Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling

The microbiota primes immune defences but the identity of specific commensal microorganisms that protect against infection is unclear. Conversely, how pathogens compete with the microbiota to establish their host niche is also poorly understood. In the present study, we investigate the antagonism between the microbiota and Klebsiella pneumoniae during colonization and transmission. We discover that maturation of the microbiota drives the development of distinct immune defence programmes in the upper airways and intestine to limit K. pneumoniae colonization within these niches. Immune protection in the intestine depends on the development of Bacteroidetes, interleukin (IL)-36 signalling and macrophages. This effect of Bacteroidetes requires the polysaccharide utilization locus of their conserved commensal colonization factor. Conversely, in the upper airways, Proteobacteria prime immunity through IL-17A, but K. pneumoniae overcomes these defences through encapsulation to effectively colonize this site. Ultimately, we find that host-to-host spread of K. pneumoniae occurs principally from its intestinal reservoir, and that commensal-colonization-factor-producing Bacteroidetes are sufficient to prevent transmission between hosts through IL-36. Thus, our study provides mechanistic insight into when, where and how commensal Bacteroidetes protect against K. pneumoniae colonization and contagion, providing insight into how these protective microorganisms could be harnessed to confer population-level protection against K. pneumoniae infection

Chemostat culture systems support diverse bacteriophage communities from human feces

BACKGROUND: Most human microbiota studies focus on bacteria inhabiting body surfaces, but these surfaces also are home to large populations of viruses. Many are bacteriophages, and their role in driving bacterial diversity is difficult to decipher without the use of in vitro ecosystems that can reproduce human microbial communities. RESULTS: We used chemostat culture systems known to harbor diverse fecal bacteria to decipher whether these cultures also are home to phage communities. We found that there are vast viral communities inhabiting these ecosystems, with estimated concentrations similar to those found in human feces. The viral communities are composed entirely of bacteriophages and likely contain both temperate and lytic phages based on their similarities to other known phages. We examined the cultured phage communities at five separate time points over 24 days and found that they were highly individual-specific, suggesting that much of the subject-specificity found in human viromes also is captured by this culture-based system. A high proportion of the community membership is conserved over time, but the cultured communities maintain more similarity with other intra-subject cultures than they do to human feces. In four of the five subjects, estimated viral diversity between fecal and cultured communities was highly similar. CONCLUSIONS: Because the diversity of phages in these cultured fecal communities have similarities to those found in humans, we believe these communities can serve as valuable ecosystems to help uncover the role of phages in human microbial communities

Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease

Background The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). Aim To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD. Methods Twenty‐five participants aged 3‐18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin 100 μg/g, “mucosal inflammation,” n = 11). 16S gene‐based metataxonomics, 1H‐NMR spectroscopy‐based metabolic profiling and protease activity assays were performed on stool samples. Results Relative abundance of Dialister species was six times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine‐learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35‐times greater in the low calprotectin group (95% CI 1.03‐1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54‐times greater in the high calprotectin group (95% CI 1.05‐2.03, P = 0.028). Conclusions This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with “mucosal healing.” It supports further investigation of these as potential novel therapeutic targets in CD

Differentiating between inherited and autocrystic zircon in granitoids

The Maniitsoq map project is supported by the Ministry of Mineral Resources, Government of Greenland. The LA-ICP-MS instruments in the JdLC were funded via an Australian Geophysical Observing System grant provided to AuScope Pty Ltd. by the AQ44 Australian Education Investment Fund program.Inherited zircon, crystals that did not form in situ from their host magma but were incorporated from either the source region or assimilated from the wall-rock, is common but can be difficult to identify. Age, chemical and/or textural dissimilarity to the youngest zircon fraction are the primary mechanisms of distinguishing such grains. However, in Zr-undersaturated magmas, the entire zircon population may be inherited and, if not identifiable via textural constraints, can lead to erroneous interpretation of magmatic crystallization age and magma source. Here, we present detailed field mapping of cross-cutting relationships, whole-rock geochemistry and zircon textural, U-Pb and trace element data of trondhjemite, granodiorite and granite from two localities in a complex Archean gneiss terrane in southwest Greenland, which reveal cryptic zircon inheritance. Zircon textural, U–Pb and trace element data demonstrate that, in both localities, trondhjemite is the oldest rock (3011 ± 5 Ma, 2σ), which is intruded by granodiorite (2978 ± 4 Ma, 2σ). However, granite intrusions, constrained by cross-cutting relationships as the youngest component, only contain inherited zircon derived from trondhjemite and granodiorite based on ages and trace element concentrations. Without age constraints on the older two lithologies, it would be tempting to consider the youngest zircon fraction as recording crystallization of the granite but this would be erroneous. Furthermore, whole-rock geochemistry indicates that the granite contains only 6 µg g-1 Zr, extremely low for a granitoid with ∼77 wt. % SiO2. Such low Zr concentration explains the lack of autocrystic zircon in the granite. We expand on a differentiation tool that uses Th/U ratios in zircon versus that in the whole rock to aid in the identification of inherited zircon. This work emphasizes the need for field observations, geochemistry, grain characterization, and precise geochronology to accurately determine igneous crystallization ages and differentiate between inherited and autocrystic zircon.PostprintPeer reviewe

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus

Background and Aims Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. Methods We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2 weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC‐MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. Results \ud In PBC patients with pruritus, serum levels of total and glyco‐conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro‐ and glyco‐conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro‐ and glyco‐ conjugated BAs and increased faecal levels of CA (P = 0.048) and CDCA (P = 0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P = 0.033) and Clostridia (P = 0.04) and decreased Bacteroidetes (P = 0.033) and Bacteroidia (P = 0.04). Conclusions Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition

Regional zircon U-Pb geochronology for the Maniitsoq region, southwest Greenland

The Ministry of Mineral Resources, Government of Greenland, funded this project. Analyses in the JdLC GeoHistory Facility were enabled by instrumentation supported by AuScope (auscope.org.au) and the Australian Government via the National Collaborative Research Infrastructure Strategy. The Tescan Mira3 FEG-SEM was funded through the Australian Research Council LIEF program.Zircon U-Pb geochronology places high-temperature geological events into temporal context. Here, we present a comprehensive zircon U-Pb geochronology dataset for the Meso- to Neoarchean Maniitsoq region in southwest Greenland, which includes the Akia Terrane, Tuno Terrane, and the intervening Alanngua Complex. The magmatic and metamorphic processes recorded in these terranes straddle a key change-point in early Earth geodynamics. This dataset comprises zircon U-Pb ages for 121 samples, including 46 that are newly dated. A principal crystallization peak occurs across all three terranes at ca. 3000 Ma, with subordinate crystallization age peaks at 3200 Ma (Akia Terrane and Alanngua Complex only), 2720 Ma and 2540 Ma. Metamorphic age peaks occur at 2990 Ma, 2820-2700 Ma, 2670-2600 Ma and 2540 Ma. Except for one sample, all dated metamorphic zircon growth after the Neoarchean occurred in the Alanngua Complex or within 20 km of its boundaries. This U-Pb dataset provides an important resource for addressing Earth Science topics as diverse as crustal evolution, fluid-rock interaction and mineral deposit genesis.Publisher PDFPeer reviewe

Measuring the humoral immune response in cats exposed to feline leukaemia virus

Retroviruses belong to an important and diverse family of RNA viruses capable of causing neoplastic disease in their hosts. Feline leukaemia virus (FeLV) is a gammaretrovirus that infects domestic and wild cats, causing immunodeficiency, cytopenia and neoplasia in progressively infected cats. The outcome of FeLV infection is influenced by the host immune response; progressively infected cats demonstrate weaker immune responses compared to regressively infected cats. In this study, humoral immune responses were examined in 180 samples collected from 123 domestic cats that had been naturally exposed to FeLV, using a novel ELISA to measure antibodies recognizing the FeLV surface unit (SU) glycoprotein in plasma samples. A correlation was demonstrated between the strength of the humoral immune response to the SU protein and the outcome of exposure. Cats with regressive infection demonstrated higher antibody responses to the SU protein compared to cats belonging to other outcome groups, and samples from cats with regressive infection contained virus neutralising antibodies. These results demonstrate that an ELISA that assesses the humoral response to FeLV SU complements the use of viral diagnostic tests to define the outcome of exposure to FeLV. Together these tests could allow the rapid identification of regressively infected cats that are unlikely to develop FeLV-related disease

The care of patients with Duchenne, Becker and other muscular dystrophies in the COVID-19 pandemic

The corona virus disease 2019 (COVID-19) pandemic has resulted in the reorganization of healthcare settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this paper, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth

Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: should we be considering probiotics during viral pandemics?

Gut microbiome manipulation to alter the gut-lung axis may potentially protect humans against respiratory infections, and clinical trials of probiotics show promise in this regard in healthy adults and children. However, comparable studies are lacking in overweight/obese people, who have increased risks in particular of viral upper respiratory tract infections (URTI). This further analyses our recent placebo-controlled trial of probiotics in overweight/obese people (focused initially on weight loss) to investigate the impact of probiotics upon the occurrence of URTI symptoms. As well as undergoing loss of weight and improvement in certain metabolic parameters, study participants taking probiotics experienced a 27% reduction in URTI symptoms control, with those ≥45 years or BMI ≥30 kg/m experiencing greater reductions. This symptom reduction is apparent within 2 weeks of probiotic use. Gut microbiome diversity remained stable throughout the study in probiotic-treated participants. Our data provide support for further trials to assess the potential role of probiotics in preventing viral URTI (and possibly also COVID-19), particularly in overweight/obese people

Wrong schools or wrong students? The potential role of medical education in regional imbalances of the health workforce in the United Republic of Tanzania

<p>Abstract</p> <p>Background</p> <p>The United Republic of Tanzania, like many other countries in sub-Saharan Africa, faces a human resources crisis in its health sector, with a small and inequitably distributed health workforce. Rural areas and other poor regions are characterised by a high burden of disease compared to other regions of the country. At the same time, these areas are poorly supplied with human resources compared to urban areas, a reflection of the situation in the whole of Sub-Saharan Africa, where 1.3% of the world's health workforce shoulders 25% of the world's burden of disease. Medical schools select candidates for training and form these candidates' professional morale. It is therefore likely that medical schools can play an important role in the problem of geographical imbalance of doctors in the United Republic of Tanzania.</p> <p>Methods</p> <p>This paper reviews available research evidence that links medical students' characteristics with human resource imbalances and the contribution of medical schools in perpetuating an inequitable distribution of the health workforce.</p> <p>Existing literature on the determinants of the geographical imbalance of clinicians, with a special focus on the role of medical schools, is reviewed. In addition, structured questionnaires collecting data on demographics, rural experience, working preferences and motivational aspects were administered to 130 fifth-year medical students at the medical faculties of MUCHS (University of Dar es Salaam), HKMU (Dar es Salaam) and KCMC (Tumaini University, Moshi campus) in the United Republic of Tanzania. The 130 students represented 95.6% of the Tanzanian finalists in 2005. Finally, we apply probit regressions in STATA to analyse the cross-sectional data coming from the aforementioned survey.</p> <p>Results</p> <p>The lack of a primary interest in medicine among medical school entrants, biases in recruitment, the absence of rural related clinical curricula in medical schools, and a preference for specialisation not available in rural areas are among the main obstacles for building a motivated health workforce which can help correct the inequitable distribution of doctors in the United Republic of Tanzania.</p> <p>Conclusion</p> <p>This study suggests that there is a need to re-examine medical school admission policies and practices.</p