DECODE: a computational pipeline to discover T cell receptor binding rules.

MOTIVATION: Understanding the mechanisms underlying T cell receptor (TCR) binding is of fundamental importance to understanding adaptive immune responses. A better understanding of the biochemical rules governing TCR binding can be used, e.g. to guide the design of more powerful and safer T cell-based therapies. Advances in repertoire sequencing technologies have made available millions of TCR sequences. Data abundance has, in turn, fueled the development of many computational models to predict the binding properties of TCRs from their sequences. Unfortunately, while many of these works have made great strides toward predicting TCR specificity using machine learning, the black-box nature of these models has resulted in a limited understanding of the rules that govern the binding of a TCR and an epitope. RESULTS: We present an easy-to-use and customizable computational pipeline, DECODE, to extract the binding rules from any black-box model designed to predict the TCR-epitope binding. DECODE offers a range of analytical and visualization tools to guide the user in the extraction of such rules. We demonstrate our pipeline on a recently published TCR-binding prediction model, TITAN, and show how to use the provided metrics to assess the quality of the computed rules. In conclusion, DECODE can lead to a better understanding of the sequence motifs that underlie TCR binding. Our pipeline can facilitate the investigation of current immunotherapeutic challenges, such as cross-reactive events due to off-target TCR binding. AVAILABILITY AND IMPLEMENTATION: Code is available publicly at https://github.com/phineasng/DECODE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Liver innervation and hepatic function: new insights.

The hepatic nervous system has a well-known impact on the regulation of liver function and organism homeostasis. The aim of this review is to summarize the new available data regarding the role of hepatic nerves. In the last decade, studies have shown that hepatic nerves exert subtle but significant modifications on the regulation of glucose and lipid metabolism, food intake, and liver regeneration. They also play a role in liver disease pathogenesis, and hepatic denervation has beneficial results to liver graft ischemia-reperfusion injury. Available data are still limited, and further research toward neural pathways involving the liver that can modify response to disease is required.

Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis.

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.

Surgical management in hepatocellular carcinoma with portal vein tumour thrombosis: is this the end of the road or a chance to expand the criteria for resectability?

Portal vein thrombosis is a common complication associated with malignancies such as hepatocellular carcinoma, with a dismal and negative impact on prognosis. A thorough literature search in Pubmed and Google Scholar, under the terms 'hepatocellular carcinoma AND portal vein thrombosis', regarding the surgical management of portal vein thrombosis was conducted by the authors, and the associated results are presented in this narrative review. Precise classification of portal vein thrombosis and identification of subgroups of patients that will benefit from surgery is of paramount importance. Evolution of novel surgical techniques in liver resection and associated low morbidity and mortality rates in specialized hepatobiliary centres worldwide have been linked with promising results from the adoption of surgical management in these patients, when compared to systemic chemotherapy or arterial chemoembolization management that has traditionally been followed in such cases.

Fecal Microbiota Transplantation and Hydrocortisone Ameliorate Intestinal Barrier Dysfunction and Improve Survival in a Rat Model of Cecal Ligation and Puncture-Induced Sepsis.

INTRODUCTION: Sepsis is a life-threatening syndrome which can progress to multiple organ dysfunction with high mortality. Intestinal barrier failure exerts a central role in the pathophysiological sequence of events that lead from sepsis to multiple organ dysfunction. The present study investigated the role of hydrocortisone (HC) administration and fecal microbiota transplantation (FMT) in several parameters of the gut barrier integrity, immune activation, and survival, in a model of polymicrobial sepsis in rats. METHODS: Forty adults male Wistar rats were randomly divided into four groups: sham (group I), cecal ligation and puncture (CLP) (group II), CLP + HC (2.8 mg/kg, intraperitoneally single dose at 6 h) (group III), and CLP + FMT at 6 h (group IV). At 24 h post-CLP, ileal tissues were harvested for histological and immunohistochemical analyses while endotoxin, IL-6, and IL-10 levels in systemic circulation were determined. In a second experiment the same groups were observed for 7 days for mortality, with daily administration of hydrocortisone (group III) and FMT (group IV) in surviving rats. RESULTS: HC administration and FMT significantly reduced mortality of septic rats by 50%. These interventions totally reversed intestinal mucosal atrophy by increasing villous density and mucosal thickness (µm, mean ±â€ŠSD: Group I: 620 ±â€Š35, Group II: 411 ±â€Š52, Group III: 622 ±â€Š19, Group IV: 617 ±â€Š44). HC and FMT reduced the apoptotic body count in intestinal crypts whereas these increased the mitotic/apoptotic index. Activated caspase-3 expression in intestinal crypts was significantly reduced by HC or FMT (activated caspase-3 (+) enterocytes/10 crypts, mean ±â€ŠSD: Group I: 1.6 ±â€Š0.5, Group II: 5.8 ±â€Š2.4, Group III: 3.6 ±â€Š0.9, Group IV: 2.3 ±â€Š0.6). Both treatments increased Paneth cell count and decreased intraepithelial CD3(+) T lymphocytes and inflammatory infiltration of lamina propria to control levels. In the sham group almost the total of intestinal epithelial cells expressed occludin (92 ±â€Š8%) and claudin-1 (98 ±â€Š4%) and CLP reduced this expression to 34 ±â€Š12% for occludin and 35 ±â€Š7% for claudin-1. Administration of HC significantly increased occludin (51 ±â€Š17%) and claudin-1 (77 ±â€Š9%) expression. FMT exerted also a significant restoring effect in tight junction by increasing occludin (56 ±â€Š15%) and claudin-1 (84 ±â€Š7%) expression. The beneficial effects of these treatments on gut barrier function led to significant reduction of systemic endotoxemia (EU/mL, mean ±â€ŠSD: Group I: 0.93 ±â€Š0.36, Group II: 2.14 ±â€Š1.74, Group III: 1.48 ±â€Š0.53, Group IV: 1.61 ±â€Š0.58), while FMT additionally decreased IL-6 and IL-10 levels. CONCLUSION: Fecal microbiota transplantation and stress dose hydrocortisone administration in septic rats induce a multifactorial improvement of the gut mechanical and immunological barriers, preventing endotoxemia and leading to improved survival.