bluuebunny/crossref_metadata_2025 huggingface dataset:
A digital score of peri-epithelial lymphocytic activity predicts malignant transformation in oral epithelial dysplasia
Authors: Bashir Raja Muhammad Saad , Shephard Adam J , Mahmood Hanya , Azarmehr Neda , Raza Shan E Ahmed , Khurram Syed Ali , Rajpoot Nasir M
Published: February 2023

Oral squamous cell carcinoma (OSCC) is amongst the most common cancers worldwide, with more than 377,000 new cases worldwide each year. OSCC prognosis remains poor, related to cancer presentation at a late stage indicating the need for early detection to improve patient prognosis. OSCC is often preceded by a premalignant state known as oral epithelial dysplasia (OED), which is diagnosed and graded using subjective histological criteria leading to variability and prognostic unreliability. In this work, we propose a deep learning approach for the development of prognostic models for malignant transformation and their association with clinical outcomes in histology whole slide images (WSIs) of OED tissue sections. We train a weakly supervised method on OED (n= 137) cases with transformation (n= 50) status and mean malignant transformation time of 6.51 years (±5.35 SD). Performing stratified 5-fold cross-validation achieves an average AUROC of ∼0.78 for predicting malignant transformations in OED. Hotspot analysis reveals various features from nuclei in the epithelium and peri-epithelial tissue to be significant prognostic factors for malignant transformation, including the count of peri-epithelial lymphocytes (PELs) (p< 0.05), epithelial layer nuclei count (NC) (p< 0.05) and basal layer NC (p< 0.05). Progression free survival using the Epithelial layer NC (p< 0.05, C-index = 0.73), Basal layer NC (p< 0.05, C-index = 0.70) and PEL count (p< 0.05, C-index = 0.73) shown association of these features with a high risk of malignant transformation. Our work shows the application of deep learning for prognostication and progression free survival (PFS) prediction of OED for the first time and has a significant potential to aid patient management. Further evaluation and testing on multi-centric data is required for validation and translation to clinical practice.
Generative AI as a Tool for Environmental Health Research Translation
Authors: Anderson Lauren B. , Kanneganti Dhiraj , Houk Mary Bentley , Holm Rochelle H. , Smith Ted
Published: February 2023

Generative artificial intelligence, popularized by services like ChatGPT, has been the source of much recent popular attention for publishing health research. Another valuable application is in translating published research studies to readers in non-academic settings. These might include environmental justice communities, mainstream media outlets, and community science groups. Five recently published (2021-2022) open-access, peer-reviewed papers, authored by University of Louisville environmental health investigators and collaborators, were submitted to ChatGPT. The average rating of all summaries of all types across the five different studies ranged between 3 and 5, indicating good overall content quality. ChatGPT’s general summary request was consistently rated lower than all other summary types. Whereas higher ratings of 4 and 5 were assigned to the more synthetic, insight-oriented activities, such as the production of a plain language summaries suitable for an 8thgrade reading level and identifying the most important finding and real-world research applications. This is a case where artificial intelligence might help level the playing field, for example by creating accessible insights and enabling the large-scale production of high-quality plain language summaries which would truly bring open access to this scientific information. This possibility, combined with the increasing public policy trends encouraging and demanding free access for research supported with public funds, may alter the role journal publications play in communicating science in society. For the field of environmental health science, no-cost AI technology such as ChatGPT holds the promise to improve research translation, but it must continue to be improved (or improve itself) from its current capability.
Estimation of the Variation in Glomerular Filtration Rate Based on Glycosylated Hemoglobin, Serum Creatinine and Age, in Type 2 Diabetic Patients with or Without Chronic Kidney Disease
Authors: Aguirre-Quispe Wilfor , Arana-Calderón Cesar Alejandro
Published: February 2023

Objective

The methods currently used to calculate GFR underestimate this measurement in the population of diabetic patients, so there is a need to look for more accurate methods of estimating GFR in this specific population. This study aims to evaluate a predictive model based on the use of HbA1c to estimate the variability of GFR in diabetic patients with or without CKD.

Methods

We analyzed data from diabetic patients belonging to a cohort of prospective follow-up of a renal health surveillance program attached to a Peruvian hospital. The following factors were included in the multiple linear regression model: age, sex, diastolic blood pressure (DBP), systolic blood pressure (SBP), body mass index (BMI), cholesterol, triglycerides, HDL, LDL, serum creatinine, Urinary creatinine, microalbuminuria, hemoglobin, basal glycemia and HbA1c.

Results

122 patients were included in the analysis. The final multivariate model, which included variation of HbA1c, age and creatinine variation, was very significant (p <0.0001) with an adjusted R2 of 80%. The other variables analyzed were not significant to predict the variation of the GFR despite showing some correlation.

Conclusions

The study shows that HbA1c, age and creatinine variation significantly predict the variation of GFR in diabetic patients with or without CKD and opens the possibility of use as a prognostic tool for this specific population.
Identifying COPD subtypes using multi-trait genetics
Authors: Ziyatdinov Andrey , Hobbs Brian D. , Kanaan-Izquierdo Samir , Moll Matthew , Sakornsakolpat Phuwanat , Shrine Nick , Chen Jing , Song Kijoung , Bowler Russell P. , Castaldi Peter J. , Tobin Martin D. , Kraft Peter , Silverman Edwin K. , Julienne Hanna , Aschard Hugues , Cho Michael H.
Published: February 2023

Chronic Obstructive Pulmonary Disease (COPD) has a simple physiological diagnostic criterion but a wide range of clinical characteristics. The mechanisms underlying this variability in COPD phenotypes are unclear. To investigate the potential contribution of genetic variants to phenotypic heterogeneity, we examined the association of genome-wide associated lung function, COPD, and asthma variants with other phenotypes using phenome-wide association results derived in the UK Biobank. Our clustering analysis of the variants-phenotypes association matrix identified three clusters of genetic variants with different effects on white blood cell counts, height, and body mass index (BMI). To assess the potential clinical and molecular effects of these groups of variants, we investigated the association between cluster-specific genetic risk scores and phenotypes in the COPDGene cohort. We observed differences in steroid use, BMI, lymphocyte counts, chronic bronchitis, and differential gene and protein expression across the three genetic risk scores. Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.
How appropriate is use of antiplatelet medications in patients with transient ischemic attacks and stroke: an analysis of 9132 patients over eight years
Authors: Naveed Hiba , Akhtar Naveed , Al-Jerdi Salman , Uy Ryan Ty , Joseph Sujatha , Morgan Deborah , Babu Blessy , Shanthi Shobana , Shuaib Ashfaq
Published: February 2023

Background and purpose

Guidelines recommend patients with high-risk TIAs and minor stroke presenting within 1-3 days from onset be offered dual antiplatelet therapy (DAPT). There is little data on real-world adherence to these recommendations. We evaluated the appropriateness of DAPT use in TIA and stroke patients in a prospective Database.

Methods

The Qatar Stroke Database began enrollment of patients with TIAs and acute stroke in 2014 and currently has ∼ 16,000 patients. For this study we evaluated the rates of guideline-adherent use of antiplatelet treatment at the time of discharge in patients with TIAs and stroke. TIAs were considered high-risk with ABCD2 score of ⍰ 4 and minor stroke was defined as NIHSS ⍰ 3. Patient demographics, clinical features, risk factors, previous medications, imaging and laboratory investigations, final diagnosis, discharge medications, and discharge and 90-day modified Rankin Scale (mRS) were analyzed.

Results

After excluding patients with ICH, mimics and rare secondary causes, 8082 patients available for final analysis (TIAs: 1357;stroke 6725). In high-risk TIAs, 282 of 666 (42.3%) patients were discharged on DAPT. In patients with minor stroke, 1207 of 3572 (33.8%) patients were discharged on DAPT. DAPT was inappropriately offered to 238 of 691 (34.4%) of low-risk TIAs and 809 of 3153 (25.7%) of non-minor stroke patients.

Conclusions

This large database of prospectively collected patients with TIAs and stroke shows that, unfortunately, despite several guidelines, a large majority of patients with TIAs and stroke are receiving inappropriate antiplatelet treatment at discharge from hospital. This requires urgent attention and further investigation.
Sex differences in atrial myocardial fibrosis and degeneration: evaluation using left atrial low-voltage areas during catheter ablation of atrial fibrillation
Authors: Masuda Masaharu , Matsuda Yasuhiro , Uematsu Hiroyuki , Sugino Ayako , Ooka Hirotaka , Kudo Satoshi , Fujii Subaru , Asai Mitsutoshi , Iida Osamu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Hata Yosuke , Toyoshima Taku , Higashino Naoko , Nakao Sho , Mano Toshiaki
Published: February 2023

Background

Atrial myocardial degeneration predisposes to atrial fibrillation (AF), ischemic stroke, and heart failure. Studies suggest the presence of sex differences in atrial myocardial degeneration. This study aimed to delineate sex differences in the prevalence, predictors, and prognostic impact of left atrial low-voltage areas (LVAs).

Methods

This observational study included 1,488 consecutive patients undergoing initial ablation for AF. Voltage mapping was performed after pulmonary vein isolation during sinus rhythm. LVAs were defined as regions where bipolar peak-to-peak voltage was < 0.50 mV. Results: LVA prevalence was higher in women (37.6%) than in men (16.0%). High age, persistent form of AF, diabetes mellitus, and a large left atrium were shown to be common predictors in both sex categories. Heart failure and history of stroke/thromboembolic events were men-specific predictors of LVA existence. Women experienced more AF recurrence than men (31.1% vs. 25.7%, p = 0.027). LVA existence was significantly associated with increased AF recurrence in each sex category, with a respective hazard ratio, 95% confidence interval and p value of 2.45, 1.87-3.22, and < 0.0001 in men and 1.82, 1.33-2.49, and < 0.0001 in women.

Conclusions

LVA was more frequent in women than men, and predicted frequent AF recurrence irrespective of sex category.
Development and evaluation of a wearable peripheral vascular compensation sensor in a swine model of hemorrhage
Authors: Bonetta-Misteli Francesca , Collins Toi , Pavek Todd , Carlgren Madison , Frolova Antonina , Shmuylovich Leonid , O’Brien Christine M.
Published: February 2023

Postpartum hemorrhage (PPH) is both the leading and most preventable cause of maternal mortality. PPH is currently diagnosed through visual estimation of blood loss or vital sign analysis of shock index (ratio of heart rate to systolic blood pressure). Visual assessment underestimates blood loss, particularly in the setting of internal bleeding, and compensatory mechanisms stabilize hemodynamics until hemorrhage is massive, beyond the point of pharmaceutical intervention. Quantitative monitoring of hemorrhage-induced compensatory processes, such as the constriction of peripheral vessels to shunt blood to the central organs, may provide an early alert for PPH. To this end, we developed a low-cost, wearable optical device that continuously monitors peripheral perfusion via laser speckle flow index (LSFI) to detect hemorrhage-induced peripheral vasoconstriction. The device was first tested using flow phantoms across a range of physiologically relevant flow rates and demonstrated a linear response. Subsequent testing occurred in swine hemorrhage studies (n=6) by placing the device on the posterior side of the swine’s front hock and withdrawing blood from the femoral vein at a constant rate. Resuscitation with intravenous crystalloids followed the induced hemorrhage. The mean LSFI vs. percent estimated blood volume loss had an average correlation coefficient of −0.95 during the hemorrhage phase and 0.79 during resuscitation, both of which were superior to the performance of the shock index. With continued development, this noninvasive, low-cost, and reusable device has global potential to provide an early alert of PPH when low-cost and accessible management strategies are most effective, helping to reduce maternal morbidity and mortality from this largely preventable problem.
Adult thymus-derived cMaf+RORγt+γδ T cells lack Scart2 chromatin accessibility and do not reach periphery
Authors: Yang Tao , Barros-Martins Joana , Janssen Anika , Wang Ziqing , León-Lara Ximena , Weiss Siegfried , Prinz Immo , Förster Reinhold , Ravens Sarina
Published: February 2023

T cell receptor (TCR) Vγ4+expressing γδT cells can be divided into IFN-γ and IL-17-producing effector T cell subsets. A bias towards γδ17 effector fate decisions is observed during early ontogeny. In contrast, the existence of Vγ4+γδ17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immatureCd24+Gzma+Vγ4 cells was found that exhibit molecular programs of γδ17 cells. These adult thymus-derived immatureCd24a+cMaf+Vγ4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore,de novogenerated γδ17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal γδT cell precursors. Together, this study provides valuable insights into developmental traits of Vγ4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of γδ17-like cells within the adult thymus.

Highlights

Transcriptional and epigenetic profiling identifies developmental plasticity ofGzma+Cd24a+Vγ4 cells in adult thymus.

Thymic c-Maf+and RORγt+Vγ4 T cells can be generated during adulthood, but do not reach the periphery under steady-state conditions.

Innate CD44highCD45RBnegγδ17 cells are completely absent upon induction of T cell development during adulthood.

Scart2 expression might be a key molecule to track developmental traits of fetal-derived γδ17 cell precursors.
Epithelial multicellular clustering enabled by polarized macrophages on soft matrices
Authors: Zmuda Hannah , Pathak Amit
Published: February 2023

Formation of epithelial structures of variegated geometries and sizes is essential for organogenesis, tumor growth, and wound repair. Although epithelial cells are predisposed with potential for multicellular clustering, it remains unclear whether immune cells and mechanical cues from their microenvironment influence this process. To explore this possibility, we co-cultured human mammary epithelial cells with pre-polarized macrophages on soft or stiff hydrogels. In the presence of M1 (proinflammatory) macrophages on soft matrices, epithelial cells migrated faster and subsequently formed larger multicellular clusters, compared to co-cultures with M0 (unpolarized) or M2 (anti-inflammatory) macrophages. By contrast, stiff extracellular matrix (ECM) disabled active clustering of epithelial cells due to their enhanced migration and cell-ECM adhesion, regardless of macrophage polarization. We found that the co-presence of soft matrices and M1 macrophages reduced focal adhesions, but enhanced fibronectin deposition and non-muscle myosin-IIA expression, which altogether optimize conditions for epithelial clustering. Upon Rho-associated kinase (ROCK) inhibition, epithelial clustering was abrogated, indicating a requirement for optimized cellular forces. In these co-cultures, Tumor Necrosis Factor (TNF)-α secretion was the highest with M1 macrophages and Transforming growth factor (TGF)-β secretion was exclusively detectable in case of M2 macrophages on soft gels, which indicated potential role of macrophage secreted factors in the observed epithelial clustering. Indeed, exogenous addition of TGB-β promoted epithelial clustering with M1 co-culture on soft gels. According to our findings, optimization of both mechanical and immune factors can tune epithelial clustering responses, which could have implications in tumor growth, fibrosis, and would healing.

Authors show proinflammatory macrophages on soft matrices enable epithelial cells to form multicellular clusters. This phenomenon is disabled on stiff matrices due to increased stability of focal adhesions. Inflammatory cytokine secretion is macrophage-dependent, and external addition of cytokines accentuates epithelial clustering on soft matrices.

Impact Statement

Formation of multicellular epithelial structures is critical to tissue homeostasis. However, it has not been shown how the immune system and mechanical environment affect these structures. The present work illustrates how macrophage type affects epithelial clustering in soft and stiff matrix environments.
PANGEA: A New Gene Set Enrichment Tool forDrosophilaand Common Research Organisms
Authors: Hu Yanhui , Comjean Aram , Attrill Helen , Antonazzo Giulia , Thurmond Jim , Li Fangge , Chao Tiffany , Mohr Stephanie E. , Brown Nicholas H. , Perrimon Norbert
Published: February 2023

Gene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented in a gene list resulting from, for example, an ‘omics’ study. Gene Ontology (GO) annotation is the most frequently used classification mechanism for gene set definition. Here we present a new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis;https://www.flyrnai.org/tools/pangea/), developed to allow a more flexible and configurable approach to data analysis using a variety of classification sets. PANGEA allows GO analysis to be performed on different sets of GO annotations, for example excluding high-throughput studies. Beyond GO, gene sets for pathway annotation and protein complex data from various resources as well as expression and disease annotation from the Alliance of Genome Resources (Alliance). In addition, visualisations of results are enhanced by providing an option to view network of gene set to gene relationships. The tool also allows comparison of multiple input gene lists and accompanying visualisation tools for quick and easy comparison. This new tool will facilitate GSEA forDrosophilaand other major model organisms based on high-quality annotated information available for these species.
Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease
Authors: D'Oliviera Angel , Dai Xuhang , Mottaghinia Saba , Olson Sophie , Geissler Evan P , Etienne Lucie , Zhang Yingkai , Mugridge Jeffrey S
Published: February 2023

The SARS-CoV-2 main protease (Mpro, or Nsp5) is critical for the production of functional viral proteins during infection and, like many viral proteases, can also target host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes global protein synthesis and cellular redox homeostasis. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. TRMT1 proteolysis results in elimination of TRMT1 tRNA methyltransferase activity and reduced tRNA binding affinity. Evolutionary analysis shows that the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. In primates, regions outside the cleavage site with rapid evolution could indicate adaptation to ancient viral pathogens. Furthermore, we determined the structure of a TRMT1 peptide in complex with Mpro, revealing a substrate binding conformation distinct from the majority of available Mpro-peptide complexes. Kinetic parameters for peptide cleavage show that the TRMT1(526-536) sequence is cleaved with comparable efficiency to the Mpro-targeted nsp8/9 viral cleavage site. Mutagenesis studies and molecular dynamics simulations together indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis that follows substrate binding. Our results provide new information about the structural basis for Mpro substrate recognition and cleavage, the functional roles of the TRMT1 zinc finger domain in tRNA binding and modification, and the regulation of TRMT1 activity by SARS-CoV-2 Mpro. These studies could inform future therapeutic design targeting Mpro and raise the possibility that proteolysis of human TRMT1 during SARS-CoV-2 infection suppresses protein translation and oxidative stress response to impact viral pathogenesis.
The impact of chemical fixation on the microanatomy of mouse brain tissue
Authors: Idziak Agata , Inavalli V.V.G. Krishna , Bancelin Stephane , Arizono Misa , Nägerl U. Valentin
Published: February 2023

Chemical fixation using paraformaldehyde (PFA) is a standard step for preserving cells and tissues for subsequent microscopic analyses such as immunofluorescence or electron microscopy. However, chemical fixation may introduce physical alterations in the spatial arrangement of cellular proteins, organelles and membranes. With the increasing use of super-resolution microscopy to visualize cellular structures with nanometric precision, assessing potential artifacts - and knowing how to avoid them - takes on special urgency.

We addressed this issue by taking advantage of live-cell super-resolution microscopy that makes it possible to directly observe the acute effects of PFA on organotypic brain slices, allowing us to compare tissue integrity in a ‘before-and-after’ experiment. We applied super-resolution shadow imaging to assess the structure of the extracellular space (ECS) and regular super-resolution microscopy of fluorescently labeled neurons and astrocytes to quantify key neuroanatomical parameters.

While the ECS volume fraction and micro-anatomical organization of astrocytes remained largely unaffected by the PFA treatment, we detected subtle changes in dendritic spine morphology and observed substantial damage to cell membranes. Our experiments show that PFA application via immersion does not cause a noticeable shrinkage of the ECS in brain slices, unlike the situation in transcardially perfused animals where the ECS typically becomes nearly depleted.

In addition to the super-resolved characterization of fixation artefacts in identified cellular and tissue compartments, our study outlines an experimental strategy to evaluate the quality and pitfalls of various fixation protocols for the molecular and morphological preservation of cells and tissues.
Experimental alteration of the microRNA profile of the mouse embryo: heritable phenotypes in the adult
Authors: Sukranli Zeynep Yilmaz , Bayram Kezban Korkmaz , Taheri Serpil , Cuzin Francois , Ozkul Yusuf , Rassoulzadegan Minoo
Published: February 2023

We previously identified a unique genetic feature of Autism Spectrum Disorder (ASD) in human patients and established mouse models, namely the low to very low level of six microRNAs, miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p. We attempted to interfere experimentally with the expression in the mouse of two of them, miR19a-3p and miR499a-5p by microinjecting into the one-cell embryo either the complementary sequence or an excess of the microRNA. Both approaches resulted in low levels in the somatic tissues and sperm of the targeted microRNAs (nascent) and their pri and pre precursors. The altered miRNA profiles were inherited by progenies of crosses with untreated partners together with behavior alterations partly characteristic of ASD patients and animal models. An excess of miRNA in the eggs leads to a specific downregulation, we propose variations of single-stranded miRNA, as effectors of its own transcription in eukaryotes.
Repeated passive visual experience modulates spontaneous and non-familiar stimuli-evoked neural activity
Authors: Niraula Suraj , Hauser William L. , Rouse Adam G. , Subramanian Jaichandar
Published: February 2023

Familiarity creates subjective memory of repeated innocuous experiences, reduces neural and behavioral responsiveness to those experiences, and enhances novelty detection. The neural correlates of the internal model of familiarity and the cellular mechanisms of enhanced novelty detection following multi-day repeated passive experience remain elusive. Using the mouse visual cortex as a model system, we test how the repeated passive experience of a 45° orientation-grating stimulus for multiple days alters spontaneous and non-familiar stimuli evoked neural activity in neurons tuned to familiar or non-familiar stimuli. We found that familiarity elicits stimulus competition such that stimulus selectivity reduces in neurons tuned to the familiar 45° stimulus; it increases in those tuned to the 90° stimulus but does not affect neurons tuned to the orthogonal 135° stimulus. Furthermore, neurons tuned to orientations 45° apart from the familiar stimulus dominate local functional connectivity. Interestingly, responsiveness to natural images, which consists of familiar and non-familiar orientations, increases subtly in neurons that exhibit stimulus competition. We also show the similarity between familiar grating stimulus-evoked and spontaneous activity increases, indicative of an internal model of altered experience.
Investigating racial disparities in carcinomas through TCGA transcriptomic and proteomic database
Authors: Lei Brian , Jiang Xinyin , Saxena Anjana
Published: February 2023

Simple Summary: Racial disparities in cancer incidence and outcome rates are prevalent in the US, with a variety of contributing factors such as socioeconomic status, differences in lifestyle and environmental exposures, and gene polymorphisms. The goal of this research was to broadly analyze public data to identify critical differences in molecular signatures and pathways between races. Additionally, to ensure the clinical translatability of our work, we analyzed the impact of these differences on patient survival. Our findings will help inform the use of novel biomarkers in clinical settings and the future development of precision therapies.

Abstract:Epidemiological studies highlight a disparity in cancer incidence and outcome rates between racial groups in the United States. In our study, we investigated molecular differences among racial groups in 10 carcinoma types. We used publicly available data from The Cancer Genome Atlas to identify patterns of differential gene expression in tumors obtained from 4,112 White, Black/African American, and Asian patients. We identified race-dependent expression of numerous genes whose mRNA transcript levels were significantly correlated with patient survival. A small subset of these genes was differentially expressed in multiple carcinomas, including genes involved in cell cycle progression such asCCNB1,CCNE1,CCNE2, andFOXM1. In contrast, genes such as transcriptional factorETS1and apoptotic geneBAK1were differ-entially expressed and clinically significant only in specific cancer types. Our analyses also revealed race-dependent regulation of relevant pathways. Importantly, homology directed repair and ERBB4-mediated nuclear signaling were both upregulated in Black patients compared to Whites in four carcinoma types. This large-scale pan-cancer study refines our understanding of the cancer health disparity and can help inform the use of novel biomarkers in clinical settings as well as the future development of precision therapies.
Neuromechanical strategies for obstacle negotiation during overground locomotion following an incomplete spinal cord injury in adult cats
Authors: Lecomte Charly G. , Mari Stephen , Audet Johannie , Yassine Sirine , Merlet Angèle N. , Morency Caroline , Harnie Jonathan , Beaulieu Claudie , Gendron Louis , Frigon Alain
Published: February 2023

Following incomplete spinal cord injury in animals, including humans, substantial locomotor recovery can occur. However, functional aspects of locomotion, such as negotiating an obstacle remains challenging. We collected kinematic and electromyography data in ten adult cats before and at weeks 1-2 and 7-8 after a lateral mid-thoracic hemisection while they negotiated obstacles of three different heights. Intact cats always cleared obstacles without contact. At weeks 1-2 after hemisection, the ipsilesional hindlimb contacted obstacles in ~50% of trials, triggering a stumbling corrective reaction or lack of response. When complete clearance occurred, we observed exaggerated ipsilesional hindlimb flexion when it crossed the obstacle with the contralesional limbs leading. At weeks 7-8 after hemisection, complete clearance increased in favor of absent responses while the proportion of stumbling corrective reactions remained relatively the same. We found redistribution of weight support after hemisection, with reduced diagonal supports and increased homolateral supports, particularly on the contralesional side. The main neural strategy for complete clearance in intact cats consisted of increased activation of muscles that flex the knee. After hemisection, knee flexor activation remained but it was insufficient or more variable as the limb approached the obstacle. Intact cats also increased their speed when stepping over an obstacle, an increase that disappeared after hemisection. The increase in complete clearance over time after hemisection paralleled the recovery of muscle activation patterns or new strategies. Our results suggest partial recovery of anticipatory control through neuroplastic changes in the locomotor control system.
Revealing the combined roles of Aβ and tau in Alzheimer’s disease via a pathophysiological activity decoder
Authors: Sanchez-Rodriguez Lazaro M. , Bezgin Gleb , Carbonell Felix , Therriault Joseph , Fernandez-Arias Jaime , Servaes Stijn , Rahmouni Nesrine , Tissot Cecile , Stevenson Jenna , Karikari Thomas K. , Ashton Nicholas J. , Benedet Andréa L. , Zetterberg Henrik , Blennow Kaj , Triana-Baltzer Gallen , Kolb Hartmuth C. , Rosa-Neto Pedro , Iturria-Medina Yasser
Published: February 2023

Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-β (Aβ) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.
Laboratory evolution identifies elongated flavodoxins that support electron transfer to sulfite reductases
Authors: Truong Albert , Myerscough Dru , Campbell Ian , Atkinson Josh , Silberg Jonathan J.
Published: February 2023

Flavodoxins (Flds) mediate the flux of electrons between oxidoreductases in diverse metabolic pathways. While dozens of Fld-partner oxidoreductases have been discovered, these only represent a subset of the oxidoreductases that couple with ferredoxin (Fd) protein electron carriers. To investigate whether Flds can support electron transfer to a sulfite reductase (SIR) that evolved to couple with a Fd, we evaluated the ability of Flds to transfer electrons from a Fd-NADP reductase (FNR) to a Fd-dependent SIR using growth complementation of a microbe with a sulfur metabolism defect. We show that Flds from cyanobacteria complement the growth of this microbe when coexpressed with an FNR and an SIR that evolved to couple with a plant Fd. To better understand the interaction of Fld with these partner oxidoreductases, we evaluated the effect of peptide insertion on Fld-mediated electron transfer. We observe a high insertion sensitivity within regions predicted to be proximal to the cofactor and partner binding sites and a high insertion tolerance within the loop that is used to differentiate short- and long-chain flavodoxins. These results represent the first evidence that Flds can support electron transfer to assimilatory SIRs, and they suggest that the pattern of peptide-insertion tolerance is influenced by interactions with oxidoreductase partners in electron transfer pathways.
Oct4 redox sensitivity potentiates reprogramming and differentiation
Authors: Shen Zuolian , Wu Yifan , Manna Asit , Yi Chongil , Cairns Bradley R. , Evason Kimberley J. , Chandrasekharan Mahesh B. , Tantin Dean
Published: February 2023

The transcription factor Oct4/Pou5f1 is a component of the regulatory circuitry governing pluripotency and is widely used to induce pluripotency from somatic cells. Here we use domain swapping and mutagenesis to study Oct4’s reprogramming ability, identifying a redox-sensitive DNA binding domain cysteine residue (Cys48) as a key determinant of reprogramming and differentiation. Oct4 Cys48 sensitizes the protein to oxidative inhibition of DNA binding activity and promotes oxidation-mediated protein ubiquitylation.Pou5f1C48Spoint mutation has little effect on undifferentiated embryonic stem cells (ESCs), but upon retinoic acid (RA) treatment causes retention of Oct4 expression, deregulated gene expression and aberrant differentiation.Pou5f1C48SESCs also form less differentiated teratomas and contribute poorly to adult somatic tissues. Finally, we describePou5f1C48S(Janky) mice, which in the homozygous condition are severely developmentally restricted after E4.5. Rare animals bypassing this restriction appear normal at birth but are sterile. Collectively, these findings uncover a novel Oct4 redox mechanism involved in both entry into and exit from pluripotency.
Socio-cultural practices may have affected sexual dimorphism in stature in Early Neolithic Europe
Authors: Cox Samantha L , Nicklisch Nicole , Francken Michael , Wahl Joachim , Meller Harald , Haak Wolfgang , Alt Kurt W , Rosenstock Eva , Mathieson Iain
Published: February 2023

Abstract

The rules and structure of human culture impact health and disease as much as genetics or the natural environment. To study the origin and evolution of these patterns, we take a multidisciplinary approach combining ancient DNA, skeletal metrics, paleopathology, and stable isotopes. Our analysis focuses on cultural, environmental, and genetic contributions to variation in stature in four populations of Early Neolithic Europe. In Central Europe, low female stature is likely due to male preference in resource allocation under conditions of stress. In contrast, shorter male stature in Mediterranean populations may reflect a lack of preference. Our analysis suggests that biological consequences of sex-specific inequities can be linked to culture as early as 7000 years before present. Understanding these patterns is key to interpreting the evolution of genetic and socio-cultural determinants of health, and our results show that culture, more than environment or genetics, drove height disparities in Early Neolithic Europe.
A toolbox of astrocyte-specific, serotype-independent adeno-associated viral vectors using microRNA targeting sequences
Authors: Gleichman Amy J. , Kawaguchi Riki , Sofroniew Michael V. , Carmichael S. Thomas
Published: February 2023

Astrocytes, one of the most prevalent cell types in the central nervous system (CNS), are critically involved in neural function in both health and disease. Genetically manipulating astrocytes is an essential tool in understanding and affecting their roles. Adeno-associated viruses (AAVs) enable rapid genetic manipulation; however, astrocyte specificity of AAVs can be limited, with high off-target expression in neurons and sparsely in endothelial cells. Here, we report the development of a cassette of four copies of six miRNA targeting sequences (4×6T) which triggers transgene degradation specifically in neurons and endothelial cells. When used in combination with the GfaABC1D promoter, 4×6T increases astrocytic specificity of Cre with a viral reporter from <50% to >99% in multiple serotypes in mice, and confers astrocyte specificity in two inducible forms of Cre; Dre; and reporters. We also present empty vectors to add 4×6T to other cargo, independently and in Cre/Dre-dependent forms. This toolbox of AAVs provides a way to rapidly manipulate astrocytes throughout the CNS, is compatible with different AAV serotypes, and demonstrates the efficacy of using multiplexed miRNA targeting sequences to decrease expression in multiple off-target cell populations simultaneously.
Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomization
Authors: Havdahl Alexandra , Hughes Amanda M , Sanderson Eleanor , Ask Helga , Cheesman Rosa , Reichborn-Kjennerud Ted , Andreassen Ole A. , Corfield Elizabeth C. , Hannigan Laurie , Magnus Per , Njølstad Pål R. , Stoltenberg Camilla , Torvik Fartein Ask , Brandlistuen Ragnhild , Smith George Davey , Ystrom Eivind , Davies Neil M
Published: February 2023

The intergenerational transmission of educational attainment from parents to their children is one of the most important and studied relationships in social science. Longitudinal studies have found strong associations between parents’ and their children’s educational outcomes, which could be due to the effects of parents. Here we provide new evidence about whether parents’ educational attainment affects their parenting behaviours and children’s early educational outcomes using within-family Mendelian randomization and data from 40,879 genotyped parent-child trios from the Norwegian Mother, Father and Child Cohort (MoBa) study. We found evidence suggesting that parents’ educational attainment affects their children’s educational outcomes from age 5 to 14. More studies are needed to provide more samples of parent-child trios and assess the potential consequences of selection bias and grandparental effects.
A confirmed association betweenDNAvariants inCAPN9,OSM, andITGAMcandidate genes and the risk of umbilical hernia in pigs
Authors: Wozniak J. , Loba W. , Iskrzak P. , Pszczola M. , Wojtczak J. , Switonski M. , Nowacka‐Woszuk J.
Published: February 2023

Umbilical hernia (UH) is one of the most prevalent defects of swine, affecting their welfare and causing considerable economic loss. The molecular mechanisms behind UH in pigs remain poorly understood. The aim of this study was to verify the association between UH and previously reported DNA variants in theCAPN9,OSM,ITGAM, andNUGGCgenes. A case/control study design was applied in two different crossbred cohorts of commercial fatteners containing 412 and 171 pigs, respectively. SNPs withinCAPN9,OSM, andITGAMwere analyzed using Sanger sequencing, and 10 SNPs inCAPN9, five inOSM, and two inITGAMwere identified.A structural variant in theNUGGCgene was studied by droplet‐digital PCR, and an elevated copy number was detected in only a single individual. Significant differences in allele frequencies for four SNPs inCAPN9were detected. The haplotype analysis showed the effect on the risk of UH for two genes. The CAGGA haplotype withinOSMand AT haplotype inITGAMreduced the relative risk of UH by 52% and 45%, respectively, confirming that variants in those genes are associated with the risk of UH in pigs. Moreover, the interaction between theCAPN9haplotype and the sex of animals had also significant impact on UH risk.
COVID‐19‐associated Brugada pattern electrocardiogram: Systematic review of case reports
Authors: Liu Kevin , Chen Kai , Uzunoglu Ekin C. , Rathore Azeem , Deol Tanya , Wu Ele , Elayi Claude S. , Suryanarayana Prakash G. , Keim Stephen G. , Catanzaro John N.
Published: February 2023

Aims

To summarize published case reports of patients diagnosed with coronavirus disease 2019 (COVID‐19) and Brugada pattern electrocardiogram (ECG).

Methods

The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses checklist were followed. A literature search was conducted using PubMed, EMBASE, and Scopus up until September 2021. The incidence, clinical characteristics, and management outcomes of COVID‐19 patients with a Brugada pattern ECG were identified.

Results

A total of 18 cases were collected. The mean age was 47.1 years and 11.1% were women. No patients had prior confirmed diagnosis of Brugada syndrome. The most common presenting clinical symptoms were fever (83.3%), chest pain (38.8%), shortness of breath (38.8%), and syncope (16.6%). All 18 patients presented with type 1 Brugada pattern ECG. Four patients (22.2%) underwent left heart catheterization, and none demonstrated the presence of obstructive coronary disease. The most common reported therapies included antipyretics (55.5%), hydroxychloroquine (27.7%), and antibiotics (16.6%). One patient (5.5%) died during hospitalization. Three patients (16.6%) who presented with syncope received either an implantable cardioverter defibrillator or wearable cardioverter defibrillator at discharge. At follow‐up, 13 patients (72.2%) had resolution of type 1 Brugada pattern ECG.

Conclusion

COVID‐19‐associated Brugada pattern ECG seems relatively rare. Most patients had resolution of the ECG pattern once their symptoms have improved. Increased awareness and timely use of antipyretics is warranted in this population.
Offspring school performance at age 12 after induction of labor vs non‐intervention at term: A linked cohort study
Authors: Burger Renée J. , Mol Ben W. , Ganzevoort Wessel , Gordijn Sanne J. , Pajkrt Eva , Van Der Post Joris A. M. , De Groot Christianne J. M. , Ravelli Anita C. J.
Published: February 2023

Introduction

The incidence of induction of labor, for both medical reasons and as an elective procedure, has been rising and a further increase in induction of labor following the ARRIVE trial may be expected. The effects of induction of labor at term on childhood neurodevelopment, however, are not well studied. We aimed to study the influence of elective induction of labor for each week of gestation separately from 37 to 42 weeks on offspring school performance at 12 years of age after uncomplicated pregnancies.

Material and methods

We performed a population‐based study among 226 684 liveborn children from uncomplicated singleton pregnancies, born from 37+0 to 42+0 weeks of gestation in cephalic presentation in 2003–2008 (no hypertensive disorders, diabetes or birthweight ≤p5) in the Netherlands. Children with congenital anomalies, of non‐white mothers and born after planned cesarean section were excluded. Birth records were linked with national data on school achievement. We compared, using a fetus‐at‐risk approach and per week of gestation, school performance score and secondary school level at age 12 in those born after induction of labor to those born after non‐intervention, ie spontaneous onset of labor in the same week plus all those born at later gestations. Education scores were standardized to a mean of 0 and a standard deviation of 1 and adjusted in the regression analyses.

Results

For each gestational age up to 41 weeks, induction of labor was associated with decreased school performance scores compared with non‐intervention (at 37 weeks −0.05 SD, 95% confidence interval [CI] −0.10 to −0.01 SD; adjusted for confounding factors). After induction of labor, fewer children reached higher secondary school level (at 38 weeks 48% vs 54%; adjusted odds ratio [aOR] 0.88, 95% CI 0.82–0.94).

Conclusions

In women with uncomplicated pregnancies at term, consistently, at every week of gestation from 37 to 41 weeks, induction of labor is associated with lower offspring school performance at age 12 and lower secondary school level compared with non‐intervention, although residual confounding may remain. These long‐term effects of induction of labor should be incorporated in counseling and decision making.
From saving to survivance: Rethinking Indigenous Papuan women's vulnerabilities in Jayapura, Indonesia
Authors: Munro Jenny , Baransano Yohana
Published: February 2023

Racism, sexism and gendered violence disadvantage Indigenous Papuan women, yet government responses often focus on individual interventions like ‘raising awareness’ or training. In this article, we build on efforts to challenge these narratives about women's vulnerabilities. We draw on life history interviews with older Papuan women in Jayapura to rethink vulnerabilities and everyday struggles in the context of structural inequalities. We interpret their stories as forms of ‘survivance’ and argue that contrary to dominant perspectives, Papuan women are not economic novices or passive victims. Rather, opportunities have narrowed over time, and women's long history of activity, strategy, persistence and resistance has largely been forgotten. Women's life histories shed light on urban colonialism and Indigenous survivance in Jayapura since the 1940s, when Jayapura was still a Dutch colonial capital and not yet an Indonesian frontier. In a time dominated by concerns about Papuan demise, their experiences are provocative for rethinking vulnerabilities.