Cooperative binding of the outer arm-docking complex underlies the regular arrangement of outer arm dynein in the axoneme

Outer arm dynein (OAD) in cilia and flagella is bound to the outer doublet microtubules every 24 nm. Periodic binding of OADs at specific sites is important for efficient cilia/flagella beating; however, the molecular mechanism that specifies OAD arrangement remains elusive. Studies using the green alga Chlamydomonas reinhardtii have shown that the OAD-docking complex (ODA-DC), a heterotrimeric complex present at the OAD base, functions as the OAD docking site on the doublet. We find that the ODA-DC has an ellipsoidal shape approximately 24 nm in length. In mutant axonemes that lack OAD but retain the ODA-DC, ODA-DC molecules are aligned in an end-to-end manner along the outer doublets. When flagella of a mutant lacking ODA-DCs are supplied with ODA-DCs upon gamete fusion, ODA-DC molecules first bind to the mutant axonemes in the proximal region, and the occupied region gradually extends toward the tip, followed by binding of OADs. This and other results indicate that a cooperative association of the ODA-DC underlies its function as the OAD-docking site and is the determinant of the 24-nm periodicity

Association of cerebral small vessel disease burden and health-related quality of life after acute ischemic stroke

Objective: Cerebral small vessel disease (SVD) is associated with increased mortality, disability and cognitive decline, depression in stroke survivors. This study examined the association between SVD burden, defined by a combination of SVD markers, and health-related quality of life (HRQoL) in acute ischemic stroke. Methods: Patients admitted with acute ischemic stroke of any etiology were prospectively screened between January 2010 to December 2014 and enrolled in the study if they met study entry criteria. HRQoL was evaluated with the 12-item Stroke Specific Quality of Life (SSQoL) at 3 months after the onset of acute ischemic stroke. SVD was ascertained by the presence of any of the SVD markers including lacune, white matter hyperintensities (WMH), cerebral microbleeds (CMB) and enlarged perivascular spaces (EPVS) in the basal ganglia or their combinations on brain magnetic resonance imaging (MRI). The presence of each individual marker scored 1 point and was summed up to generate an ordinal “SVD score” (0–4) capturing total SVD burden. Linear regression was used to determine the associations between SVD burden and HRQoL. Results: Of the743 acute ischemic stroke patients that formed he study sample (mean age: 66.3 ± 10.6 years; 41.7% women), 49.3%, 22.5%, 16.0%, 9.2% and 3.1% had SVD scores of 0, 1, 2, 3 and 4, respectively. After adjusting for demographic, clinical and imaging variables, the SVD score was independently associated with lower overall score of SSQoL (B = − 1.39, SE = 0.56, p = 0.01), and its domains of mobility (B = − 0.41, SE = 0.10, p \u3c 0.001) and vision (B = − 0.12, SE = 0.06, p = 0.03). Acute infract volume (B = − 1.44, SE = 0.54, p = 0.01), functional independence (B = 5.69, SE = 0.34, p \u3c 0.001) and anxious (B = − 1.13, SE = 0.23, p \u3c 0.001) and depressive symptoms (B = − 3.41, SE = 0.22, p \u3c 0.001) were also the significant predictors of the overall score of SSQoL. Conclusion: The brain’s SVD burden predicts lower HRQoL, predominantly in domains of mobility and vision at 3 months after acute ischemic stroke. The evaluation of SVD burden could facilitate developing individual treatment strategies

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

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

Conservative management for iatrogenic gastric perforation by transesophageal echocardiography

Abstract Background Though several cases of upper gastrointestinal tract injury caused by transesophageal echocardiography (TEE) have been reported, gastric perforation is very rare. Herein, we report the case of TEE-associated gastric perforation that was successfully treated conservatively. Case presentation An 82-year-old man underwent mitral valve repair. Postoperative esophagogastroduodenoscopy and computed tomography revealed gastric perforation. Surgical treatment was initially considered, but conservative management was selected to avoid increasing operative stress, to minimize the need for total gastrectomy (including the lower esophagus), and to minimize the risk of a potential intraperitoneal infection spreading to the thoracic cavity. Conclusion Conservative management of gastric perforation can be successful even when the perforation is recognized later than 12 h following the event, provided that there are no abdominal symptoms and no signs of peritoneal effusion or sepsis. Our experience suggests that conservative management is a feasible option for treating TEE-associated gastric perforation in appropriately selected cases

Strigolactone perception and deactivation by a hydrolase receptor DWARF14

植物の枝分かれ制御ホルモン「ストリゴラクトン」の受容メカニズムを解明 --受容体タンパクがストリゴラクトンの受容と不活性化を担うことを発見--. 京都大学プレスリリース. 2019-01-18.The perception mechanism for the strigolactone (SL) class of plant hormones has been a subject of debate because their receptor, DWARF14 (D14), is an α/β-hydrolase that can cleave SLs. Here we show via time-course analyses of SL binding and hydrolysis by Arabidopsis thaliana D14, that the level of uncleaved SL strongly correlates with the induction of the active signaling state. In addition, we show that an AtD14D218A catalytic mutant that lacks enzymatic activity is still able to complement the atd14 mutant phenotype in an SL-dependent manner. We conclude that the intact SL molecules trigger the D14 active signaling state, and we also describe that D14 deactivates bioactive SLs by the hydrolytic degradation after signal transmission. Together, these results reveal that D14 is a dual-functional receptor, responsible for both the perception and deactivation of bioactive SLs