Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity.

Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differ- ential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotox- icity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhib- ited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced con- version of tilimycin to tilivalline, and activation of PXR

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Walking the journey: the student experience

Offers the collective voice of Aboriginal and Torres Strait Islander and allied colleagues as a foundation for creating the conditions of possibility that will aid in the transformation of Australian social work into a field of work that honours its ethical and moral aims. Bennett ACU, Green UNSW, Gilbert Uni of Newcastle, Bessarab Curtin Uni. [Book Synopsis

Sense and Avoid

Team Awesome AOC (Aircraft Operations Challenge) is developing a Sense-and-Avoid system that will take in ADS-B information (978Mhz UAT (Universal Access Transceiver)) and information from the autopilot to will predict if a conflict with another plane will occur, and autonomously change the flight plan in order to avoid the conflict. A conflict is defined as violating the minimum separation distances between aircraft. The team is working to develop a system which includes a small UAS platform, a Commercial off the shelf autopilot, a company sponsored ADS-B solution, and custom Sense-and-Avoid hardware and software. The system must be able to fly several 40 minute long scenarios with multiple possible conflicts while flying a pre-set flight plan. This solution is being developed to help students understand the problems limiting the use of UAS in the national airspace and for the UASAOC competition

The impact of telephone follow up on adverse events for Aboriginal people with chronic disease in new South Wales, Australia: a retrospective cohort study

Abstract Background Chronic diseases are more prevalent and occur at a much younger age in Aboriginal people in Australia compared with non-Aboriginal people. Aboriginal people also have higher rates of unplanned hospital readmissions and emergency department presentations. There is a paucity of research on the effectiveness of follow up programs after discharge from hospital in Aboriginal populations. This study aimed to assess the impact of a telephone follow up program, 48 Hour Follow Up, on rates of unplanned hospital readmissions, unplanned emergency department presentations and mortality within 28 days of discharge among Aboriginal people with chronic disease. Methods A retrospective cohort of eligible Aboriginal people with chronic diseases was obtained through linkage of routinely-collected health datasets for the period May 2009 to December 2014. The primary outcome was unplanned hospital readmissions within 28 days of separation from any acute New South Wales public hospital. Secondary outcomes were mortality, unplanned emergency department presentations, and at least one adverse event (unplanned hospital readmission, unplanned emergency department presentation or mortality) within 28 days of separation. Logistic regression models were used to assess outcomes among Aboriginal patients who received 48 Hour Follow Up compared with eligible Aboriginal patients who did not receive 48 Hour Follow Up. Results The final study cohort included 18,659 patients with 49,721 separations, of which 8469 separations (17.0, 95% confidence interval (CI): 16.7–17.4) were recorded as having received 48 Hour Follow Up. After adjusting for potential confounders, there were no significant differences in rates of unplanned readmission or mortality within 28 days between people who received or did not receive 48 Hour Follow Up. Conversely, the odds of an unplanned emergency department presentation (Odds ratio (OR) = 0.92; 95% CI: 0.85, 0.99; P = 0.0312) and at least one adverse event (OR = 0.91; 95% CI: 0.85,0.98; P = 0.0136) within 28 days were significantly lower for separations where the patient received 48 Hour Follow Up compared with those that did not receive follow up. Conclusions Receipt of 48 Hour Follow Up was associated with both a reduction in emergency department presentations and at least one  adverse event within 28 days of discharge, suggesting there may be merit in providing post-discharge telephone follow up to Aboriginal people with chronic disease

Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation

Differentiation of hematopoietic stem cells (HSCs) after birth is largely restricted to the bone marrow cavity, where HSCs are associated closely with osteoblasts (OBs). How OBs localize HSCs to the endosteal niche remains unclear. To explore adhesive interactions between HSCs and OBs, a cell blot analysis was used that revealed 2 major bands that corresponded to monomers and multimers of annexin II (Anxa2). Immunohistochemistry revealed that OBs and marrow endothelial cells express Anxa2 at high levels. Function-blocking studies confirmed that Anxa2 mediates HSC adhesion mainly via the N-terminal portion of the Anxa2 peptide. Adhesion of HSCs to OBs derived from Anxa2-deficient animals (Anxa2−/−) was significantly impaired compared with OBs obtained from wild-type animals (Anxa2+/+). Moreover, fewer HSCs were found in the marrow of Anxa2−/− versus Anxa2+/+ animals. Short-term lodging, engraftment, and survival of irradiated mice with whole marrow cells were substantially inhibited by N-terminal peptide fragments of Anxa2 or anti-Anxa2 antibodies. Similar findings were noted in long-term competitive repopulation studies. Collectively, these findings reveal that Anxa2 regulates HSC homing and binding to the bone marrow microenvironment and suggest that Anxa2 is crucial for determining the bone marrow niche of HSCs