Low-Cost and Fast Failure Recovery Using In-VM Containers in Clouds

Recently, various services are provided using virtual machines (VMs) in clouds. Therefore, it is necessary to prepare for system failures of VMs, hosts running VMs, and even data centers, e.g., using active/standby clustering. However, a trade-off exists between the maintenance cost for additional VMs and the recovery time in traditional techniques. For example, hot standby can rapidly fail over to the secondary system on a system failure, but the secondary system has to always run the same number of VMs as the primary system. In contrast, cold standby does not need to run VMs until a system failure, but it has to boot VMs on failure recovery. In this paper, we propose VCRecovery, which is the system for achieving both low-cost and fast failure recovery. VCRecovery consolidates services using containers inside VMs (in-VM containers) in the secondary system. For hot standby, it can reduce the maintenance cost by using only a smaller number of VMs in the secondary system. For cold standby, it can reduce the recovery time by quickly booting in-VM containers. If a VM is overloaded after the recovery, VCRecovery can migrate several in-VM containers to other VMs. To synchronize storage between VMs in the primary system and in-VM containers in the secondary system, it efficiently performs minimum file-based synchronization based on software packages. We have implemented VCRecovery using LXD and Zabbix and examined the performance.IEEE 17th International Conference on Dependable, Autonomic and Secure Computing / IEEE 17th International Conference on Pervasive Intelligence and Computing / IEEE 5th International Conference on Cloud and Big Data Computing / IEEE 4th Cyber Science and Technology Congress(DASC-PICom-CBDCom-CyberSciTech 2019), August 5-8 2019, Fukuoka, Japa

High Level of Rheumatoid Factor is Associated with Hepatitis B Viremia in Patients with Chronic Hepatitis B

Hepatitis viruses are causative agents for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. However these viruses are also associated with lymphoproliferative disorders (LPDs), such as essential mixed cryoglobulinemia and B-cell non-Hodgkin\u27s lymphoma. Indeed, hepatitis C virus infection has been confirmed to be associated with LPDs, but the pathogenic mechanism remains unclear. In this study, we investigated the relationship between hepatitis B virus (HBV) infection and LPDs in 84 patients with chronic hepatitis B (CH-B). LPD markers, such as cryoglobulinemia, high levels of rheumatoid factor (RF), hypocomplementemia, and B cell clonality, were measured and analyzed along with viral factors. Results showed that high levels of RF were observed in 39.5% of patients with CH-B. These high RF levels were not associated with abnormal levels of other LPD markers, but only with the presence of HBV DNA in the sera of these patients. Undergoing therapy with nucleotide analogues was also associated with high RF. In two patients with CH-B, decreasing levels of RF were observed during antiviral therapy. In conclusion, high RF levels are associated with HBV viremia in patients with CH-B. HBV infection also plays an important role in the genesis of LPDs in patients with viral hepatitis

EGFR mutation and ALK fusion-positive non-small cell lung cancer: a multicenter prospective cohort study in Nagano Prefecture, Japan

Introduction. We prospectively examined current clinical practices in patients with inoperable epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion-positive (EGFR+ and ALK+, respectively) non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan.  Material and methods. The study population consisted of newly diagnosed patients with inoperable EGFR+ and ALK+ NSCLC in 14 hospitals in Nagano between May 2016 and March 2019. Both initial and subsequent treatment decisions were made at the discretion of the attending physician.  Results. A total of 281 patients with EGFR+ NSCLC (mean age, 74 years, 59.1% female) and 26 patients with ALK+ NSCLC (mean age, 66 years, 53.8% female) were included in the study. The study population consisted of 148/107/29/20/3 cases with performance status 0/1/2/3/4 and 6/2/31/194/75 cases with clinical stage I/II/III/IV/recurrence, respectively. First-line therapy with tyrosine kinase inhibitors was performed in 259 (92.2%) and 22 (84.6%) patients with EGFR+ and ALK+ NSCLC, respectively. The median overall survival rate was 41.2 months (95% CI 36.8–45.6 months) with EGFR+. It was not reached with ALK+ .  Conclusions. This observational analysis represents a valuable resource for evaluating the outcomes of treatment in patients with NSCLC

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

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution