bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell landscape of sex differences in the progression of multiple sclerosis
Authors: Soler-Sáez Irene , Gómez-Cabañes Borja , Grillo-Risco Rubén , Galiana-Roselló Cristina , Barea-Moya Lucas , Carceller Héctor , Dolader-Rabinad Beatriz , del Rey Díez Natalia , Virués-Morales Alejandro , Casanova-Ferrer Franc , Gordillo-González Fernando , Yanguas-Casas Natalia , de la Iglesia-Vayá María , Gil-Perotin Sara , Tepavčević Vanja , Hidalgo Marta R. , García-García Francisco 
Published: June 2024

ABSTRACTBackgroundOne of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. The factors mediating this heterogeneity remain unresolved. However, it is known that sex plays a crucial role; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity.ResultsWe profiled 48,919 central nervous system and 336,934 peripheral immune cells, covering the multiple sclerosis spectrum. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8+ T cells progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the user-friendly interactive webtoolhttps://bioinfo.cipf.es/cbl-atlas-ms/.ConclusionsWe identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis progression. We consider this molecular description of sex differences to be valuable resources to promote future targeted approaches to specific molecular mechanisms considering the sex of the individual.
Network nature of ligand-receptor interactions underlies disease comorbidity in the brain
Authors: Grant-Peters Melissa , Fairbrother-Browne Aine , Hicks Amy , Guo Boyi , Reynolds Regina H. , Huuki-Myers Louise , Eagles Nick , Brenton Jonathan , Garcia-Ruiz Sonia , Wood Nicholas , Gandhi Sonia , Maynard Kristen , Collado-Torres Leonardo , Ryten Mina 
Published: June 2024

AbstractNeurodegenerative disorders have overlapping symptoms and have high comorbidity rates, but this is not reflected in overlaps of risk genes. We have investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes associated with disease risk can impact overlapping outcomes. We found that LRIs are likely disrupted in neurological disease and that the ligand-receptor networks associated with neurological diseases have substantial overlaps. Specifically, 96.8% of LRIs associated with disease risk are interconnected in a single LR network. These ligands and receptors are enriched for roles in inflammatory pathways and highlight the role of glia in cross-disease risk. Disruption to this LR network due to disease-associated processes (e.g. differential transcript use, protein misfolding) is likely to contribute to disease progression and risk of comorbidity. Our findings have implications for drug development, as they highlight the potential benefits and risks of pursuing cross-disease drug targets.
Identifying miRNA Signatures Associated with Pancreatic Islet Dysfunction in a FOXA2-Deficient iPSC Model
Authors: Elsayed Ahmed K. , Aldous Noura , Alajez Nehad M. , Abdelalim Essam M. 
Published: June 2024

AbstractThe pathogenesis of diabetes involves complex changes in the expression profiles of mRNA and non-coding RNAs within pancreatic islet cells. Recent progress in induced pluripotent stem cell (iPSC) technology have allowed the modeling of diabetes-associated genes. Our recent study using FOXA2-deficient human iPSC models has highlighted an essential role for FOXA2 in the development of human pancreas. Here, we aimed to provide further insights on the role of microRNAs (miRNAs) by studying the miRNA-mRNA regulatory networks in iPSC-derived islets lacking the FOXA2 gene. Consistent with our previous findings, the absence of FOXA2 significantly downregulated the expression of islet hormones, INS, and GCG, alongside other key developmental genes in pancreatic islets. Concordantly, RNA-Seq analysis showed significant downregulation of genes related to pancreatic development and upregulation of genes associated with nervous system development and lipid metabolic pathways. Furthermore, the absence of FOXA2 in iPSC-derived pancreatic islets resulted in significant alterations in miRNA expression, with 61 miRNAs upregulated and 99 downregulated. The upregulated miRNAs targeted crucial genes involved in diabetes and pancreatic islet cell development. In contrary, the absence of FOXA2 in islets showed a network of downregulated miRNAs targeting genes related to nervous system development and lipid metabolism. These findings highlight the impact of FOXA2 absence on pancreatic islet development and suggesting intricate miRNA-mRNA regulatory networks affecting pancreatic islet cell development.
Vocal error monitoring in the primate auditory cortex
Authors: Eliades Steven J , Tsunada Joji 
Published: June 2024

AbstractSensory-motor control requires the integration and monitoring of sensory feedback resulting from our behaviors. This self-monitoring is thought to result from comparisons between predictions of expected sensory consequences of action and the feedback actually received, resulting in activity that encodes feedback error. Although similar mechanisms have been proposed during speech and vocal production, including sensitivity to experimentally-perturbed auditory feedback, evidence for a vocal ‘error signal’ has been limited. Here, we recorded from the auditory cortex of vocalizing non-human primates, using real-time frequency shifts to introduce feedback errors of varying magnitude and direction. We found neural activity that scaled with the magnitude of feedback error in both directions, consistent with vocal error monitoring at both the individual unit and population levels. This feedback sensitivity was greater than that predicted based upon passive sensory responses and was more specific for units in the vocal frequency range. Similar patterns of sensitivity were seen in response to natural variations in produced vocal acoustics. These results provide evidence that the auditory cortex encodes the degree of vocal feedback error using both unit-level error calculations and changes in the population of neurons involved. These mechanisms may provide critical error information necessary for feedback-dependent vocal control.
Epstein-Barr virus noncoding RNA EBER1 promotes the expression of a ribosomal protein paralog to boost oxidative phosphorylation
Authors: Paudel Sita , Lee Nara 
Published: June 2024

AbstractEpstein-Barr virus (EBV) is a highly successful pathogen that infects ∼95% of the adult population and is associated with diverse cancers and autoimmune diseases. The most abundant viral factor in latently infected cells is not a protein but a noncoding RNA called EBV-encoded RNA 1 (EBER1). Even though EBER1 is highly abundant and was discovered over forty years ago, the function of EBER1 has remained elusive. EBER1 interacts with the ribosomal protein L22, which normally suppresses the expression of its paralog L22-like 1 (L22L1). Here we show that when L22 binds EBER1, it cannot suppress L22L1, resulting in L22L1 being expressed and incorporated into ribosomes. We further show that L22L1-containing ribosomes preferentially translate mRNAs involved in the oxidative phosphorylation pathway. Moreover, upregulation of L22L1 is indispensable for growth transformation and immortalization of resting B cells upon EBV infection. Taken together, our results suggest that the function of EBER1 is to modulate host gene expression at the translational level, thus bypassing the need for dysregulating host gene transcription.
SOD1 Enzymatic Activity in CSF from ALS patients with and withoutSOD1mutations
Authors: Leykam Laura , Forsberg Karin M.E. , Nordström Ulrika , Hjertkvist Karin , Öberg Agneta , Jonsson Eva , Andersen Peter M. , Marklund Stefan L. , Zetterström Per 
Published: June 2024

AbstractSuperoxide dismutase-1 (SOD1) mutations are a common cause of amyotrophic lateral sclerosis (ALS). Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduceSOD1expression shows significant effects on disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for four different inactivatingSOD1mutations developing the Infantile SOD1 Deficiency Syndrome (ISODDES) with injury to both upper and lower motor systems suggests that low SOD1 activities may be deleterious in humans. Monitoring SOD1 activity in cerebrospinal fluid (CSF) from tofersen-treated patients is advisable but difficult due to low levels and the presence of the isoenzyme SOD3. We here present a method to efficiently remove SOD3 from CSF using highly specific immobilized antibodies and subsequent measurement of the SOD activity as a sensitive assay for the SOD1 activity in CSF. We applied the method on CSF samples from ALS patients and controls and used paired erythrocyte samples for comparison. In ALS patients with wildtypeSOD1,the SOD1 activity in CSF was the same as in controls, but patients with mutantSOD1show lower activity in CSF, even patients with mutants previously reported to have full activity in erythrocytes. Activity variation is large among patients carrying the sameSOD1mutation and larger than seen in erythrocytes and in post-mortem central nervous system tissue. SOD1 in CSF shows a high specific activity, indicating that it is mainly native. Lastly, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies for SOD1 ELISA-quantification are raised against the native wildtype enzyme, the content of mutant SOD1s may be underestimated. Direct analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering compounds.
Evolution of polyamine resistance inStaphylococcus aureusthrough modulation of potassium transport
Authors: Campbell Killian , Kowalski Caitlin H. , Kohler Kristin M. , Barber Matthew F. 
Published: June 2024

AbstractMicrobes must adapt to diverse biotic and abiotic factors encountered in host environments. Polyamines are an abundant class of aliphatic molecules that play essential roles in fundamental cellular processes across the tree of life. Surprisingly, the bacterial pathogenStaphylococcus aureusis highly sensitive to polyamines encountered during infection, and acquisition of a polyamine resistance locus has been implicated in spread of the prominent USA300 methicillin-resistantS. aureuslineage. At present, alternative pathways of polyamine resistance in staphylococci are largely unknown. Here we applied experimental evolution to identify novel mechanisms and consequences ofS. aureusadaption when exposed to increasing concentrations of the polyamine spermine. Evolved populations ofS. aureusexhibited striking evidence of parallel adaptation, accumulating independent mutations in the potassium transporter genesktrAandktrD. Mutations in eitherktrAorktrDare sufficient to confer polyamine resistance and function in an additive manner. Moreover, we find that ktr mutations provide increased resistance to multiple classes of unrelated cationic antibiotics, suggesting a common mechanism of resistance. Consistent with this hypothesis, ktr mutants exhibit alterations in cell surface charge indicative of reduced affinity and uptake of cationic molecules. Finally, we observe that laboratory-evolved ktr mutations are also present in diverse naturalS. aureusisolates, suggesting these mutations may contribute to antimicrobial resistance during human infections. Collectively this study identifies a new role for potassium transport inS. aureuspolyamine resistance with consequences for susceptibility to both host-derived and clinically-used antimicrobials.
Endothelial Drp1 Couples VEGF-induced Redox Signaling with Glycolysis Through Cysteine Oxidation to Drive Angiogenesis
Authors: Nagarkoti Sheela , Kim Young-Mee , Das Archita , Ash Dipankar , A.Vitriol Eric , Read Tracy-Ann , Sudhahar Varadarajan , Hossain Md. Selim , Yadav Shikha , McMenamin Malgorzata , Kelley Stephanie , Lucas Rudolf , Stepp David , Belin de Chantemele Eric J. , Caldwell Ruth B. , Fulton David JR. , Fukai Tohru , Ushio-Fukai Masuko 
Published: June 2024

AbstractAngiogenesis plays a vital role for postnatal development and tissue repair following ischemia. Reactive oxygen species (ROS) generated by NADPH oxidases (NOXes) and mitochondria act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly relies on aerobic glycolysis for ATP production. However, the connections linking redox signaling with glycolysis are not well understood. The GTPase Drp1 is a member of the dynamin superfamily that moves from cytosol to mitochondria through posttranslational modifications to induce mitochondrial fission. The role of Drp1 in ROS-dependent VEGF signaling and angiogenesis in ECs has not been previously described. Here, we identify an unexpected function of endothelial Drp1 as a redox sensor, transmitting VEGF-induced H2O2signals to enhance glycolysis and angiogenesis. Loss of Drp1 expression in ECs inhibited VEGF-induced angiogenic responses. Mechanistically, VEGF rapidly induced the NOX4-dependent sulfenylation (CysOH) of Drp1 on Cys644, promoting disulfide bond formation with the metabolic kinase AMPK and subsequent sulfenylation of AMPK at Cys299/304via the mitochondrial fission-mitoROS axis. This cysteine oxidation of AMPK, in turn, enhanced glycolysis and angiogenesis.In vivo, mice with EC-specific Drp1 deficiency or CRISPR/Cas9-engineered “redox-dead” (Cys to Ala) Drp1 knock-in mutations exhibited impaired retinal angiogenesis and post-ischemic neovascularization. Our findings uncover a novel role for endothelial Drp1 in linking VEGF-induced mitochondrial redox signaling to glycolysis through a cysteine oxidation-mediated Drp1-AMPK redox relay, driving both developmental and reparative angiogenesis.
Helper NLR immune protein NRC3 evolved to evade inhibition by a cyst nematode virulence effector
Authors: Sugihara Yu , Kourelis Jiorgos , Contreras Mauricio P. , Pai Hsuan , Selvaraj Muniyandi , Toghani AmirAli , Martínez-Anaya Claudia , Kamoun Sophien 
Published: June 2024

ABSTRACTParasites can counteract host immunity by suppressing nucleotide binding and leucine-rich repeat (NLR) proteins that function as immune receptors. We previously showed that a cyst nematode virulence effector SPRYSEC15 (SS15) binds and inhibits oligomerisation of helper NLR proteins in the expanded NRC1/2/3 clade by preventing intramolecular rearrangements required for NRC oligomerisation into an activated resistosome. Here we examined the degree to which NRC proteins from multiple Solanaceae species are sensitive to suppression by SS15 and tested hypotheses about adaptive evolution of the binding interface between the SS15 inhibitor and NRC proteins. Whereas all tested orthologs of NRC2 were inhibited by SS15, some natural variants of NRC1 and NRC3 are insensitive to SS15 suppression. Ancestral sequence reconstruction combined with functional assays revealed that NRC3 transitioned from an ancestral suppressed form to an insensitive one over 19 million years ago. Our analyses revealed the evolutionary trajectory of coevolution between a parasite inhibitor and its NLR immune receptor target, identifying key evolutionary transitions in helper NLRs that counteract this inhibition. This work reveals a distinct type of gene-for-gene interaction between parasite or pathogen immunosuppressors and host immune receptors that contrasts with the coevolution between AVR effectors and immune receptors.
Microtubule pivoting driven by spindle elongation rescues polar chromosomes to ensure faithful mitosis
Authors: Koprivec Isabella , Štimac Valentina , Mikec Petra , Tolić Iva M. 
Published: June 2024

AbstractPolar chromosomes represent a subset of ∼7 chromosomes in human cells that first attach to the mitotic spindle behind the spindle pole. These chromosomes are delayed in congression to the metaphase plate and prone to segregation errors. Yet, their mechanism of congression remains elusive. By using stimulated emission depletion (STED) and lattice light-sheet (LLS) microscopy, here we show that polar chromosomes require a unique congression step to transit across the spindle pole. This step occurs independently of the known congression drivers, including CENP-E, kinetochore dynein, chromokinesins, and actomyosin. Instead, it relies on the pivoting of chromosome-carrying astral microtubules around the centrosome towards the spindle surface. During pivoting, polar chromosomes form complex attachments with astral microtubules that persist throughout the process. By altering the kinesin-5 Eg5/KIF11 activity to reverse, restore, or block spindle elongation, we show that spindle elongation drives the pivoting and dictates its direction and magnitude. We reveal impaired spindle elongation as a major cause of congression defects and segregation errors of polar chromosomes in RPE1 cells after Mps1 kinase inhibition, and in the high-grade serous ovarian carcinoma OVSAHO cells. Increasing spindle elongation efficiency by depleting the kinesin-4 KIF4A rescued polar chromosomes in OVSAHO cells, supporting the causal relationship between spindle elongation and resolution of polar chromosomes. We conclude that polar chromosomes depend on spindle elongation to propel the pivoting of their astral microtubules, enabling their contact with the spindle surface, congression, and proper segregation. In the context of disease, our findings suggest that altering spindle elongation has the potential to modify mitotic errors in certain cancer cells.
Imputation for Lipidomics and Metabolomics (ImpLiMet): Online application for optimization and method selection for missing data imputation
Authors: Ou Huiting , Surendra Anuradha , McDowell Graeme S.V. , Hashimoto-Roth Emily , Xia Jianguo , Bennett Steffany A.L. , Čuperlović-Culf Miroslava 
Published: June 2024

AbstractMotivationMissing values are often unavoidable in modern high-throughput measurements due to various experimental or analytical reasons. Imputation, the process of replacing missing values in a dataset with estimated values, plays an important role in multivariate and machine learning analyses. Three missingness patterns have been conceptualized: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). Each describes unique dependencies between the missing and observed data. As a result, the optimal imputation method for each dataset depends on the type of data, the cause of the missing data, and the nature of relationships between the missing and observed data. The challenge is to identify the optimal imputation solution for a given dataset.ResultsImpLiMet: is a user-friendly UI-platform that enables users to impute missing data using eight different methods. For the user’s dataset, ImpLiMet can suggest the optimal imputation solution through a grid search-based investigation of the error rate for imputation across three missingness data simulations. The effect of imputation can be visually assessed by histogram, kurtosis and skewness analyses, as well as principal component analysis (PCA) comparing the impact of the chosen imputation method on the distribution and overall behaviour of the data.Availability and implementationImpLiMet is freely available athttps://complimet.ca/shiny/implimet/with software accessible athttps://github.com/complimet/ImpLiMetContactsteffanyann.bennett@uottawa.caandmiroslava.cuperlovic-culf@nrc-cnrc.gca.Supplementary informationSupplementary data are available at Bioinformatics Advances online.
Genome-wide association study reveals the unique genetic structure of active blood donors
Authors: Clancy Jonna , Toivonen Jarkko , Lauronen Jouni , Koskela Satu , Partanen Jukka ,   FinnGen, Arvas Mikko , Ritari Jarmo 
Published: June 2024

AbstractThe healthy donor effect (HDE) refers to the observed lower mortality rate among blood donors compared to the general population. While membership biases such as HDE arise due to healthier individuals being more likely to participate, the extent to which it is influenced by genetic differences remains largely unclear. To elucidate the genetic basis of HDE, we conducted a genome-wide association study (GWAS) involving 53,688 active blood donors with extensive donation histories and 228,060 controls from biobank cohorts within the FinnGen project. Our results identified 2,973 genome-wide significant loci associated with repeated blood donation and impacting several health-related endpoints and protein level alteration. Importantly, significant variants related not only to blood groups but also influenced the predisposition to somatic and mental diseases, suggesting that HDE is not solely tied to blood donation eligibility criteria. In conclusion, in this work we show that HDE is partially explained by genetic factors affecting various disease categories.
Analyzing Diversity in Healthcare LLM Research: A Scientometric Perspective
Authors: Restrepo David , Wu Chenwei , Vásquez-Venegas Constanza , Matos João , Gallifant Jack , Celi Leo Anthony , Bitterman Danielle S. , Nakayama Luis Filipe 
Published: June 2024

AbstractThe deployment of large language models (LLMs) in healthcare has demonstrated substantial potential for enhancing clinical decision-making, administrative efficiency, and patient outcomes. However, the underrepresentation of diverse groups in the development and application of these models can perpetuate biases, leading to inequitable healthcare delivery. This paper presents a comprehensive scientometric analysis of LLM research for healthcare, including data from January 1, 2021, to July 1, 2024. By analyzing metadata from PubMed and Dimensions, including author affiliations, countries, and funding sources, we assess the diversity of contributors to LLM research. Our findings highlight significant gender and geographic disparities, with a predominance of male authors and contributions primarily from high-income countries (HICs). We introduce a novel journal diversity index based on Gini diversity to measure the inclusiveness of scientific publications. Our results underscore the necessity for greater representation in order to ensure the equitable application of LLMs in healthcare. We propose actionable strategies to enhance diversity and inclusivity in artificial intelligence research, with the ultimate goal of fostering a more inclusive and equitable future in healthcare innovation.