Bacterial cell wall polymers (peptidoglycan-polysaccharide) cause reactivation of arthritis.

Intraperitoneal (i.p.) injection of peptidoglycan-polysaccharide derived from group A streptococci (PG-APS) causes chronic arthritis with spontaneous remissions and exacerbations. We hypothesized that, following i.p. injection, PG-APS released from hepatic stores mediated spontaneous recurrences of arthritis. We tested whether transplanted livers with large amounts of PG-APS were able to reactivate quiescent arthritis. Saline-loaded (group 1) or PG-APS-loaded (group 2) livers were transplanted into rats which had been injected intra-articularly 10 days earlier with PG-APS in one joint and saline in the other. A comparison was made with the arthritis that occurred in rats injected i.p. with PG-APS which did not receive transplants (group 3). Arthritis was monitored by serial measurement of joint diameters. Transplantation of saline-loaded livers (group 1) caused no reactivation of arthritis. However, transplantation of PG-APS-loaded livers (group 2) reactivated arthritis (P < 0.0001). Injection of PG-APS i.p. (group 3) induced the most-severe arthritis. PG-APS levels in plasma decreased with time, and PG-APS accumulated in the spleen in groups 2 and 3. Plasma and hepatic levels of PG-APS in rats injected i.p. with PG-APS were greater than levels in rats transplanted with PG-APS-loaded livers, which in turn were greater than levels in rats with saline-loaded livers. Plasma tumor necrosis factor did not correlate with recurrence of arthritis. Transplantation with PG-APS-loaded livers induced reactivation of arthritis in preinjured joints. The extent of arthritis was proportional to hepatic PG-APS content. Reactivation of arthritis may be mediated by slow release of liver-sequestered PG-APS or cytokines (not tumor necrosis factor) released by the liver

Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites

Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose radiation to live normal life spans. These "elite-survivors" harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa Lachnospiraceae and Enterococcaceae were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses

A microscopic equation of state for protoneutron stars

We study the structure of protoneutron stars within the finite temperature Brueckner-Bethe-Goldstone many-body theory. If nucleons, hyperons, and leptons are present in the stellar core, we find that neutrino trapping stiffens considerably the equation of state, because hyperon onsets are shifted to larger baryon density. However, the value of the critical mass turns out to be smaller than the ``canonical'' value 1.44 $M_\odot$. We find that the inclusion of a hadron-quark phase transition increases the critical mass and stabilizes it at about 1.5--1.6 $M_\odot$.Comment: 8 pages, 6 figures, to appear in Astrophysics and Space Science, Proceedings of "Isolated Neutron Stars: from the Interior to the Surface", edited by D. Page, R. Turolla, and S. Zan

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Management of Patients With Crohn's Disease and Ulcerative Colitis During the Coronavirus Disease-2019 Pandemic: Results of an International Meeting

The International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) is the only global organization devoted to the study of and management of the inflammatory bowel diseases (IBDs), namely, Crohn?s disease and ulcerative colitis. Membership is composed of physician-scientists who have established expertise in these diseases. The organization hosts an annual meeting and a number of working groups addressing issues of the epidemiology of IBD, diet and nutrition, and the development and use of treatments for IBD. There are currently 89 members of IOIBD representing 26 different countries. The organization has taken particular interest in the coronavirus disease-2019 (COVID-19) pandemic and how it may affect the IBD patient population. This document summarizes the results of 2 recent virtual meetings of the group and subsequent expert guidance for patients and providers

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation.

Loss of intestinal epithelial cell (IEC) homeostasis and apoptosis negatively affect intestinal barrier function. Uncontrolled activation of the unfolded protein response (UPR) in IEC contributes to an impaired barrier and is implicated in the pathogenesis of inflammatory bowel diseases. However, the contribution of the UPR target gene C/EBP homologous protein (CHOP), an apoptosis-associated transcription factor, to inflammation-related disease susceptibility remains unclear. Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis. To elucidate the molecular mechanisms of IEC-specific CHOP expression, we generated a conditional transgenic mouse model (Chop(IEC Tg/Tg)). Chop overexpression increased the susceptibility toward dextran sodium sulfate (DSS)-induced intestinal inflammation and mucosal tissue injury. Furthermore, a delayed recovery from DSS-induced colitis and impaired closure of mechanically induced mucosal wounds was observed. Interestingly, these findings seemed to be independent of CHOP-mediated apoptosis. In vitro and in vivo cell cycle analyses rather indicated a role for CHOP in epithelial cell proliferation. In conclusion, these data show that IEC-specific overexpression impairs epithelial cell proliferation and mucosal tissue regeneration, suggesting an important role for CHOP beyond mediating apoptosis