bluuebunny/crossref_metadata_2025 huggingface dataset:
Human spinal interneurons repair the injured spinal cord through synaptic integration
Authors: Zholudeva Lyandysha V. , Fortino Tara , Agrawal Ayushi , Vila Olaia F. , Williams Maggie , McDevitt Todd , Lane Michael A. , Srivastava Deepak
Published: January 2024

Advances in cell therapy offer promise for some of the most devastating neural injuries, including spinal cord injury (SCI). Endogenous VSX2-expressing spinal V2a interneurons have been implicated as a key component in plasticity and therapeutically driven recovery post-SCI. While transplantation of generic V2a neurons may have therapeutic value, generation of human spinal V2a neurons with rostro-caudal specificity and assessment of their functional synaptic integration with the injured spinal cord has been elusive. Here, we efficiently differentiated optogenetically engineered cervical V2a spinal interneurons (SpINs) from human induced pluripotent stem cells and tested their capacity to form functional synapses with injured diaphragm motor networks in a clinically-relevant sub-acute model of cervical contusion injury. Neuroanatomical tracing and immunohistochemistry demonstrated transplant integration and synaptic connectivity with injured host tissue. Optogenetic activation of transplanted human V2a SpINs revealed functional synaptic connectivity to injured host circuits, culminating in improved diaphragm activity assessed by electromyography. Furthermore, optogenetic activation of host supraspinal pathways revealed functional innervation of transplanted cells by host neurons, which also led to enhanced diaphragm contraction indicative of a functional neuronal relay. Single cell analyses pre- and post-transplantation suggested thein vivoenvironment resulted in maturation of cervical SpINs that mediate the formation of neuronal relays, as well as differentiation of glial progenitors involved in repair of the damaged spinal cord. This study rigorously demonstrates feasibility of generating human cervical spinal V2a interneurons that develop functional host-transplant and transplant-host connectivity resulting in improved muscle activity post-SCI.
Morphologically defined substages of tail morphogenesis inC. elegansmales
Authors: Kiontke Karin , Fernandez Porfirio , Woronik Alyssa , Fitch David H. A.
Published: January 2024

Background

Sex-specific morphogenesis occurs inC. elegansin the vulva of the hermaphrodite and in the male tail during the last larval stage. Temporal progression of vulva morphogenesis has been described in fine detail. However, a similar precise description of male tail morphogenesis was lacking.

Results

We here describe morphogenesis of the male tail at time points matching vulva development with special focus on morphogenesis of the tail tip. Using fluorescent reporters, we follow changes in cell shapes, cell fusions, nuclear migration, modifications in the basement membrane and formation of a new apical extracellular matrix at the end of the tail.

Conclusion

Our analysis answers two open questions about tail tip morphogenesis (TTM) by showing that one of the four tail tip cells, hyp11, remains separate while the other cells fuse with each other and with two additional tail cells to form a ventral tail syncytium. This fusion begins early during TTM but is only completed towards the end of the process. This work provides a framework for future investigations of cell-biological factors that drive male tail morphogenesis.
Do microsaccades vary with discriminability around the visual field?
Authors: Purokayastha Simran , Roberts Mariel , Carrasco Marisa
Published: January 2024

Microsaccades–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

Nonsense 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

Interleukin-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

Neuromuscular 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

Myocardial 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

Motivation

Understanding 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.

Results

In 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/genopyc

Contact

francesco.gualdi01@estudiant.upf.edu

Supplementary information

supplementary 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

The 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

The 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

Purpose

To 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.

Methods

The 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.

Results

Fundus 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.

Conclusion

NIR 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 Relevance

Multispectral 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

Only 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

Background

Despite 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.

Methods

We 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.

Results

XGBoost 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.

Conclusions

We 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

Individual 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.
Critically-ill COVID-19 susceptibility geneCCR3shows natural selection in sub-Saharan Africans
Authors: Sun Zewen , Pan Lin , Tian Aowen , Chen Peng
Published: January 2024

The prevalence of COVID-19 critical illness varies across ethnicities, with recent studies suggesting that genetic factors may contribute to this variation. The aim of this study was to investigate natural selection signals of genes associated with critically-ill COVID-19 in sub-Saharan Africans. Severe COVID-19 SNPs were obtained from the HGI website. Selection signals were assessed in 661 sub-Sahara Africans from 1000 Genomes Project using integrated haplotype score (iHS), cross-population extended haplotype homozygosity (xpEHH), and fixation index (Fst). Allele frequency trajectory analysis of ancient DNA samples were used to validate the existing of selection in sub-Sahara Africans. We also used Mendelian randomization to decipher the correlation between natural selection and critically-ill COVID-19. We identified thatCCR3exhibited significant natural selection signals in sub-Sahara Africans. Within theCCR3gene, rs17217831-A showed both high iHS (Standardized iHS = 2) and high XP-EHH (Standardized XP-EHH = 2.5) in sub-Sahara Africans. Allele frequency trajectory ofCCR3rs17217831-A revealed natural selection occurring in the recent 1,500 years. Natural selection resulted in increasedCCR3expression in sub-Sahara Africans. Mendelian Randomization provided evidence that increased bloodCCR3expression and eosinophil counts lowered the risk of critically ill COVID-19. Our findings suggest that sub-Saharan Africans are less vulnerable to critically ill COVID-19 due to natural selection and identifyCCR3as a potential novel therapeutic target.
Limited Research Investigating the Value of MRI in Predicting Future Cognitive Morbidity in Survivors of Paediatric Brain Tumours: A Call to Action for Clinical Neuroimaging Researchers
Authors: Griffiths-King Daniel , Delivett Christopher , Peet Andrew , Waite Jane , Novak Jan
Published: January 2024

Survivors of pediatric brain tumour patients are at high risk of cognitive morbidity. There is clinical benefit in being able to reliably predict, at the individual patient level, whether a patient will experience these difficulties or not, the degree of impairment, and the domains affected. Whilst established risk factors exist, quantitative analysis of MRI could provide added predictive value towards this goal, above and beyond existing clinical risk models. The current systematic review aims to answer the question “Do MRI markers predict future cognitive functioning in pediatric brain tumour survivors?”. Studies of pediatric brain tumour patients which test the value of MRI variables in predicting later neuropsychological outcomes were searched up to March 2024. Only included were studies where MRI scans were acquired at an earlier timepoint and used to predict a child’s performance on cognitive tests at a later timepoint. Surprisingly few studies were identified by the systematic search process, but those that were identified specifically investigated MRI measures of cerebellar and white matter damage as features in predicting cognitive outcomes. Ultimately, the key finding of this review is that the current literature is limited. Those studies identified had small sample sizes and were rated as poor quality for the purposes of prediction. Therefore, current findings are at high risk of bias and thus the quality and conclusions are limited. Given the significant impact for this clinical population that predictive models would enable, the current review affirms the need for a ‘call to action’ for medical imaging researchers in pediatric neurooncology.
Beyond Pain Control: Exploring Regional Anaesthesia’s Potential to Improve Gastric Cancer Surgery Survival Rates: A Retrospective Cohort Study
Authors: Tatsuki Onishi , Onishi Yoshika
Published: January 2024

Background

Gastric cancer management remains fraught with high morbidity and mortality rates owing to surgical interventions. Postoperative complications and extended hospitalisation profoundly affect patient survival, with elderly and medically compromised patients facing greater risks. We hypothesised that regional anaesthesia may reduce the surgical stress response and thus mortality. Hence, this study was aimed at investigating whether adjunctive application of regional anaesthesia during gastric cancer surgery attenuates the stress response to surgery, thereby improving postoperative survival outcomes.

Methods

In this study, we critically examined the potential role of regional anaesthesia in modulating perioperative immune and inflammatory responses, which are vital for improving oncological outcomes. Previous studies using diverse methodologies have provided heterogeneous and inconclusive results regarding the effectiveness of regional anaesthesia in enhancing cancer-related survival. Our study addresses these inconsistencies using a robust research design that was focused on a well-defined patient cohort.

Results

Preliminary evidence suggests that regional anaesthesia can modulate immune responses. However, its clinical benefits in cancer recurrence and survival have not been consistently demonstrated. The extant literature reflects a gap between preclinical promise and clinical efficacy, with no substantial evidence supporting a reduction in cancer recurrence after gastroesophageal cancer surgery under regional anaesthesia.

Conclusion

This study provides new insights into the role of regional anaesthesia in reducing the overall mortality in gastric cancer surgery. By employing stringent inclusion criteria and a well-defined patient cohort, this study aimed to provide clarity in a field marked by inconclusive evidence and guide future clinical practices and high-quality research initiatives.
Assessing Performance of Multimodal ChatGPT-4 on an image based Radiology Board-style Examination: An exploratory study
Authors: Bera Kaustav , Gupta Amit , Jiang Sirui , Berlin Sheila , Faraji Navid , Tippareddy Charit , Chiong Ignacio , Jones Robert , Nemer Omar , Nayate Ameya , Tirumani Sree Harsha , Ramaiya Nikhil
Published: January 2024

Objective

To evaluate the performance of multimodal ChatGPT 4 on a radiology board-style examination containing text and radiologic images.s

Materials and Methods

In this prospective exploratory study from October 30 to December 10, 2023, 110 multiple-choice questions containing images designed to match the style and content of radiology board examination like the American Board of Radiology Core or Canadian Board of Radiology examination were prompted to multimodal ChatGPT 4. Questions were further sub stratified according to lower-order (recall, understanding) and higher-order (analyze, synthesize), domains (according to radiology subspecialty), imaging modalities and difficulty (rated by both radiologists and radiologists-in-training). ChatGPT performance was assessed overall as well as in subcategories using Fisher’s exact test with multiple comparisons. Confidence in answering questions was assessed using a Likert scale (1-5) by consensus between a radiologist and radiologist-in-training. Reproducibility was assessed by comparing two different runs using two different accounts.

Results

ChatGPT 4 answered 55% (61/110) of image-rich questions correctly. While there was no significant difference in performance amongst the various sub-groups on exploratory analysis, performance was better on lower-order [61% (25/41)] when compared to higher-order [52% (36/69)] [P=.46]. Among clinical domains, performance was best on cardiovascular imaging [80% (8/10)], and worst on thoracic imaging [30% [3/10)]. Confidence in answering questions was confident/highly confident [89%(98/110)], even when incorrect There was poor reproducibility between two runs, with the answers being different in 14% (15/110) questions.

Conclusion

Despite no radiology specific pre-training, multimodal capabilities of ChatGPT appear promising on questions containing images. However, the lack of reproducibility among two runs, even with the same questions poses challenges of reliability.
Mendelian randomization study on the association between cheese intake and diabetes
Authors: Yang Si-Qi , Xu Yu , Zhang Yan-Bing , Wang Wei-Xing
Published: January 2024

Objective

To explore whether there is a causal relationship between cheese intake and diabetes through Mendel randomization (MR).

Methods

Two samples of MR were used to verify the causal effect of cheese intake on diabetes. The analysis was conducted using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We used a meta-analysis of publicly available genome-wide association studies (GWAS) to compile statistical datasets, and cheese intake data as exposure factors were sourced from individuals of European ancestry in the UK biobank (n=451486). At the same time, GWAS’s public summary statistical data set is also used for self reporting non cancer disease codes: diabetes data included in the Finnish database (total n=184404; case=1219, control=183185) (http://www.finngen.fi/en)as a result.

Result

We selected 108 single nucleotide polymorphisms (SNPs) with genome-wide significance as instrumental variables from the GWAS intake of cheese. IVW method results show a causal relationship between cheese intake and diabetes (β=- 1.196, SE=0.3817, P=0.001729). MR Egger regression results show that directed pleiotropy is unlikely to bias the results (intercept=0.015; P=0.58), but there is no causal relationship between cheese intake and diabetes (β=- 2.073, SE=1.621, P=0.206). The results of weighted median method also showed that there was no causal relationship between cheese intake and diabetes (β=- 0.7828, SE=0.5701, P=0.1698). Cochran’s Q-test and funnel plot indicate no evidence of heterogeneity and asymmetry, indicating the absence of directed pleiotropy.

Conclusion

The results of MR analysis support that cheese intake may have a causal relationship with the reduced risk of diabetes.
The Association Between Medicare Eligibility on Elective Procedures and Hospital Transfers: A regression discontinuity design applied to the National Inpatient Sample
Authors: Swaminathan Akshay , Kumar Wasan , Jacobson Benjamin , Liou Lathan , Lopez Ivan , Yao Caroline , Shah Sarthak
Published: January 2024

Introduction

Access to affordable health coverage for individuals aged 51 and older, particularly those transitioning out of employer-sponsored insurance or with existing health conditions, is challenging in the United States. This study investigates the potential impact of lowering the Medicare eligibility age on healthcare utilization, focusing on elective procedures among late middle-aged individuals. Previous studies indicate significant increases in healthcare utilization around the Medicare eligibility threshold, but a national-level analysis is needed to understand the implications of policy changes in Medicare eligibility.

Methods

This retrospective cohort study utilized 2019 data from the National Inpatient Sample (NIS), encompassing over seven million hospital stays and covering more than 97% of the U.S. population. We compared two groups: uninsured patients aged 63-64 and Medicare-insured patients aged 65-66. The analysis focused on nine common elective surgical procedures, employing a regression discontinuity design to minimize confounding. Patients were exactly matched on several variables, including reason for hospitalization, sex, race, and hospitalization type (elective vs. emergent).

Results

The matched cohort, after exact matching, included 70,916 admissions (47,262 from Medicare patients aged 65-66 and 23,654 from uninsured patients aged 63-64). The study found significantly higher utilization rates of elective procedures, including cataract surgery, glaucoma surgery, joint replacement, and spinal fusion, among the Medicare-eligible group compared to the younger, uninsured group. Rates of elective procedures approximately doubled post-eligibility for Medicare. Additionally, being below the Medicare eligibility age was associated with decreased odds of undergoing these procedures and increased odds of hospital transfers.

Discussion

Lowering the Medicare eligibility age could lead to increased access to elective medical procedures for late middle-aged individuals, potentially reducing delays in treatment and associated complications.
Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95
Authors: Dharmasri Poorna A. , DeMarco Emily M. , Anderson Michael C. , Levy Aaron D. , Blanpied Thomas A.
Published: January 2024

Nanoscale protein organization within the active zone (AZ) and post-synaptic density (PSD) influences synaptic transmission. Nanoclusters of presynaptic Munc13-1 are associated with readily releasable pool size and neurotransmitter vesicle priming, while postsynaptic PSD-95 nanoclusters coordinate glutamate receptors across from release sites to control their opening probability. Nanocluster number, size, and protein density vary between synapse types and with development and plasticity, supporting a wide range of functional states at the synapse. Whether or how the receptors themselves control this critical architecture remains unclear. One prominent PSD molecular complex is the NMDA receptor (NMDAR). NMDARs coordinate several modes of signaling within synapses, giving them the potential to influence synaptic organization through direct protein interactions or through signaling. We found that loss of NMDARs results in larger synapses that contain smaller, denser, and more numerous PSD-95 nanoclusters. Intriguingly, NMDAR loss also generates retrograde reorganization of the active zone, resulting in denser, more numerous Munc13-1 nanoclusters, more of which are aligned with PSD-95 nanoclusters. Together, these changes to synaptic nanostructure predict stronger AMPA receptor-mediated transmission in the absence of NMDARs. Notably, while prolonged antagonism of NMDAR activity increases Munc13-1 density within nanoclusters, it does not fully recapitulate these trans-synaptic effects. Thus, our results confirm that NMDARs play an important role in maintaining pre- and postsynaptic nanostructure and suggest that both decreased NMDAR expression and suppressed NMDAR activity may exert distinct effects on synaptic function, yet through unique architectural mechanisms.

Significance Statement

Synaptic transmission is shaped by the trans-synaptic coordination of molecular ensembles required for neurotransmitter release and receptor retention, but how receptors themselves influence this critical architecture remains unclear. Using state-of-the-art super-resolution microscopy, we report that loss of NMDA receptors from excitatory synapses alters both pre- and postsynaptic nano-organizational features. Notably, pharmacological antagonism of NMDA receptors also alters presynaptic features, but without fully mimicking effects of the knockout. This suggests that both NMDA receptor activity and presence at the synapse exert retrograde influence on active zone organization. Because numerous disease and activity states decrease expression or function of NMDA receptors, our results suggest that distinct nanostructural states contribute to the unique functional status of synapses in these disorders.
Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice
Authors: Blank Heidi M. , Hammer Staci E. , Boatright Laurel , Roberts Courtney , Heyden Katarina E. , Nagarajan Aravindh , Tsuchiya Mitsuhiro , Brun Marcel , Johnson Charles D. , Stover Patrick J. , Sitcheran Raquel , Kennedy Brian K. , Adams L. Garry , Kaeberlein Matt , Field Martha S. , Threadgill David W. , Andrews-Polymenis Helene L. , Polymenis Michael
Published: January 2024

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual’s age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.
Discovery and characterisation of new phage targeting uropathogenicEscherichia coli
Authors: Kangachar Shahla Asgharzadeh , Logel Dominic Y. , Trofimova Ellina , Zhu Hannah X , Zaugg Julian , Schembri Mark A. , Weynberg Karen D. , Jaschke Paul R.
Published: January 2024

Antimicrobial resistance (AMR) is increasing at an escalating rate with few new therapeutic options in the pipeline. Urinary tract infections (UTIs) are one of the most prevalent bacterial infections globally and are particularly prone to becoming recurrent and antibiotic resistant. The aim of this study was to discover and characterise new bacterial viruses (phage) against uropathogenicEscherichia coli(UPEC), which is the leading cause of UTIs. Six phages from theAutographiviridaefamily andGuernseyvirinaesub-family were isolated from wastewater and sequenced. The length of the isolated phage genomes was between 39,471 bp and 45,233 bp, with a GC content between 45.0% and 51.0%, and 57 to 84 predicted coding sequences (CDS) per genome. These phages were found to infect between 25 – 75% of the twelve UPEC strains tested. Using sequence comparison and predicted structural alignments, we show a similarity between the C-terminal domain of the tail fiber proteins of two phage that correlates with their host range.In vitrocharacterisation of phage cocktails against a single bacterial strain did not perform better than the best-performing phage, but did show synergistic improvement against a mixed UPEC strain population. Lastly, we measured the effectiveness of treatment with phage with different lytic kinetics in a sequential treatment and found it was improved over single phage treatment.
FOXO-regulated Deaf1 controls muscle regeneration through autophagy
Authors: Goh Kah Yong , Lee Wen Xing , Choy Sze Mun , Krishnan Priyadarshini Gopal , Chua Kenon , Tan Qian Hui , Low Shin Yi , Chin Hui San , Wong Chee Seng , Huang Shu-Yi , Fu Nai Yang , Nishiyama Jun , Harmston Nathan , Tang Hong-Wen
Published: January 2024

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deformed epidermal autoregulatory factor 1 (Deaf1) - a transcriptional factor downstream of FOXO signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that Deaf1 targets to PI3KC3 and Atg16l1 promoter regions and suppresses their expressions.Deaf1depletion therefore induces autophagy, which in turn blocks MuSC survival and differentiation. In contrast,Deaf1overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. Interestingly,Deaf1depletion and overexpression both lead to defects in muscle regeneration, highlighting the importance of fine tuning Deaf1-regulated autophagy during muscle regeneration. We further showed thatDeaf1expression is altered in aging and cachectic MuSCs. Remarkably, manipulation ofDeaf1expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for Deaf1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.