Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth

Objective. Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth. Research Design and Methods. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords “preterm birth,” “TLR”, “RAGE”, “danger signal”, “alarmin”, “genomewide,” “microarray,” and “proteomics” with specific expression profiles of genes and proteins. Results. This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands “alarmin” for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively. Conclusions. TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Passive exoskeleton enhanced temporal component of gait adaptation in split-belt adaptation task

Unilateral sensorimotor pathologies like stroke can cause gait asymmetry. This challenge can be countered using assistive devices such as an exoskeleton. While researches have investigated the benefits of exoskeleton use on gait patterns in general, it is still unclear how such devices assist gait adaptation. This is important because diseases like stroke, substantially impair adaptation, such that recovery becomes difficult. Therefore, this study aimed to determine characteristic gait adaptation patterns that result from exoskeleton usage during a split-belt adaptation task. Eighteen participants were assigned to an exoskeleton or a non-exoskeleton group. Individuals in the EXO group wore a passive exoskeleton on their right leg. All participants performed a split-belt adaptation task on the treadmill. Participants self-selected their preferred walking speed and fast walking speed. Slow walking speed was calculated as half of the FWS. For the split-belt task, the ratio of fast belt to slow belt was 2:1. Spatiotemporal variables were calculated to quantify adaptation. For each variable, symmetry was quantified using symmetry indices (SI). For adaptation analysis, trials were divided into the early adaptation (EA), late adaptation (LA), de-adaptation (DA), and transfer effect (TR). In spatial variables, group and interaction effects were significant only for the DA condition. However, group, condition and interaction effects were significant for EA, LA and DA for temporal variables, especially stance time. These results showed that the exoskeleton-assisted gait adaptation affects temporal components more than the spatial components. In conclusion, characteristic gait adaptation patterns emerged when split-belt adaptation was performed with passive exoskeleton assistance

TURNING REVEALS CHARACTERTISTIC INTER-LIMB COORDIANTION PATTERNS IN PARKINSON’S DISEASE

Changing direction by turning during walking is particularly hard for patients with Parkinson Disease (PD), and can reveal coordination deficits that maybe hidden during regular walking. The aim of this study was to investigate how inter-limb coordination between arms and legs are affected by PD during walking with turning. Participants with idiopathic PD with freezing of gait (FOG) and without freezing of gait (nonFOG) and healthy older adults performed overground walking trials. Participants were instructed to walk at a comfortable pace back and forth continuously between two lines wearing wireless inertial sensor on the wrists and ankles. Data analysis was done separately for the whole walking trial that included both straights and turns and only the straight walking portion. To quantify the duration of coordination between the limbs, cross recurrence quantification analysis (cRQA) was used, and to measure the synchrony between the limbs, cross sample entropy (cSE) was used. The results showed that a) duration of coordination between the arms for the straights was shorter for FOG and nonFOG compared to controls; b) these differences disappeared for the whole; c) asynchrony between arms was increased for straights in both PD groups though only control and nonFOG was different in whole. In summary, the control of inter-limb coordination during walking may be restricted by the complexity the task if it includes turning. Turning can reveal unique coordination patterns among people with PD. Future studies should investigate the balance control during turning which can be targeted with potential rehabilitation paradigms

Asymmetric mobility deficits at the ankle and knee compromises balance control

Stroke is one of the leading causes of disability in the United States including sensory deficits, weaker muscles, and reduced lower limb mobility. These deficits lead to gait and balance impairments including slower walking speed, reduced balance control in standing or walking, and asymmetrical bilateral coordination. Many stroke survivors show reduced ankle and knee mobility due to spasticity, weakness, or reduced muscle tone. This leads them to show compensatory movements like hip hiking and circumductory gait to achieve foot clearance and leg swing. However, this creates asymmetrical lateral shifts, such as a more significant margin of stability in the less affected leg compared to the more affected leg thereby compromising mediolateral (ML) balance control. Previous studies showed that stroke survivors become more unstable when the balance is perturbed by ML cable pulling or treadmill translations during walking. Our central hypothesis is that hip movements for compensating reduced mobility at the ankle and knee asymmetrically during walking compromise ML balance control. Our objective is to prove the hypothesis by testing it first in a healthy model and then in a stroke sample. We ask the following: Could induced ankle and knee immobilization asymmetrically in healthy young participants cause poor mediolateral balance control during lateral treadmill translation perturbations? Is there a relationship between compensatory hip movements due to asymmetric mobility deficits after stroke and poor balance control during walking? Answering these questions could provide new insights into current stroke rehabilitation for dynamic balance control and complement the treatment methods for stroke survivors in the future