bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation
Authors: Bathla S , Datta D , Bolat D , Woo E , Duque A , Arellano J , Arnsten AFT , Nairn AC
Published: December 2024

Tau pathology in sporadic Alzheimer’s disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation. Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways. Our findings reveal age-related decreases in PDE4 phosphodiesterases that hydrolyze cAMP and increases in calpain-2 and GCPII that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau). These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, primes tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.
Biofabrication of a filtration barrier by integrating electrospun membranes and flow in a glomerular co-culture
Authors: Mussoni Camilla , Rederer Anna , Stepanenko Vladimir , Würthner Frank , Stahlhut Philipp , Groll Jürgen , Schiffer Mario , Ahmad Taufiq , Müller-Deile Janina
Published: December 2024

The glomerulus is the functional unit of the kidney, where urine is filtered from blood. This process happens through the glomerular filtration barrier (GFB) which is composed of glomerular endothelial cells, podocytes, and glomerular basement membrane (GBM). Damage to any component of GFB results in failure of the barrier’s function, causing proteinuria that can lead to end-stage kidney failure. There is a high need for reliablein vitromodels of the GFB to study pathological conditions and to test potential novel therapeutic options. We established an artificial GBM generated by electrospinning of poly-L-lactic acid fibers that were coated with polydopamine and gelatin and seeded with human glomerular endothelial cells and podocytes onto different sides. The orientation of fibers in the artificial GBM, their surface chemistry and effects on glomerular cells were characterized in depth. Glomerular endothelial cells and podocytes, including hiPSC-derived podocytes formed monolayers on the artificial GBM and revealed cell type-specific marker expression and morphology. Cell-cell communication was possible between podocytes and glomerular endothelial cells in both directions though the artificial membrane. Different molecular dextrans showed size selective permeability of theex vivoGFB model. Introduction of shear stress by applying flow with a 3D printed micro-bioreactor improved cellular ultrastructure with formation of glomerular endothelial cell fenestrae-like structures and long podocyte foot process-like protrusions that both are usually absent in otherin vitromodels. Personalized hiPSC-derived podocytes within our model will allow to study the role of patient-specific podocyte mutations or individual treatment responseex vivoin the future.
A subset of mouse hippocampus CA1 pyramidal neurons learns sparse synaptic input patterns
Authors: Shahul Anzal K , Bhalla Upinder Singh
Published: December 2024

Synaptic plasticity in the hippocampus is fundamental to learning and memory, yet few studies examine how pattern learning occurs across multiple synapses. Such cross-synapse learning is fundamental to emergent properties of pattern discrimination and generalisation, which depend on assumptions about independence of plasticity and linearity of summation. We used sparse optogenetic spatio-temporal ‘pattern stimulation in the CA3 coupled with postsynaptic depolarization to elicit plasticity on CA1 pyramidal neurons, and found that ‘trained’ patterns were selectively strengthened, but only in a subset of postsynaptic cells. Increased resting membrane potential and background mini-EPSP rates were predictive of learner cells. Summation following plasticity became more linear in learners compared to non-learners, consistent with the observed elevated post-stimulus hyperpolarization on non-learner cells. Thus our exploration of biologically plausible sparse activity supports pattern-selective learning, but in a heterogeneous manner modulated by both cell-intrinsic and network features.
Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy
Authors: Kashiwakura Yuji , Nakajima Yuto , Horinaka Kio , Lopes Tiago Jose da Silva , Furuta Yuma , Yamaguchi Yuki , Baatartsogt Nemekhbayar , Hayakawa Morisada , Katakai Yuko , Uchiyama Susumu , Nureki Osamu , Nogami Keiji , Ohmori Tsukasa
Published: December 2024

The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). Here, we developed engineered human B-domain-deleted FVIIIs (FVIIISQs) with enhanced secretion and coagulation potential. Intracellular accumulation was markedly reduced in some engineered FVIIISQs, resulting in reduced unfolded protein responses. The administration of AAV vectors carrying engineered FVIIISQ to hemophilia A mice resulted in approximately eight-fold higher FVIII activity and four-fold higher FVIII antigen levels compared with wild-type FVIIISQ administration. The specific FVIII activity of the engineered FVIIISQ was 3.6 times higher than that of the wild-type FVIIISQ, and its binding to activated coagulation factor IX was significantly enhanced, which is supported by the structural analysis. In macaques, the administration of AAV5 vector carrying the engineered FVIIISQ without CpG sequences resulted in a supra-physiological increase in plasma FVIII activity at a dose one-thirtieth that of valoctocogene roxaparvovec (2 x 10 to the power of 12 vg/kg). The engineered FVIIISQ may thus provide stable, long-term therapeutic efficacy in AAV-mediated hemophilia A gene therapy even at low doses.
More than 2,500 coding genes in the human reference gene set still have unsettled status
Authors: Maquedano Miguel , Cerdán-Vélez Daniel , Tress Michael L.
Published: December 2024

In 2018 we analysed the three main repositories for the human proteome, Ensembl/GENCODE, RefSeq and UniProtKB. They disagreed on the coding status of one of every eight annotated coding genes. The analysis inspired bilateral collaborations between annotation groups.

Here we have repeated our analysis with updated versions of the three reference coding gene sets. Superficially, little appears to have changed. Although there are slightly fewer genes predicted as coding overall, the three groups still disagree on the status of 2,606 annotated genes. However, a comparison without read-through genes and immunoglobulin fragments shows that the three reference sets have merged or reclassified more than 700 genes since the last analysis and that just 0.6% of Ensembl/GENCODE coding genes are not also annotated by the other two reference sets.

We used eight features indicative of non-coding genes to examine the 21,873 coding genes annotated across the three reference sets. We found that more than 2,000 had one or more potential non-coding features. While some of these genes will be protein coding, we believe that most are likely to be non-coding genes or pseudogenes. Our results suggest that annotators still vastly overestimate the number of true coding genes.
A Novel Taxonomic Database for eukaryotic Mitochondrial Cytochrome Oxidase subunit I Gene (eKOI): Enhancing taxonomic resolution at community-level in metabarcoding analyses
Authors: González-Miguéns Rubén , Gàlvez-Morante Alex , Skamnelou Margarita , Antó Meritxell , Casacuberta Elena , Richter Daniel J. , Vaulot Daniel , del Campo Javier , Ruiz-Trillo Iñaki
Published: December 2024

Metabarcoding has emerged as a robust method for understanding biodiversity patterns by retrieving environmental DNA (eDNA) directly from ecosystems. Its low cost and accessibility have extended its use across biological topics, from symbiosis to biogeography, and ecology. A successful metabarcoding application depends on accurate and comprehensive reference databases for proper taxonomic assignment. The 18S rRNA gene is the primary genetic marker used for general/broad eukaryotic metabarcoding due to its combination of conserved and hypervariable regions, and the availability of extensive taxonomically-informed reference databases like PR2 and SILVA. Despite its advantages, 18S rRNA has certain limitations at lower taxonomic levels, depending on the lineage. Alternative fast-evolving molecular markers, such as the mitochondrial cytochrome oxidase subunit I (COI) gene, have been adopted as widely used "barcoding genes" for eukaryotes due to their resolution to the species level. However, the COI gene lacks a curated taxonomically-informed database covering all eukaryotes, including protists, comparable to those available for 18S rRNA. To address this gap, we introduce eKOI, a curated COI gene database aimed at enhancing the taxonomic annotation and primer design for COI-based metabarcoding at the community level. This database integrates COI gene data from GenBank and mitochondrial genomes that are publicly available, followed by rigorous manual curation to eliminate redundancies and contaminants and to correct taxonomic annotations. We validate using the eKOI database for taxonomic annotation of protists by re-annotating several COI-based metabarcoding studies, revealing previously unidentified biodiversity. Phylogenetic analyses confirmed the accuracy of the taxonomic annotations, highlighting the potential of eKOI to uncover new biodiversity in various eukaryotic lineages.
One Hundred Neural Networks and Brains Watching Videos: Lessons from Alignment
Authors: Sartzetaki Christina , Roig Gemma , Snoek Cees G.M. , Groen Iris Isabelle Anna
Published: December 2024

What can we learn from comparing video models to human brains, arguably the most efficient and effective video processing systems in existence? Our work takes a step towards answering this question by performing the first large-scale benchmarking of deep video models on representational alignment to the human brain, using publicly available models and a recently released video brain imaging (fMRI) dataset. We disentangle four factors of variation in the models (temporal modeling, classification task, architecture, and training dataset) that affect alignment to the brain, which we measure by conducting Representational Similarity Analysis across multiple brain regions and model layers. We show that temporal modeling is key for alignment to brain regions involved in early visual processing, while a relevant classification task is key for alignment to higher-level regions. Moreover, we identify clear differences between the brain scoring patterns across layers of CNNs and Transformers, and reveal how training dataset biases transfer to alignment with functionally selective brain areas. Additionally, we uncover a negative correlation of computational complexity to brain alignment. Measuring a total of 99 neural networks and 10 human brains watching videos, we aim to forge a path that widens our understanding of temporal and semantic video representations in brains and machines, ideally leading towards more efficient video models and more mechanistic explanations of processing in the human brain.
Trial-by-trial inter-areal interactions in visual cortex in the presence or absence of visual stimulation
Authors: Hidalgo Dianna , Dellaferrera Giorgia , Xiao Will , Papadopouli Maria , Smirnakis Stelios , Kreiman Gabriel
Published: December 2024

State-of-the-art computational models of vision largely focus on fitting trial-averaged spike counts to visual stimuli using overparameterized neural networks. However, a computational model of the visual cortex should predict the dynamic responses of neurons in single trials across different experimental conditions. In this study, we investigated trial-by-trial inter-areal interactions in the visual cortex by predicting neuronal activity in one area based on activity in another, distinguishing between stimulus-driven and non-stimulus-driven shared variability. We analyzed two datasets: calcium imaging from mouse V1 layers 2/3 and 4, and extracellular neurophysiological recordings from macaque V1 and V4. Our results show that neuronal activity can be predicted bidirectionally between L2/3 and L4 in mice, and between V1 and V4 in macaques, with the latter interaction exhibiting directional asymmetry. The predictability of neuronal responses varied with the type of visual stimulus, yet responses could also be predicted in the absence of visual stimulation. In mice, we observed a bimodal distribution of neurons, with some neurons primarily driven by visual inputs and others showing predictable activity during spontaneous activity despite lacking consistent visually evoked responses. Predictability also depended on intrinsic neuronal properties, receptive field overlap, and the relative timing of activity across areas. Our findings highlight the presence of both stimulus- and non-stimulus-related components in interactions between visual areas across diverse contexts and underscore the importance of non-visual shared variability between visual regions in both mice and macaques.
A scalable method for modulating plant gene expression using a multispecies genomic model and protoplast-based massively parallel reporter assay
Authors: Jevtic Sania , Drapek Colleen , Gaillochet Christophe , Brockman Andrew , Cadman James , Flesch Timo , Kral Nicolas
Published: December 2024

Precision breeding tools such as CRISPR-Cas genome editing can speed up innovation in plant biotechnology and boost crop yields. The challenge remains to efficiently apply precision breeding methods to plant gene regulation. Endogenous gene regulatory sequences are subject to complex transcriptional control, a bottleneck in altering gene expression patterns in a predictable way. Here we present the CRE.AI.TIVE platform, enabling upregulation of plant gene activity withouta prioriknowledge of individual cis-regulatory elements or their specific location. A predictive machine learning model underpinning the platform has been trained on a wide range of tissue specific transcriptomic and epigenomic coverage datasets from DNA sequence of 12 plant species, showing competitive performance on RNA-seq coverage prediction across all species. Our platform further combinesin silicoDNA sequence mutagenesis and a protoplast-based massively parallel reporter assay (MPRA). We demonstrate the platform’s functionality by mutagenesis of a proximal promoter of the tomato gene SlbHLH96 which yields predictions of variant gene activityin silico. 2,000 sequence candidates with varying predicted gene expression strength were validated with MPRA in plant protoplasts, identifying variants with significantly upregulated gene activity. A portion of functional sequence variants were further individually evaluated with a fluorescence reporter assay and were observed to contain a new order of known cis-regulatory elements. The CRE.AI.TIVE platform offers a first-of-its-kind scalable method of gene upregulation in plants with native DNA sequences without the need for CRE cataloguing and rational promoter design.
Phylodynamic inference on single-cell data
Authors: Dieselhorst Tobias , Berg Johannes
Published: December 2024

The way mutations accumulate over the course of evolution fundamentally differs between macroevolutionary settings and cellular reproduction. In macroevolution, mutations generally accumulate continuously over time. Under cellular reproduction, like somatic evolution within a tumor or evolution within a bacterial population, mutations occur largely in discrete steps at individual reproductive events. In this paper, we address the problem of phylodynamic inference under cellular reproduction. We find that when mutations occur at cell divisions, the number of mutations along a phylogenetic branch follows a compound Poisson statistics rather than a Poisson statistics, and this affects the inference from phylogenetic data. Based on the likelihood of a birth-death model, we set up an inference scheme for the relative death-to-birth rate and the number of mutations per generation and apply this method to haematopoietic stem cells. Our approach is computationally efficient thus allowing a broad range of applications, in particular on lineage trees from single-cell data.
Score matching for differential abundance testing of compositional high-throughput sequencing data
Authors: Ostner Johannes , Li Hongzhe , Müller Christian L.
Published: December 2024

The class of a-b power interaction models, proposed by Yu et al. (2024), provides a general framework for modeling sparse compositional count data with pairwise feature interactions. This class includes many distributions as special cases and enables modeling of zero counts through power transformations, making it particularly suitable for modern high-throughput sequencing data with excess zeros, including single-cell RNA-Seq and microbial amplicon data. Here, we present an extension of this class of models that allows inclusion of covariate information, thus enabling accurate characterization of covariate dependencies in heterogeneous populations. Combining this model with a tailored differential abundance (DA) test leads to a novel DA testing scheme, cosmoDA, that can reduce false positive detection rate caused by correlated features. cosmoDA uses penalized generalized score matching for parsimonious model fitting. We show on simulated benchmarks that cosmoDA can accurately estimate feature interactions in the presence of population heterogeneity and significantly reduces the false discovery rate when testing for differential abundance of correlated features. Using single-cell and amplicon data, we illustrate cosmoDA's ability to estimate data-adaptive Box-Cox-type data transformations and assess the impact of zero replacement and power transformations on downstream differential abundance results. cosmoDA is available at https://github.com/bio-datascience/cosmoDA.
Interleukin-4 induces CD11c+microglia leading to amelioration of neuropathic pain in mice
Authors: Kohno Keita , Shirasaka Ryoji , Hirose Keita , Masuda Takahiro , Tsuda Makoto
Published: December 2024

Neuropathic pain, a debilitating chronic pain condition, is a major clinical challenge. The pleiotropic cytokine interleukin-4 (IL-4) has been shown to suppress neuropathic pain in rodent models, but its underlying mechanism remains unclear. Here, we show that intrathecal administration of IL-4 to mice with spinal nerve transection (SpNT) increased the number of CD11c+microglia (a microglia subset important for pain remission) in the spinal dorsal horn (SDH) and that this effect of IL-4 was essential for its ameliorating effect on SpNT-induced pain hypersensitivity. Furthermore, in mice with spared nerve injury (SNI), another model in which pain remission does not occur, the emergence of CD11c+SDH microglia was curtailed, but intrathecal IL-4 increased their emergence and ameliorated pain hypersensitivity in a CD11c+microglia-dependent manner. Our study reveals a mechanism by which intrathecal IL-4 ameliorates pain hypersensitivity after nerve injury and provides evidence that IL-4 increases CD11c+microglia with a function that ameliorates neuropathic pain.
Modelling inter-shot variability for robust temporal sub-sampling of dynamic, GABA-edited MR spectroscopy data
Authors: Craven Alexander R. , Ersland Lars , Hugdahl Kenneth , Grüner Renate
Published: December 2024

Variability between individual transients in an MRS acquisition presents a challenge for reliable quantification, particularly in functional scenarios where discrete subsets of the available transients may be compared. The current study aims to develop and validate a model for removing unwanted variance from GABA-edited MRS data, whilst preserving variance of potential interest – such as metabolic response to a functional task.

A linear model is used to describe sources of variance in the system: intrinsic, periodic variance associated with phase cycling and spectral editing, and abrupt changes associated with subject movement. We broadly hypothesize that modelling these factors appropriately will improve spectral quality and reduce variance in quantification outcomes, without introducing bias to the estimates. We additionally anticipate that the models will improve (or at least maintain) sensitivity to functional changes, outperforming established methods in this regard.

In vivo GABA-edited MRS data (203 subjects from the publicly available Big GABA collection) were sub-sampled strategically to assess individual components of the model, benchmarked against the uncorrected case and against established approaches such as spectral improvement by Fourier thresholding (SIFT). Changes in metabolite concentration and lineshape simulating response to a functional task were synthesized, and sensitivity to such changes was assessed.

Composite models yielded improved SNR and reduced variability of GABA+ estimates compared to the uncorrected case in all scenarios, with performance for individual model components varying. Similarly, while some model components in isolation led to increased variability in estimates, no bias was observed in these or in the composite models. While SIFT yielded the greatest reductions in unwanted variance, the resultant data were substantially less sensitive to synthetic functional changes.

We conclude that the modelling presented is effective at reducing unwanted variance, whilst retaining temporal dynamics of interest for functional MRS applications, and recommend its inclusion in fMRS processing pipelines.

Highlights

A novel technique for modelling unwanted variance between transients is investigated.

Suitable covariate models yield improved SNR and reduced variability in GABA+ estimates from the resultant spectra.

Extracted spectra remain sensitive to temporal dynamics of interest for functional MRS applications.

Graphical Abstract

In dynamic MRS analysis, unwanted variability between transients may confound findings when sub-sampling within a single acquisition. We investigate covariate models and lineshape matching strategies to address this. We present composite models yielding improved quality metrics and within-scan repeatability while maintaining sensitivity to (synthetic) functional changes.
Loss of multiple micro-RNAs uncovers multi-level restructuring of gene regulation in rodents
Authors: Langschied Felix , Leisegang Matthias S. , Günther Stefan , Hahner Fabian , Brandes Ralf P. , Ebersberger Ingo
Published: December 2024

Background

The regulatory network that coordinates gene expression ultimately determines the phenotype of an organism. Micro-RNAs (miRNAs) are post-transcriptional regulators involved in key biological processes. Lineage-specific losses of multiple miRNA families are rare, and reported cases of multiple miRNA losses coincide with significant changes in gene regulation resulting in body plan modifications. Recently, 15 mammalian miRNA families were found to be missing in theEumuroidea, the rodent lineage that includes the model organisms mouse and rat. However, the impact of their absence on the gene regulatory networks in this lineage remains unknown.

Results

Thein silicocharacterization of all 15 miRNAs revealed that their absence is best explained by multiple independent losses. Analyzing their target genes in humans reveals a significant enrichment of GO- terms linked to cellular and developmental processes. Overexpressing two of the co-absent miRNAs, Mir-197 and Mir-769, in human and mouse inducible pluripotent stem cells (iPSCs) resulted in significantly perturbed expression patterns in both species.In silicotarget site prediction revealed a significant enrichment of direct targets exclusively in the down-regulated genes. Four genes were down-regulated in both mouse and human and maximum parsimony suggests that the corresponding miRNA target sites were already present in the last common ancestor of mammals. The response of these genes to miRNA overexpression in mice, therefore, unveils remnants of the ancient gene regulatory network that have persisted until today. The evolutionary age of these regulatory connections provides initial evidence that the miRNA losses inEumuroideamust have had consequences for the regulation of gene expression. Notably, we show that the miRNA loss in the Eumuroidea coincides with the largest lineage-specific loss of transcription factors within the mammals.

Conclusions

The impact of miRNA losses has thus far been investigated on a gene-by-gene basis. Our findings indicate that cooperative effects between miRNAs should be considered when assessing the impact of miRNA loss. We provide evidence that theEumuroideahave modified their gene regulatory networks on two levels, transcriptionally and post-transcriptionally. It will now be interesting to precisely chart the differences in gene regulation and assess their combined impact on the suitability of mice and rats as model systems for human disease.
Divalent siRNA for prion disease
Authors: Gentile Juliana E , Corridon Taylor L , Echeverria Dimas , Serack Fiona E , Kennedy Zachary E , Gallant-Behm Corrie L , Hassler Matthew R , Kinberger Garth , Kamath Nikita G , Gross Katherine Y , Lian Yuan , Miller Rachael , DeSouza-Lenz Kendrick , Howard Michael , Guzman Kenia , Chan Nathan , Laversenne Vanessa , Curtis Daniel T , Fettes Kevin , Lemaitre Marc , Cappon Gregg , Jackson Aimee L , Yamada Ken , Alterman Julia F , Coffey Alissa A , Minikel Eric Vallabh , Khvorova Anastasia , Vallabh Sonia M
Published: December 2024

Pharmacologic lowering of PrP expression is efficacious against prion disease in animal models and is now being tested clinically. 50% lowering of PrP increases both survival time and healthy life in prion-infected mice, but does not prevent symptom onset nor halt disease progression. Additional drug candidates should seek to reduce PrP expression to even lower levels. Divalent siRNA is a novel oligonucleotide drug modality with promising potency, durability, and biodistribution data in preclinical models, inspiring us to seek in this technology a new drug candidate for prion disease. Here, we first identify a tool compound against the mouse PrP gene and establish the efficacy of PrP-lowering divalent siRNA in prion-infected mice. We then introduce humanized transgenic mouse lines harboring the full non-coding sequence of the human PrP gene as tools for identifying human sequence-targeted drugs. We identify a highly potent siRNA sequence against the human PrP gene and determine that a chemical scaffold incorporating extended nucleic acid and a 3′ antisense tail unmatched to the RNA target yields superior potency. We nominate PrP-lowering divalent siRNA 2439-s4 as a new drug candidate for human prion disease.
The discovery of 5mC-selective deaminases and their application to ultra-sensitive direct sequencing of methylated sites at base resolution
Authors: Yang Weiwei , Lee Yan-Jiun , Silva Rebekah M. B. , DeLiberto Amanda , Yancey Colleen , McCallum Daria , Buss Jackson , Moncion Rey , Ong Jennifer , Mabuchi Megumu , Hough Dave , Weigele Peter R. , Ettwiller Laurence M.
Published: December 2024

Mining phages for new enzymatic activities continues to be important for the development of new tools for biotechnology. In this study, we used MetaGPA—a method linking genotype to phenotype in metagenomic data—to identify deoxycytidine deaminases, a protein family highly associated with cytosine modifications in metaviromes. Unexpectedly, a subset of these deaminases exhibited a preference for 5-methylcytosine (5mC) over cytosine (C) in both mononucleotide and single-stranded DNA substrates. In a methylome sequencing workflow, preferential deamination of 5mC by these enzymes enabled direct conversion of methylated cytosine while completely eliminating any background deamination of unmodified cytosine. This direct conversion allows for precise identification of methylated sites at single-base resolution with unmatched sensitivity enabling broad applications for the simultaneous sequencing of genome and methylome.
Rifaximin does not increase the rate of 30-day mortality in patients with cirrhosis and daptomycin in two National US-based cohorts
Authors: Silvey Scott , Patel Nilang , Khoruts Alexander , Bajaj Jasmohan S
Published: December 2024

Recently, a higher rate of resistance to daptomycin in patients exposed to rifaximin has been shown. However, since laboratory resistance patterns foundin silicoorex vivodo not account for the complex pharmacokinetic, pharmacodynamic, microbial, and host-related factors in patients, the clinical impact of rifaximin on resistance to daptomycin needs clarification. Although rifaximin is commonly used for irritable bowel syndrome and traveler’s diarrhea, the main reason for long-term use is hepatic encephalopathy (HE) in cirrhosis. Here we show that 30-day outcomes (transplant or mortality) in two large US-based cohorts (Veterans Affairs Corporate Data Warehouse and TriNetX database) in daptomycin users on rifaximin were not different compared to those without daptomycin. with or without pre-existing rifaximin use.
A Titin Missense Variant Causes Atrial Fibrillation
Authors: Pavel Mahmud Arif , Chen Hanna , Hill Michael , Sridhar Arvind , Barney Miles , DeSantiago Jaime , Owais Asia , Sandu Shashank , Darbar Faisal A. , Ornelas-Loredo Aylin , Al-Azzam Bahaa , Chalazan Brandon , Rehman Jalees , Darbar Dawood
Published: December 2024

Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such asTTNhave also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. WhileTTNtruncating variants (TTNtvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We report that rareTTNmvs are associated with adverse clinical outcomes in AF patients and we have identified a mechanism by which aTTNmv (T32756I) causes AF. Modeling theTTN-T32756I variant using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) revealed that the mutant cells display aberrant contractility, increased activity of a cardiac potassium channel (KCNQ1, Kv7.1), and dysregulated calcium homeostasis without compromising the sarcomeric integrity of the atrial cardiomyocytes. We also show that a titin-binding protein, the Four-and-a-Half Lim domains 2 (FHL2), has increased binding with KCNQ1 and its modulatory subunit KCNE1 in theTTN-T32756I-iPSC-aCMs, enhancing the slow delayed rectifier potassium current (Iks). Suppression of FHL2 in mutant iPSC-aCMs normalized theIks, supporting FHL2 as anIksmodulator. Our findings demonstrate that a single amino acid change in titin not only affects function but also causes ion channel remodeling and AF. These findings emphasize the need for high-throughput screening to evaluate the pathogenicity ofTTNmvs and establish a mechanistic link between titin, potassium ion channels, and sarcomeric proteins that may represent a novel therapeutic target.
Analysis of germline genetic variants that cause hereditary colorectal cancer in bahia
Authors: Miguel Diego S. C. G. , Alves Maria E. A. V. , Cerqueira Polianna M. , Costa Luíza C. , Carvalho Rafael N. D. , Sampaio Rodrigo A. , Carvalho David B. O. D. , Castro e Iza C. S.
Published: December 2024

Background

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Approximately 10% of CRC cases are linked to hereditary germline variants. Understanding regional genetic predispositions is crucial for developing personalized medicine strategies.

Objective

This study aims to analyze pathogenic germline variants associated with polyposis and non-polyposis syndromes in individuals from Bahia, Brazil.

Methods

A cross-sectional, observational study was conducted on 3,100 probands from a private laboratory in Salvador, Bahia, between August 2017 and February 2023. Probands underwent Next Generation Sequencing (NGS) targeting 37 genes. Variants classified as pathogenic (P) or probably pathogenic (PP) in 11 high/moderate penetrance genes were analyzed.

Results

Among the 3,100 probands, 97 (3.12%) had P/PP variants. Polyposis syndromes accounted for 47 cases (1.51%), with prevalent variants in MUTYH, APC, and PTEN genes. Non-polyposis (Lynch) syndrome was observed in 50 cases (1.61%), predominantly involving MSH2 and MLH1 genes. Notably, a novel variant, MLH1 c.1127_1130dup, was identified.

Conclusion

This study highlights the genetic diversity in CRC predisposition in Bahia, emphasizing the need for targeted regional genetic screening and personalized healthcare strategies. Identifying recurrent pathogenic variants suggests possible shared ancestry among individuals, offering insights for future genetic counseling and public health policies.
The Effect of Telenursing on the Quality of Life in Elderly Stroke Survivors: A Triple-Blind Randomized Controlled Trial
Authors: Nazari Elham , Roumi Azin , Sabooteh Toomaj
Published: December 2024

Introduction

Telenursing is a cost-effective and highly accessible approach that can enhance awareness of care principles, ultimately contributing to the improvement of quality of life (QoL) in stroke patients. This study aimed to assess the impact of telenursing via telephone consultations and video chats on the quality of life of stroke patients.

Materials and Methods

This randomized controlled trial included stroke patients discharged from hospitals in Khorramabad city in 2022. A total of 80 patients were selected using non-probability consecutive sampling and randomly allocated to either an intervention group (n=40) or a control group (n=40) using a permuted block randomization method. The study was conducted in a triple-blind design. Research tools included a demographic information form and the Stroke-Specific Quality of Life (SS-QoL) questionnaire developed by Williams et al. (1999). Data were analyzed using independent t-tests and SPSS version 26.

Results

The findings indicated a statistically significant difference in the mean QoL scores between the two groups (P<0.001, t = -36.560). The mean difference between the groups was 56.900 ± 1.556. Additionally, the results demonstrated that the telenursing intervention improved various dimensions of stroke patients’ QoL (P < 0.001).

Conclusion

Telenursing can be effectively utilized to facilitate the care of chronic patients and improve their quality of life by providing practical and specialized information.
Performance of Hb HemoCue machine compared to automated hematology analyzer for hemoglobin measurements among adult patients at Kilimanjaro Christian Medical Centre
Authors: Kassam Nancy A. , Mwanga Goodluck A. , Yusuph Elia L. , Maundi Elda M. , Josephat Mose , Kulaya Neema B. , Lasway Daniel B. , Laizer Zacharia L. , Ndossy Goodluck G. , Kimaro James S. , Ndaro Arnold
Published: December 2024

Background

Automated hematology analyzers offer precise hemoglobin measurements, but are expensive and impractical for field, point of care, primary care and remote settings use. The portable and cost-effective Hemocue device provides an alternative. Comparing their accuracies is crucial to prevent diagnostic discrepancies and misdiagnoses. This study aimed to determine the accuracy of Hb HemoCue machine by comparing its performance to automated analyzer at KCMC clinical laboratory where both equipment are used.

Methods

A cross-sectional study was conducted at Kilimanjaro Christian Medical Centre (KCMC) Clinical Laboratory among adult patients whose hemoglobin concentrations were measured in May to June 2024. Hemoglobin levels were estimated using two distinct methods: the Hb HemoCue machine and repeatedly tested using an automated hematology analyzer.

Results

Hemoglobin (Hb) concentration values obtained from the HemoCue machine and the automated analyzer, had a mean difference of 0.001 g/dl (95% Cl: -0.036 to 0.038), t value of 0.062, and ap-value of 0.95, indicating a non-statistically significant differences between the two measurement methods. The Bland-Altman plot analysis indicated that the mean difference (bias) between the two methods was 0.0012 g/dL, and the limits of agreement ranged from - 0.481 to 0.482 g/dL, suggesting that the HemoCue machine tends to slightly overestimate Hb values compared to the automated hematology analyzer. The Pearson correlation coefficient for the Hb concentrations measured using HemoCue and automated analyzer was 0.995, indicating a very strong positive correlation. Receiver operating characteristics (ROC) curve showed that the area under the curve (AUC) for analyzer and HemoCue was 1.000 indicating that both methods have good diagnostic accuracy of measuring Hb concentrations.

Conclusion

The study revealed strong agreement between HemoCue and automated hematology analyzer for measuring hemoglobin concentrations. Both methods demonstrated high diagnostic accuracy suitable for clinical use. Although HemoCue slightly overestimated hemoglobin, this difference was deemed insignificant. The study endorses HemoCue as a reliable tool for hemoglobin concentration measurement alongside automated analyzers.
Socioeconomic inequalities of 3-year survival in formal employees with colorectal cancer between 2012 and 2019 in Colombia
Authors: Sánchez-Santiesteban Daniela , Patiño-Benavidez Andrés Felipe , Buitrago Giancarlo
Published: December 2024

Objective

This study aimed to assess socioeconomic inequalities in three-year survival among formal employees diagnosed with colorectal cancer in Colombia between 2012 and 2019, using legal monthly minimum wages (MMW) as a proxy for socioeconomic status.

Methods

A retrospective cohort study used administrative databases, including healthcare and mortality records. Formal employees newly diagnosed with colorectal cancer were identified through diagnostic and oncological procedure codes and followed for three years from diagnosis or until death. Patients were stratified into MMW quartiles, and Cox regression models were employed to estimate adjusted hazard ratios (HRs) for survival. Socioeconomic gradients were quantified using the Relative Index of Inequality (RII) and Slope Index of Inequality (SII).

Results

The cohort included 1,913 formal employees (mean age: 49.9 years), with 660 deaths (34.5%) recorded over the follow-up period. Patients in the lowest MMW quartile experienced the highest three-year mortality (39.5%) compared to those in the highest quartile (30.7%). After adjusting for confounders, individuals in the highest quartile had a 25% lower risk of death than those in the lowest quartile (aHR: 0.74; 95% CI: 0.59–0.92). The RII indicated a 50% higher risk of death in the lowest income group (RII: 1.50; 95% CI: 1.13–1.99), while the SII revealed an absolute difference of 0.16 deaths per 1,000 individuals (p=0.01).

Conclusion

Significant income-based disparities in colorectal cancer survival were observed among formal employees in Colombia despite the theoretically equitable healthcare system. These findings underscore the persistent influence of socioeconomic factors on health outcomes, even within populations assumed to have better access to care.
Low Back Pain’s Hidden Partners: Stigma, Anxiety, and Functional Decline in Adults with Cerebral Palsy
Authors: Stutzbach Julie A. , Sarmiento Cristina A. , Kenkre Tanya S. , Oleszek Joyce L. , Wisniewski Stephen R , Gannotti Mary E. ,   Cerebral Palsy Research Network
Published: December 2024

AIM

Determine biopsychosocial factors associated with pain interference and pain intensity in adults with cerebral palsy (CP) and chronic low back pain (LBP).

METHOD

Cross-sectional secondary data analysis of a community survey examining function and chronic pain in adults with CP and LBP. We examined bivariate relationships and built two regression models with pain interference with general activities and pain intensity as dependent variables and biopsychosocial factors as explanatory factors.

RESULTS

We included 295 participants with CP and LBP in our analyses. Average age was 43.2 ± 13.9 years, and 81% were ambulatory (GMFCS I-III). Pain was present for 17.9 ± 13.4 years. Ordinary least squares regression models indicated greater pain interference with: change in best motor function since childhood (p=0.002), stigma (p=0.01), and anxiety (p=0.01; N=238; adjusted R2=0.17); and greater pain intensity with: lower income (p=0.01), Hispanic/Latino ethnicity (p=0.04), anxiety (p=0.01), and less satisfaction with social roles, (p<0.001; N=290, R2=0.18; Adjusted R2=0.16).

INTERPRETATION

These findings emphasize the importance of assessing and interpreting chronic pain in the context of biopsychosocial factors, particularly anxiety, stigma, race, ethnicity, income, satisfaction with social roles, and changes in motor function.
Eye Movements During the Iowa Gambling Task in Parkinson’s Disease: A Brief Report
Authors: Doshier Kirby , Ryals Anthony J. , Nejtek Vicki A. , Salvatore Michael F.
Published: December 2024

Parkinson’s disease (PD) is characterized by motor and cognitive impairments. Subtle cognitive impairment may precede motor impairment. There is a substantial need for innovative assessments, such as those involving decision-making, to detect PD in the premotor phase. Evidence suggests executive dysfunction in PD can impede strategic decision-making relying on learning and applying feedback. The Iowa Gambling Task (IGT), when combined with eye-tracking, may be a valuable synergistic strategy for predicting impaired decision-making and therapeutic non-compliance. Participants with PD and matched healthy controls completed the Movement Disorders Society’s modified Unified Parkinson’s Disease Rating Scale (UPDRS-MDS), 6-minute Walk test (6MWT), Timed Up and Go test (TUG), Trail Making Test A and B (TMT A and B), Controlled Oral Word Association Test (COWAT), and the Barratt Impulsiveness Scale (BIS). Eye tracking was recorded during the IGT. The PD group scored significantly higher on UPDRS subscales and covered less distance during the 6MWT despite equivalent performance on the TUG. The PD group also had longer completion times on TMT A and B and more errors on TMT B. Overall IGT winning scores were marginally worse in PD. However, when analyzed as a function of performance over time, the PD group performed significantly worse by task end, thus suggesting impaired decision-making. PD participants exhibited a 72% reduction in blinks despite equivalent outcomes in other eye-movements. Combined with established motor and executive function tests, the IGT and similar tasks combined with eye-tracking may be a powerful noninvasive method to detect and monitor PD early in progression.
Novel plasma biomarkers of amyloid plaque pathology and cortical thickness: evaluation of the NULISA targeted proteomic platform in an ethnically diverse cohort
Authors: Zeng Xuemei , Sehrawat Anuradha , Lafferty Tara K. , Chen Yijun , Rawat Mahika , Kamboh M. Ilyas , Villemagne Victor L. , Lopez Oscar L. , Cohen Ann D. , Karikari Thomas K.
Published: December 2024

INTRODUCTION

Proteomic evaluation of plasma samples could accelerate the identification of novel Alzheimer’s disease (AD) biomarkers. We evaluated the novel NUcleic acid Linked Immuno-Sandwich Assay (NULISATM) proteomic method in an ethnically diverse cohort.

METHODS

Plasma biomarkers were measured with NULISA in the Human Connectome Project, a predominantly preclinical biracial community cohort in southwestern Pennsylvania. Selected biomarkers were additionally measured using Simoa and Quest immunoassays.

RESULTS

On NULISA, phosphorylated tau (p-tau217, p-tau231, p-tau181), GFAP, and MAPT-tau showed the top significant association with Aβ PET status, followed by neuroinflammation markers CCL2, CHIT1, CXCL8, and the synaptic marker NRGN. Biomarkers associated with cortical thickness included astrocytic protein CHI3L1, cytokine CD40LG, growth factor BDNF, Aβ-associated metalloprotein TIMP3, and FCN2 linked with brain atrophy in AD. Furthermore, moderate to strong between-platform correlations were observed for various assays.

DISCUSSION

NULISA multiplexing advantage allowed concurrent assessment of established and novel plasma biomarkers of Aβ pathology and neurodegeneration.
Structural basis for aminoacylation of cellular modified tRNALys3by human lysyl-tRNA synthetase
Authors: Devarkar Swapnil C. , Budding Christina R. , Pathirage Chathuri , Kavoor Arundhati , Herbert Cassandra , Limbach Patrick A. , Musier-Forsyth Karin , Xiong Yong
Published: December 2024

The average eukaryotic tRNA contains 13 posttranscriptional modifications; however, their functional impact is largely unknown. Our understanding of the complex tRNA aminoacylation machinery in metazoans also remains limited. Herein, using a series of high-resolution cryo-electron microscopy (cryo-EM) structures, we provide the mechanistic basis for recognition and aminoacylation of fully-modified cellular tRNALys3by human lysyl-tRNA synthetase (h-LysRS). The tRNALys3anticodon loop modifications S34 (mcm5s2U) and R37 (ms2t6A) play an integral role in recognition by h-LysRS. Modifications in the T-, variable-, and D-loops of tRNALys3are critical for ordering the metazoan-specific N-terminal domain of LysRS. The two catalytic steps of tRNALys3aminoacylation are structurally ordered; docking of the 3′-CCA end in the active site cannot proceed until the lysyl-adenylate intermediate is formed and the pyrophosphate byproduct is released. Association of the h-LysRS-tRNALys3complex with a multi-tRNA synthetase complex-derived peptide shifts the equilibrium towards the 3′-CCA end ‘docked’ conformation and allosterically enhances h-LysRS catalytic efficiency. The insights presented here have broad implications for understanding the role of tRNA modifications in protein synthesis, the human aminoacylation machinery, and the growing catalog of metabolic and neurological diseases linked to it.