bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractState-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

AbstractPrecision 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.
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

AbstractNeuropathic 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

AbstractVariability 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.HighlightsA 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 AbstractIn 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

AbstractBackgroundThe 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.ResultsThein 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.ConclusionsThe 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

AbstractPharmacologic 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

AbstractMining 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

AbstractRecently, 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

ABSTRACTRare 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

ABSTRACTBackgroundColorectal 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.ObjectiveThis study aims to analyze pathogenic germline variants associated with polyposis and non-polyposis syndromes in individuals from Bahia, Brazil.MethodsA 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.ResultsAmong 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.ConclusionThis 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

ABSTRACTIntroductionTelenursing 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 MethodsThis 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.ResultsThe 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).ConclusionTelenursing 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

AbstractBackgroundAutomated 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.MethodsA 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.ResultsHemoglobin (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.ConclusionThe 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.