Drug-induced Fatal Arrhythmias: Acquired long QT and Brugada Syndromes

Since the early 1990s, the concept of primary “inherited” arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes

Vegetacija in ekologija barij v Sloveniji

We confirmed infection of 2 patients with Borrelia miyamotoi in Japan by retrospective surveillance of Lyme disease patients and detection of B. miyamotoi DNA in serum samples. One patient also showed seroconversion for antibody against recombinant glycerophosphodiester phosphodiesterase of B. miyamotoi. Indigenous relapsing fever should be considered a health concern in Japan

Sea Surface Temperature and Salinity in Lombok Strait Reconstructed From Coral Sr/Ca and δ18O, 1962–2012

Coral geochemical tracers have been used in studies of the paleoclimatology and paleoceanography of the tropics and subtropics. We measured Sr/Ca and oxygen isotope ratios (δ18O) in a coral sample collected from the southern part of Lombok Strait, a significant outlet of the Indonesian Throughflow (ITF) to the Indian Ocean, to reconstruct the historical record of sea surface temperature (SST) and seawater δ18O. Seawater δ18O can be used to approximate sea surface salinity (SSS) because it reflects the balance of evaporation and precipitation. The resulting time series reconstructed SST and SSS, covering the period 1962–2012, shows no clear trend of global warming, although the record includes a large cooling event (~4°C) during 1996–1997. Although neither SST nor SSS shows a systematic relationship with El Niño–Southern Oscillation and Indian Ocean Dipole (IOD), weak but significant correlations are found partly. In addition, the coral data show signals of major IOD and El Niño events in 1994 and 1997, respectively, although climatic trends recorded in the coral are not consistent with those found along the Java-Sumatra coast. To evaluate other influences on the ITF in Lombok Strait, we compared our coral record with coral records from sites in the Java Sea, the southern part of Makassar Strait, and Ombai Strait. During the northwest monsoon (December–January–February), variations in SST and SSS at Lombok Strait site are similar to those at the Java Sea and southern Makassar sites for the period 1962–1995, which suggests that low-salinity water from the Java Sea is carried at least to the southern part of Makassar Strait where it suppresses the ITF upstream from Lombok Strait. However, the SST and SSS records differ at the three sites during the southeast monsoon (June–July–August), indicating that surface conditions in Lombok Strait vary separately from those in the Java Sea. In the longer term, although global warming has been widely identified in the Indonesian Seas, the coral record shows no clear warming trend in the southern part of Lombok Strait, where fluctuations in the ITF may be modulating the distribution of heat in the surface waters of the western Pacific and eastern Indian Ocean

School grade and sex differences in domain-specific sedentary behaviors among Japanese elementary school children: a cross-sectional study

Background: It is vital to reduce the proportion of sedentary behavior in children. Understanding the duration and behavioral context is needed. The present study examined school-grade and sex differences in domain-specificsedentary times and concurrence with screen-time guidelines among Japanese elementary school children.Methods: A total of 625 children (330 boys) were surveyed in 2010 and 2014. Using a questionnaire, data regarding participants’ grade (first through third grades: lower grades; fourth through six grades: higher grades), sex, weight, and height were collected in addition to the time spent per day engaging in each specific sedentary behavior separately:(1) reading or listening to music, (2) TV or video viewing, (3) TV game use, (4) internet use excluding class, (5) homework, and (6) car travel. Two-way analysis of covariance and logistic regression analyses, adjusted for BMI and moderate to vigorous physical activity, were used to examine school-grade and sex differences in sedentary behaviors and the independent risk of exceeding recommended total daily screen time (< 2 h).Results:On 625 children, mean minutes (SD) of sedentary behavior per week in (1) – (6) were 90.3 (123.4), 535.0 (356.6),167.3 (222.1), 23.9 (70.9), 264.9 (185.3), and 33.4 (61.2) in weekdays and 42.1 (70.0), 323.9 (232.0), 123.0 (96.4),15.8 (49.9), 74.4 (96.4), and 71.3 (84.9) in weekends, respectively. There were differences in the minutes of sedentary behavior between participants of 2010 and 2014; e.g., TV game use and homework in weekdays and weekdays and car travel in weekends. Boys spent more time in TV game use, and girls spent more time reading, listening to music, doing homework, and car travel. Higher-grade students spent more time reading or listening to music, using a computer, and doing homework. Higher-grade students were 2.09 times (95% CI: 1.32 − 3.30) in whole week, 2.08 times (95% CI: 1.45 − 3.00) in weekday, and 1.88 times (95% CI: 1.29 − 2.74) in weekend more likely to spend ≥2 h per day in domains (2) − (4) (screen-time) than lower-grade students.Conclusions: Time spent engaging in each domain-specific sedentary behavior differed according to sex and school grade. Higher-grade students were less likely to meet screen-time guidelines. These findings highlight the need fordomain-focused strategies to decrease sedentary behavior in Japanese school-age children

Cd, Hg, Pb, and As in European species of wild growing forest landscape fungi : a review

Kadmij (Cd), živo srebro (Hg), svinec (Pb) in arzen (As) so kovine, ki se naravno ali kot posledica človekove dejavnosti pojavljajo v okolju, tudi v gozdni krajini, kjer so rastišča številnih evropskih vrst gliv. Namen članka je bil pripraviti pregled vrst in količin izbranih kovin v trosnjakih gliv terprimerjati lastne raziskave, opravljene v različno onesnaženih območjih v Sloveniji (Zgornja Mežiška, Šaleška in Poljanska dolina), s podatki evropskih raziskav. Vsebnosti kovin v trosnjakih gliv iz neonesnaženih območij pravilomanajdemo v naslednjih intervalih: <0,5 mg/kg suhe teže (Cd), < 0,5 mg/kg do 10 mg/kg suhe teže (Hg), < 0,5 mg/kg do 5 mg/kg suhe teže (Pb) in < 0,5 mg/kg do 1 (2) mg/kg suhe teže (As). Na podlagi pregleda vsebnosti izbranih kovin v trosnjakih gliv ugotavljamo, da sta problematični kovini predvsem Cd in Hg. Omenjeni kovini lahko dosegata velike vsebnosti celo v glivah, ki rastejo v neonesnaženih območjih. Za vse analizirane kovin je značilno, da v trosnjakih gliv iz močno onesnaženih območji dosegajo velike, celo ekstemne vsebnosti, ki nekajkrat prekoračujejo vsebnosti iz neonesnaženih območij. Upoštevaje primerjavo z evropskimi raziskavami ugotavljamo, da je Zgornja Mežiška dolina obremenjena s Pb in Cd, Šaleška dolina pa s Cd in As.Metals, which originate from anthropogenic and natural activities, frequently occur in forest landscape with habitats of many European species of wild growing fungi. The presented review focuses on cadmium (Cd), mercury (Hg), lead (Pb), and arsenic (As) levels in fruiting bodies of wild growing European species of fungi of forest landscape. Furthermore, a comparison with studies of this kind performed in Slovenia was made with the aim to assess themetals levels in fungi from differently polluted areas in Slovenia (the Upper Meža Valley, the Šalek Valley, the Poljana Valley). The usual reported levels for most species grown in unpolluted areas are in the following ranges:Cd: < 0,5 mg/kg - 5 mg/kg dry weight (dw), Hg: < 0,5 mg/kg - 10 mg/kg dw, Pb: < 0,5 mg/kg - 5 mg/kg dw, As: < 0,5 mg/kg -1 (2) mg/kg dw (As), respectively. The presented data reveal that cadmium (Cd) and mercury (Hg) have probably been the most detrimental trace elements in fruiting bodies, which can reach increased levels even in unpolluted areas. It is evident for all analyzed trace elements that values can considerably increase in fungi picked in severely polluted areas. According to data regarding Slovene studies and comparison with other European studies, it is obvious that the Šalek Valley is enriched with Cd and As, while the Upper Meža Valley is considerably polluted with Pb and Cd

Responsiveness of genes to manipulation of transcription factors in ES cells is associated with histone modifications and tissue specificity

<p>Abstract</p> <p>Background</p> <p>In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before.</p> <p>Results</p> <p>We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (<it>N </it>= 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (<it>N </it>= 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters.</p> <p>Conclusions</p> <p>We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity.</p

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