Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic ...strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC.
Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are ...frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.
Validation and standardization of methodologies for microbial community measurements by high-throughput sequencing are needed to support human microbiome research and its industrialization. This ...study set out to establish standards-based solutions to improve the accuracy and reproducibility of metagenomics-based microbiome profiling of human fecal samples.
In the first phase, we performed a head-to-head comparison of a wide range of protocols for DNA extraction and sequencing library construction using defined mock communities, to identify performant protocols and pinpoint sources of inaccuracy in quantification. In the second phase, we validated performant protocols with respect to their variability of measurement results within a single laboratory (that is, intermediate precision) as well as interlaboratory transferability and reproducibility through an industry-based collaborative study. We further ascertained the performance of our recommended protocols in the context of a community-wide interlaboratory study (that is, the MOSAIC Standards Challenge). Finally, we defined performance metrics to provide best practice guidance for improving measurement consistency across methods and laboratories.
The validated protocols and methodological guidance for DNA extraction and library construction provided in this study expand current best practices for metagenomic analyses of human fecal microbiota. Uptake of our protocols and guidelines will improve the accuracy and comparability of metagenomics-based studies of the human microbiome, thereby facilitating development and commercialization of human microbiome-based products. Video Abstract.
Interaction Analysis in Hunting Behavior of Finless Porpoises Konda, Mikiko; Kubo, Takatomi; Morimura, Naruki ...
2019 Asia-Pacific Signal and Information Processing Association Annual Summit and Conference (APSIPA ASC),
2019-Nov.
Conference Proceeding
Finless porpoises (Neophocaena asiaeorintalis) usually live in a relatively small group. Aggregated porpoises prey on fish simultaneously and they do not show explicit allotted roles like other ...dolphins. However, whether each individual hunt fish independently from others is not clear. In this study, we tried to find dependency in porpoises' hunting using movies of their feeding taken by a drone.
Objective To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke.Design Prospective cohort study with more than 50 years of follow-up.Setting ...Atomic bomb survivors in Hiroshima and Nagasaki, Japan.Participants 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy).Main outcome measures Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation.Results About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen.Conclusion Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.
PDF
