bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do microsaccades vary with discriminability around the visual field?
Authors: Purokayastha Simran , Roberts Mariel , Carrasco Marisa 
Published: January 2024

AbstractMicrosaccades–tiny fixational eye movements– improve discriminability in high acuity tasks in the foveola. To investigate whether they help compensate for low discriminability at perifovea, we examined MS characteristics relative to the adult visual performance field, which is characterized by two perceptual asymmetries: Horizontal-Vertical Anisotropy (better discrimination along the horizontal than vertical meridian), and Vertical Meridian Asymmetry (better discrimination along the lower-than upper-vertical meridian). We investigated whether and to what extent microsaccade directionality varies when stimuli are at isoeccentric locations along the cardinals under conditions of heterogeneous discriminability (Experiment 1) and homogeneous discriminability, equated by adjusting stimulus contrast (Experiment 2). Participants performed a two-alternative forced-choice orientation discrimination task. In both experiments, performance was better on trials without microsaccades between ready signal onset and stimulus offset than on trials with microsaccades. Across the trial sequence the microsaccade rate and directional pattern were similar across locations. Our results indicate that microsaccades were similar regardless of stimulus discriminability and target location, except during the response period–once the stimuli were no longer present and target location no longer uncertain–when microsaccades were biased toward the target location. Thus, this study reveals that microsaccades do not flexibly adapt as a function of varying discriminability in a basic visual task around the visual field.
Optimization of Anticodon Edited Transfer RNAs (ACE-tRNAs) Function in Translation for Suppression of Nonsense Mutations
Authors: Porter Joseph J. , Ko Wooree , Sorensen Emily G. , Lueck John D. 
Published: January 2024

SUMMARYNonsense suppressor tRNAs or AntiCodon-Edited tRNAs (ACE-tRNAs) have long been envisioned as a therapeutic approach to overcome genetic diseases resulting from the introduction of premature stop codons (PTCs). The ACE-tRNA approach for the rescue of PTCs has been hampered by ineffective delivery through available modalities for gene therapy. Here we have screened a series of ACE-tRNA expression cassette sequence libraries containing >1,800 members to optimize ACE-tRNA function and provide a roadmap for optimization in the future. By optimizing PTC suppression efficiency of ACE-tRNAs, we have decreased the amount of ACE-tRNA required by ∼16-fold for the most common cystic fibrosis-causing PTCs.
Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy
Authors: Yu Juntao , Li Qian , Luo Shenggen , Wang Xiaona , Cheng Qiang , Hu Rongkuan 
Published: January 2024

AbstractInterleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNPLocal) and to pulmonary (LNPLung). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNPLocaland LNPLung, respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNPLungin non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers.
Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS
Authors: Chen Daniel , Philippidou Polyxeni , Brenha Bianca de Freitas , Schaffer Ashleigh E. , Miranda Helen C. 
Published: January 2024

ABSTRACTNeuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging. Prior NMJ studies heavily relied upon the use of mouse, chick, or isolated primary human cells, which have demonstrated limited fidelity for disease modeling. To enable the study of NMJ dysfunction and model genetic diseases, we, and others, have developed methods to generate human NMJs from pluripotent stem cells (PSCs), embryonic stem cells, and induced pluripotent stem cells. However, published studies have highlighted technical limitations associated with these complexin vitroNMJ models. In this study, we developed a robust PSC-derived motor neuron and skeletal muscle co-culture method, and demonstrated its sensitivity in modeling motor neuron disease. Our method spontaneously and reproducibly forms human NMJs. We developed multiwell-multielectrode array (MEA) parameters to quantify the activity of PSC-derived skeletal muscles, as well as measured the electrophysiological activity of functional human PSC-derived NMJs. We further leveraged our method to morphologically and functionally assess NMJs from the familial amyotrophic lateral sclerosis (fALS) PSCs,C9orf72hexanucleotide (G4C2)n repeat expansion (HRE),SOD1A5V, andTDP43G298Sto define the reproducibility and sensitivity of our system. We observed a significant decrease in the numbers and activity of PSC-derived NMJs developed from the different ALS lines compared to their respective controls. Furthermore, we evaluated a therapeutic candidate undergoing clinical trials and observed a variant-dependent rescue of functionality of NMJs. Our newly developed method provides a platform for the systematic investigation of genetic causes of NMJ neurodegeneration and highlights the need for therapeutic avenues to consider patient genotype.
Histone H2A.Z Deacetylation and Dedifferentiation in Infarcted/Tip60-depleted Cardiomyocytes
Authors: Wang Xinrui , Kulik Katherine , Wan Tina C. , Lough John W. , Auchampach John A. 
Published: January 2024

ABSTRACTMyocardial infarction (MI) results in the loss of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction. To re-muscularize injured myocardium, new CMs must be generated via renewed proliferation of surviving CMs. Approaches to induce proliferation of CMs after injury have been insufficient. Toward this end we are targeting the acetyltransferase Tip60, encoded by theKat5gene, based on the rationale that its pleiotropic functions combine to block CM proliferation at multiple checkpoints. We previously demonstrated that genetic depletion of Tip60 in a mouse model after MI reduces scarring, retains cardiac function, and activates the CM cell-cycle, although it remains unclear whether this culminates in the generation of daughter CMs. In order for pre-existing CMs in the adult heart to undergo proliferation, it has become accepted that they must first dedifferentiate, a process highlighted by loss of maturity, epithelial to mesenchymal transitioning (EMT), and reversion from fatty acid oxidation to glycolytic metabolism, accompanied by softening of the myocardial extracellular matrix (ECM). Based on recently published findings that Tip60 induces and maintains the differentiated state of hematopoietic stem cells and neurons via site-specific acetylation of the histone variant H2A.Z, we assessed levels of acety-lated H2A.Z and dedifferentiation markers after depleting Tip60 in CMs post-MI. We report that genetic depletion of Tip60 from CMs after MI results in the near obliteration of acetylated H2A.Z in CM nuclei, accompanied by the altered expression of genes indicative of EMT induction, ECM softening, decreased fatty acid oxidation, and depressed expression of genes that regulate the TCA cycle. In accord with the possibility that site-specific acet-ylation of H2A.Z maintains adult CMs in a mature state of differentiation, CUT&Tag revealed enrichment of H2A.ZacK4/K7in genetic motifs and in GO terms respectively associated with CM transcription factor binding and muscle development/differentiation. Along with our previous findings, these results support the notion that Tip60 has multiple targets in CMs that combine to maintain the differentiated state and prevent proliferation.
Genopyc: a python library for investigating the genomic basis of complex diseases
Authors: Gualdi Francesco , Oliva Baldomero , Piñero Janet 
Published: January 2024

AbstractMotivationUnderstanding the genetic basis of complex diseases is a paramount challenge in modern genomics. However, current tools often lack the versatility to efficiently analyze the intricate relation-ships between genetic variations and disease outcomes. To address this, we introduce Genopyc, a novel Python library designed for comprehensive investigation of the genetics underlying complex dis-eases. Genopyc offers an extensive suite of functions for heterogeneous data mining and visualization, enabling researchers to delve into and integrate biological information from large-scale genomic da-tasets with ease.ResultsIn this study, we present the Genopyc library through application to real-world genome wide association studies variants. Using Genopyc to investigate variants associated to intervertebral disc degeneration (IDD) enabled a deeper understanding of the potential dysregulated pathways involved in the disease, which can be explored and visualized by exploiting the functionalities featured in the package. Genopyc emerges as a powerful asset for researchers, fostering advancements in the un-derstanding of complex diseases and thus paving the way for more targeted therapeutic interventions. Availability: Genopyc is available at pip (https://pypi.org/project/genopyc/) and the source code of Genopyc is available athttps://github.com/freh-g/genopycContactfrancesco.gualdi01@estudiant.upf.eduSupplementary informationsupplementary data are available atBioinformaticsonline.
A new tridimensional effective method to calculate Real Contact Surface Area (RCSA) between renal tumor and surrounding kidney parenchyma: An Innovative Tool with predictive power of intraoperative outcomes in nephron sparing surgery
Authors: Traverso Paolo , Carfì Alessandro , Bulanti Alessandra , Fabbi Martina , Giasotto Veronica , Mattiauda Matilde , Monaco Lorenzo Lo , Tappero Stefano , Guano Giovanni , Balzarini Federica , Borghesi Marco , Mastrogiovanni Fulvio , Terrone Carlo 
Published: January 2024

AbstractThe Contact Surface Area (CSA) is a predictor for peri-operative parameters and represent the contact area between the tumor and the respective organ. Nowadays, a precise method for calculating CSA is yet to be found in the literature. We tested a new CSA calculation method as a predictor of intra-operative parameters in robot assisted partial nephrectomy (RAPN).The study population consisted of all consecutive patients treated with RAPN at a single high-volume European institution (between 2020 to 2023; 82 patients). We proposed a new method to measure the real value of CSA using an algorithm that leverages the geometry of kidneys and tumors obtained from 3D reconstruction. These reconstructions were obtained using the certified medical software Materialized Mimics InPrint. Peri-operative parameters of patients were recorded in an anonymous database.We explored the correlation between RCSA, CSA of Hsieh (HCSA), PADUA and R.E.N.A.L. scores with peri-operative parameters using Spearman’s correlation. Furthermore, we examined which of RCSA, PADUA and R.E.N.A.L. score better describes the intra-operative parameters, Warm Ischemia Time (WIT), Operating Time (OT), and Estimated Blood Loss (EBL) using Receiver Operating Characteristic (ROC) curve analysis. Multivariable linear regression analyses were performed.We observed a significant correlation between RCSA and WIT, OT and EBL. Moreover, RCSA outperformed both the PADUA and R.E.N.A.L. score as demonstrated in the ROC curve analysis. In ROC analysis was chosen a threshold for each of the parameters: for WIT 20 minutes, for OT 180 minutes and for EBL 200 mL. At multivariable regression analysis, RCSA emerged as the only independent predictor for WIT, OT and EBL (B=0.39 & p=0.03, B=0.35 & p=0.01, B=0.48 & p<0.001, respectively).Our original and effective 3D RCSA calculation method was favorably associated to intra-operative surgical outcomes. As compared to PADUA and RENAL score, our calculated RCSA represented a better predictor of intra-operative parameters.
Urinary Astrocyte-derived Extracellular Vesicles: A Non-invasive Tool for Capturing HumanIn VivoMolecular “Movies” of Brain
Authors: Xie Xin-hui , Chen Mian-mian , Xu Shu-xian , Mei Jun-hua , Yang Qing , Wang Chao , Liu Zhongchun 
Published: January 2024

AbstractThe identification of particularly individual-level biomarkers, for certain central nervous system (CNS) diseases remains challenging. A recent approach involving the enrichment of brain-derived extracellular vesicles (BDEVs) from peripheral blood has emerged as a promising method to obtain directin vivoCNS data, bypassing the blood-brain barrier. However, for rapidly evolving CNS diseases (e.g., weeks or even days), the Nyquist-Shannon sampling theorem dictates the need for a high-frequency sampling rate. Obviously, daily collection of blood or cerebrospinal fluid from human subjects is impractical. Thus, we innovated a novel method to isolate astrocyte-derived EVs from urine (uADEVs). It involves three main steps: 1) concentrating urine samples, 2) isolating total EVs from urine (uTEVs) using ultracentrifugation, and 3) using an anti-glutamate/aspartate transporter (GLAST) antibody to isolate GLAST+EVs from uTEVs. Subsequently, we confirmed the identity of these GLAST+EVs as uADEVs using transmission electron microscopy, nanoparticle tracking analysis, western blotting, and the measurement of astrocyte-related neurotrophins. Furthermore, we applied the uADEVs protocol to depict the detailed trajectory of the N-methyl-d-aspartic acid receptor (NMDAR) subunit zeta-1 (GluN1) in an anti-NMDAR encephalitis patient, demonstrated the potential of this method for capturing intricate trajectories of CNS-specific molecularin vivosignals at the individual level. This non-invasive approach enables frequent sampling, up to daily or even half-daily, analogous to capturing molecular “movies” of the brain, coupled with appropriate signal processing algorithms, holds promise for identifying novel biomarkers or illuminating the etiology of rapidly evolving CNS diseases by tracking the precise trajectories of target molecules.
Multispectral Fundus Photography of Choroidal Nevi with Trans-Palpebral Illumination
Authors: Rahimi Mojtaba , Rossi Alfa , Son Taeyoon , Dadzie Albert K. , Ebrahimi Behrouz , Abtahi Mansour , Heiferman Michael J. , Yao Xincheng 
Published: January 2024

AbstractPurposeTo investigate the spectral characteristics of choroidal nevi and assess the feasibility of quantifying the basal diameter of choroidal nevi using multispectral fundus images captured with trans-palpebral illumination.MethodsThe study employed a widefield fundus camera with multispectral (625 nm, 780 nm, 850 nm, and 970 nm) trans-palpebral illumination. Geometric features of choroidal nevi, including border clarity, overlying drusen, and lesion basal diameter, were characterized. Clinical imagers, including scanning laser ophthalmoscopy (SLO), autofluorescence (AF), and optical coherence tomography (OCT), were utilized for comparative assessment.ResultsFundus images captured with trans-palpebral illumination depicted nevi as dark regions with high contrast against the background. Near-infrared (NIR) fundus images provided enhanced visibility of lesion borders compared to visible light fundus images and SLO images. Lesion-background contrast measurements revealed 635 nm SLO at 11% and 625 nm fundus at 42%. Significantly enhanced contrasts were observed in NIR fundus images at 780 nm (73%), 850 nm (63%), and 970 nm (67%). For quantifying the basal diameter of nevi, NIR fundus images at 780 nm and 850 nm yielded a deviation of less than 10% when compared to OCT B-scan measurements.ConclusionNIR fundus photography with trans-palpebral illumination enhances nevi visibility and boundary definition compared to SLO. Agreement in basal diameter measurements with OCT validates the accuracy and reliability of this method for choroidal nevi assessment.Translational RelevanceMultispectral fundus imaging with trans-palpebral illumination improves choroidal nevi visibility, accurately measures basal diameter, promising to enhance clinical practices in screening, diagnosis, and monitoring of choroidal nevi.
Identifying novel gene dysregulation associated with opioid overdose death: A meta-analysis of differential gene expression in human prefrontal cortex
Authors: Carter Javan K. , Quach Bryan C. , Willis Caryn , Minto Melyssa S. ,   PGC-SUD Epigenetics Working Group, Hancock Dana B. , Montalvo-Ortiz Janitza , Corradin Olivia , Logan Ryan W. , Walss-Bass Consuelo , Maher Brion S. , Johnson Eric Otto 
Published: January 2024

AbstractOnly recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged human prefrontal cortex RNAseq data from four independent OOD studies and conducted a transcriptome-wide DGE meta-analysis (N = 285). Using a unified gene expression data processing and analysis framework across studies, we meta-analyzed 20LJ098 genes and found 335 significant differentially expressed genes (DEGs) by OOD status (false discovery rate < 0.05). Of these, 66 DEGs were among the list of 303 genes reported as OOD-associated in prior prefrontal cortex molecular studies, including genes/gene families (e.g.,OPRK1, NPAS4,DUSP, EGR). The remaining 269 DEGs were not previously reported (e.g.,NR4A2, SYT1, HCRTR2, BDNF). There was little evidence of genetic drivers for the observed differences in gene expression between opioid addiction cases and controls. Enrichment analyses for the DEGs across molecular pathway and biological process databases highlight an interconnected set of genes and pathways from orexin and tyrosine kinase receptors through MEK/ERK/MAPK signaling to affect neuronal plasticity.
Reducing Inequalities Using an Unbiased Machine Learning Approach to Identify Births with the Highest Risk of Preventable Neonatal Deaths
Authors: Ramos Antonio P. , Caldieraro Fabio , Nascimento Marcus L. , Saldanha Rafael 
Published: January 2024

AbstractBackgroundDespite contemporaneous declines in neonatal mortality, recent studies show the existence of left-behind populations that continue to have higher mortality rates than the national averages. Additionally, many of these deaths are from preventable causes. This reality creates the need for more precise methods to identify high-risk births so that policymakers can more precisely target them. This study fills this gap by developing unbiased machine-learning approaches to more accurately identify births with a high risk of neonatal deaths from preventable causes.MethodsWe link administrative databases from the Brazilian health ministry to obtain birth and death records in the country from 2015 to 2017. The final dataset comprises 8,797,968 births, of which 59,615 newborns died before reaching 28 days alive (neonatal deaths). These neonatal deaths are categorized into preventable deaths (42,290) and non-preventable deaths (17,325). Our analysis identifies the death risk of the former group, as they are amenable to policy interventions. We train six machine-learning algorithms, test their performance on unseen data, and evaluate them using a new policy-oriented metric. To avoid biased policy recommendations, we also investigate how our approach impacts disadvantaged populations.ResultsXGBoost was the best performance algorithm for our task: the 5% births of the highest predicted risk from this model capture more than 85% of the actual deaths. Furthermore, the risk predictions exhibit no statistical differences in the proportion of actual preventable deaths from disadvantaged populations, defined by race, education, marital status, and maternal age. These results are similar for other thresh-old levels.ConclusionsWe show that, by using publicly available administrative data sets and ML methods, it is possible to identify the births with the highest risk of preventable deaths with a high degree of accuracy. This is useful for policymakers as they can target health interventions to those who need them the most and where they can be effective without producing bias against disadvantaged populations. Overall, our approach can guide policymakers in reducing neonatal mortality rates and their health inequalities. Finally, it can be adapted to be used in other developing countries.
The Gut Microbiome Strongly Mediates the impact of Lifestyle combined variables on Cardiometabolic Phenotypes
Authors: Adriouch Solia , Belda Eugeni , Swartz Timothy D , Forslund Sofia , Le Roy Tiphaine , Prifti Edi , Aron-Wisnewsky Judith , Chakaroun Rima , Nielsen Trine , Andrikopoulos Petros , Chechi Kanta , Puig-Castellví Francesc , Froguel Philippe , Holmes Bridget , Alili Rohia , Andreelli Fabrizio , Soula Hedi , Salem Joe-Elie , Falony Gwen , Vieira-Silva Sara , Galazzo Gianluca ,   MetaCardis Consortium, Raes Jeroen , Bork Peer , Stumvoll Michael , Pedersen Oluf , Ehrlich S. Dusko , Dumas Marc-Emmanuel , Oppert Jean-Michel , Dao Maria Carlota , Zucker Jean-Daniel , Clément Karine 
Published: January 2024

AbstractIndividual lifestyle factors moderately impact the gut microbiome and host biology. This study explores whether their combined influence significantly alters the gut microbiome and determines the mediating role of the gut microbiome in the links between lifestyle and phenomes. Analyzing 1,643 individuals from the Metacardis European study, we created a non-exhaustive composite lifestyle score (QASD score) incorporating diet quality and diversity, physical activity and smoking. This score shows higher explanatory power for microbiome composition variation compared to individual lifestyle variables. It positively associates with microbiome gene richness, butyrate-producing bacteria, and serum metabolites like Hippurate linked metabolic health. It inversely associates withClostridium bolteaeandRuminococcus gnavus,serum branched-chain amino acids and dipeptides observed in chronic diseases. Causal inference analyses found 135 cases where the microbiome mediates >20% of QASD score effects on host metabolome. Microbiome gene richness also emerged as a strong mediator in the QASD score’s impact on markers of host glucose metabolism (27.3% of the effect on HOMA- IR), despite bidirectional associations between the microbiome and clinical phenotypes. This study emphasizes the importance of combining lifestyle factors to understand their collective contribution to the gut microbiota and the mediating effects of the gut microbiome on the impact of lifestyle on host metabolic phenotypes and metabolomic profiles.