cell cycle by orchestrating the timely proteolysis of mitotic cyclins and other cell cycle regulatory proteins. Although structures of multiple human APC/C complexes have been extensively studied over the past decade, theS. cerevisiaeAPC/C has been less extensively investigated. Here, we describe medium resolution structures of threeS. cerevisiaeAPC/C complexes: unphosphorylated apo-APC/C and the ternary APC/CCDH1-substrate complex, and phosphorylated apo-APC/C. Whereas the overall architectures of human andS. cerevisiaeAPC/C are conserved, as well as the mechanism of CDH1 inhibition by CDK-phosphorylation, specific variations exist, including striking differences in the mechanism of coactivator-mediated stimulation of E2 binding, and the activation of APC/CCDC20by phosphorylation. In contrast to human APC/C in which coactivator induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, inS. cerevisiaeapo-APC/C the catalytic module is already positioned to bind E2. Furthermore, we find no evidence of a phospho-regulatable auto-inhibitory segment of APC1, that in the unphosphorylated human APC/C, sterically blocks the CDC20C-boxbinding site of APC8. Thus, although the functions of APC/C are conserved fromS. cerevisiaeto humans, molecular details relating to their regulatory mechanisms differ.
Identify Regulatory eQTLs by Multiome Sequencing in Prostate Single Cells
Authors: Tian Yijun , Wu Lang , Huang Chang-Ching , Wang Liang 
Published: June 2024

AbstractWhile genome-wide association studies and expression quantitative trait loci (eQTL) analysis have made significant progress in identifying noncoding variants associated with prostate cancer risk and bulk tissue transcriptome changes, the regulatory effect of these genetic elements on gene expression remains largely unknown. Recent developments in single-cell sequencing have made it possible to perform ATAC-seq and RNA-seq profiling simultaneously to capture functional associations between chromatin accessibility and gene expression. In this study, we tested our hypothesis that this multiome single-cell approach allows for mapping regulatory elements and their target genes at prostate cancer risk loci. We applied a 10X Multiome ATAC + Gene Expression platform to encapsulate Tn5 transposase-tagged nuclei from multiple prostate cell lines for a total of 65,501 high quality single cells from RWPE1, RWPE2, PrEC, BPH1, DU145, PC3, 22Rv1 and LNCaP cell lines. To address data sparsity commonly seen in the single-cell sequencing, we performed targeted sequencing to enrich sequencing data at prostate cancer risk loci involving 2,730 candidate germline variants and 273 associated genes. Although not increasing the number of captured cells, the targeted multiome data did improve eQTL gene expression abundance by about 20% and chromatin accessibility abundance by about 5%. Based on this multiomic profiling, we further associated RNA expression alterations with chromatin accessibility of germline variants at single cell levels. Cross validation analysis showed high overlaps between the multiome associations and the bulk eQTL findings from GTEx prostate cohort. We found that about 20% of GTEx eQTLs were covered within the significant multiome associations (p-value ≤ 0.05, gene abundance percentage ≥ 5%), and roughly 10% of the multiome associations could be identified by significant GTEx eQTLs. We also analyzed accessible regions with available heterozygous SNP reads and observed more frequent association in genomic regions with allelically accessible variants (p= 0.0055). Among these findings were previously reported regulatory variants including rs60464856-RUVBL1 (multiomep-value = 0.0099 in BPH1)and rs7247241-SPINT2 (multiomep-value = 0.0002- 0.0004 in 22Rv1). We also functionally validated a new regulatory SNP and its target gene rs2474694-VPS53 (multiomep-value = 0.00956 in BPH1 and 0.00625 in DU145) by reporter assay and SILAC proteomics sequencing. Taken together, our data demonstrated the feasibility of the multiome single-cell approach for identifying regulatory SNPs and their regulated genes.
Similarities and differences between brain and skinGNAQp.R183Q driven capillary malformations
Authors: Nasim Sana , Bichsel Colette , Pinto Anna , Alexandrescu Sanda , Kozakewich Harry , Bischoff Joyce 
Published: June 2024

AbstractCapillary malformations (CM) are congenital vascular irregularities of capillary and venous blood vessels that appear in the skin, leptomeninges of the brain, and the choroid of the eye in the disorder known as Sturge Weber Syndrome (SWS). More common are non-syndromic CM found only in the skin, without brain or ocular involvement. A somatic activating mutation inGNAQ(p.R183Q) is found in ∼90% of syndromic and non-syndromic CM specimens and is present in CD31posendothelial cells isolated from brain and skin CM specimens. Endothelial expression of theGNAQp.R183Q variant is sufficient to form CM-like vessels in mice. Given the distinct features and functions of blood vessels in the brain versus the skin, we examined the features of CM vessels in both tissues to gain insights into the pathogenesis of CM. Herein, we present morphologic characteristics of CM observed in specimen from brain and skin. TheGNAQp.R183Q variant allelic frequency in each specimen was determined by droplet digital PCR. Sections were stained for endothelial cells, tight junctions, mural cells, and macrophages to assess the endothelium as well as perivascular constituents. CM blood vessels in brain and skin were enlarged, exhibited fibrin leakage and reduced zona occludin-1, and were surrounded by MRC1pos/LYVE1posmacrophages. In contrast, the CMs from brain and skin differ in endothelial sprouting activity and localization of mural cells. These characteristics might be helpful in the development of targeted and/or tissue specific therapies to prevent or reverse non-syndromic and syndromic CM.Statements and DeclarationsNone
PathogenicBacteroides fragilisstrains can emerge from gut-resident commensals
Authors: Oles Renee E. , Terrazas Marvic Carrillo , Loomis Luke R. , Neal Maxwell J. , Paulchakrabarti Mousumi , Zuffa Simone , Hsu Chia-Yun , Vasquez Ayala Adriana , Lee Michael H. , Tribelhorn Caitlin , Belda-Ferre Pedro , Bryant MacKenzie , Zemlin Jasmine , Young Jocelyn , Dulai Parambir , Sandborn William J. , Sivagnanam Mamata , Raffatellu Manuela , Pride David , Dorrestein Pieter C. , Zengler Karsten , Choudhury Biswa , Knight Rob , Chu Hiutung 
Published: June 2024

SUMMARYBacteroides fragilisis a prominent member of the human gut microbiota, playing crucial roles in maintaining gut homeostasis and host health. Although it primarily functions as a beneficial commensal,B. fragiliscan become pathogenic. To determine the genetic basis of its duality, we conducted a comparative genomic analysis of 813B. fragilisstrains, representing both commensal and pathogenic origins. Our findings reveal that pathogenic strains emerge across diverse phylogenetic lineages, due in part to rapid gene exchange and the adaptability of the accessory genome. We identified 16 phylogenetic groups, differentiated by genes associated with capsule composition, interspecies competition, and host interactions. A microbial genome-wide association study identified 44 genes linked to extra-intestinal survival and pathogenicity. These findings reveal how genomic diversity within commensal species can lead to the emergence of pathogenic traits, broadening our understanding of microbial evolution in the gut.
ER-GUARD: an evolutionarily conserved antioxidant defense system at ER membranes
Authors: Ji Zhijian , Pandey Taruna , de Belly Henry , Wang Bingying , Weiner Orion D. , Tang Yao , Guang Shouhong , Goddard Thomas D. , Ma Dengke K. 
Published: June 2024

AbstractOxidative protein folding in the endoplasmic reticulum (ER) is essential for all eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species (ROS). The ER-transmembrane protein that provides reducing equivalents to ER and guards the cytosol for antioxidant defense remains unidentified. Here we combine AlphaFold2- based and functional reporter screens inC. elegansto identify a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles.DeletingC. elegansERGU-1 causes excessive H2O2 and transcriptional gene up- regulation through SKN-1, homolog of mammalian antioxidant master regulator NRF2. ERGU-1 deficiency also impairs organismal reproduction and behaviors. BothC. elegansand human ERGU-1 proteins localize to ER membranes and form network reticulum structures. We name this system ER-GUARD,EndoplasmicReticulumGuardianAegis ofRedoxDefense. Human andDrosophilahomologs of ERGU-1 can rescueC. elegansmutant phenotypes, demonstrating evolutionarily ancient and conserved functions. Together, our results reveal an ER-membrane-specific protein machinery and defense-net system ER-GUARD for peroxide detoxification and suggest a previously unknown but conserved pathway for antioxidant defense in animal cells.
An Open-Source Deep Learning-Based GUI Toolbox For Automated Auditory Brainstem Response Analyses (ABRA)
Authors: Erra Abhijeeth , Chen Jeffrey , Chrysostomou Elena , Barret Shannon , Miller Cayla , Kassim Yasmin M. , Friedman Rick A. , Ceriani Federico , Marcotti Walter , Carroll Cody , Manor Uri 
Published: June 2024

AbstractIn this paper, we introduce a new, open-source software developed in Python for analyzing Auditory Brainstem Response (ABR) waveforms. ABRs are a far-field recording of synchronous neural activity generated by the auditory fibers in the ear in response to sound, and used to study acoustic neural information traveling along the ascending auditory pathway. Common ABR data analysis practices are subject to human interpretation and are labor-intensive, requiring manual annotations and visual estimation of hearing thresholds. The proposed new Auditory Brainstem Response Analyzer (ABRA) software is designed to facilitate the analysis of ABRs by supporting batch data import/export, waveform visualization, and statistical analysis. Techniques implemented in this software include algorithmic peak finding, threshold estimation, latency estimation, time warping for curve alignment, and 3D plotting of ABR waveforms over stimulus frequencies and decibels. The excellent performance on a large dataset of ABR collected from three labs in the field of hearing research that use different experimental recording settings illustrates the efficacy, flexibility, and wide utility of ABRA.
Long-Lived Coherence on a
μHz
Scale Optical Magnetic Quadrupole Transition
Authors: Klüsener V. , Pucher S. , Yankelev D. , Trautmann J. , Spriestersbach F. , Filin D. , Porsev S. G. , Safronova M. S. , Bloch I. , Blatt S. 
Published: June 2024

We report on the coherent excitation of the ultranarrow S01–P23 magnetic quadrupole transition in Sr88. By confining atoms in a state insensitive optical lattice, we achieve excitation fractions of 97(1)% and observe linewidths as narrow as 58(1) Hz. With Ramsey spectroscopy, we find coherence times of 14(1) ms, which can be extended to 266(36) ms using a spin-echo sequence. We determine the lifetime of the P23 level for spontaneous emission of magnetic quadrupole radiation to be 110(31) min, confirming long-standing theoretical predictions. These results establish an additional clock transition in strontium and pave the way for applications of the metastable P23 state in quantum computing and quantum simulations.

Published by the American Physical Society
2024