Intestinal microbiota transplantation reveals the role of microbiota in dietary regulation of RegIII beta and RegIII gamma expression in mouse intestine

RegIII beta and RegIII gamma are antimicrobial peptides expressed in intestinal epithelial cells. Expression of these peptides is reportedly decreased by high-fat diet (HFD) and increased by indigestible oligosaccharides in mice. Clearly, these dietary regimens change the structure of intestinal microbiota. We employed an intestinal microbiota transplantation (IMT) to test whether diet-induced changes in the expression of these peptides are mediated by gut microbiota. C57BL/61 mice were fed either a normal-fat diet (NFD), a HFD, or a NFD supplemented with or without 1-kestose (KES), an indigestible oligosaccharide. Ileal RegIII beta and RegIII gamma mRNA levels were lower in mice receiving IMT from HFD-fed mice than in those receiving NFD-fed mice and higher in mice receiving IMT from KES-supplemented mice than in those receiving the mice without KES supplementation. Western blot analysis showed that serum RegIII beta levels changed in parallel with the ileal mRNA levels. We propose that HFD- and KES-induced changes in the ileal RegIII beta and RegIII gamma expression and in the circulating RegIII beta levels are mediated, at least in part, by intestinal microbiota. (C) 2020 Elsevier Inc. All rights reserved

Intramedullary screw fixation with bone autografting to treat proximal fifth metatarsal metaphyseal-diaphyseal fracture in athletes: a case series

Abstract Background Delayed unions or refractures are not rare following surgical treatment for proximal fifth metatarsal metaphyseal-diaphyseal fractures. Intramedullary screw fixation with bone autografting has the potential to resolve the issue. The purpose of this study was to evaluate the result of the procedure. Methods The authors retrospectively reviewed 15 athletes who underwent surgical treatment for proximal fifth metatarsal metaphyseal-diaphyseal fracture. Surgery involved intramedullary cannulated cancellous screw fixation after curettage of the fracture site, followed by bone autografting. Postoperatively, patients remain non weight-bearing in a splint or cast for two weeks and without immobilization for an additional two weeks. Full weight-bearing was allowed six weeks postoperatively. Running was permitted after radiographic bone union, and return-to-play was approved after gradually increasing the intensity. Results All patients returned to their previous level of athletic competition. Mean times to bone union, initiation of running, and return-to-play were 8.4, 8.8, and 12.1 weeks, respectively. Although no delayed unions or refractures was observed, distal diaphyseal stress fractures at the distal tip of the screw occurred in two patients and a thermal necrosis of skin occurred in one patient. Conclusions There were no delayed unions or refractures among patients after carrying out a procedure in which bone grafts were routinely performed, combined with adequate periods of immobilization and non weight-bearing. These findings suggest that this procedure may be useful option for athletes to assuring return to competition level.</p

Local free fatty acids trigger the expression of lipopolysaccharide-binding protein in murine white adipose tissue

Although lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase protein mainly produced by hepatocytes, it has also been proposed to be a pro-inflammatory adipokine. Obesity and the consumption of a high-fat diet (HFD) are reportedly associated with elevated levels of LPS in plasma and free fatty acids (FFAs) in white adipose tissue (WAT). We examined whether circulating LPS or local FFAs are responsible for the HFD-induced increase of LBP in WAT. Male C57BL/6J mice were fed either a normal-fat diet (NFD) or an HFD. The mRNA levels in the liver and mesenteric WAT (mWAT), total FFA content in mWAT, and LBP and LPS concentrations in plasma were determined. The Lbp mRNA level in mWAT was higher in mice fed the HFD than in those fed the NFD for 3, 7, or 28 days or 14 weeks, whereas the hepatic Lbp mRNA level did not diller between the groups. The Lbp mRNA level in mWAT was also increased by the HFD in germ-free mice, which do not have gut microbiota, the source of LPS. The plasma LPS level did not show a significant correlation with the mWAT Lbp mRNA level. The total FFA content in mWAT was higher in mice fed the HFD than in those fed the NFD and positively correlated with the Lbp mRNA level. Supplementation with palmitic acid increased the Lbp mRNA level in 3T3-L1 adipocytes. We propose that local FFAs, but not circulating LPS, are the trigger for increased Lbp expression in mWAT of mice fed the HFD

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia.

Funder: Princess Takamatsu Cancer Research FundFunder: Japan Foundation for Pediatric Research Funai Foundation for Information TechnologyKMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy