Myeloid spatial and transcriptional molecular signature of ischemia-reperfusion injury in human liver transplantation.

Background: Ischemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants.

Plasma proteome perturbation for CMV DNAemia in kidney transplantation.

Background: Cytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).

Methods: LC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients.

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality.

Retraction Note: Role of the NF-κB signaling cascade and NF-κB-targeted genes in failing human hearts.

The Editor-in-Chief has retracted this article [1] because a number of lanes in Figs. 3, 4 and 6 of this article are duplicated.

PRMT1 Plays a Critical Role in Th17 Differentiation by Regulating Reciprocal Recruitment of STAT3 and STAT5.

Th17 cells are a class of Th cells that secrete IL-17 and mediate pathogenic immunity responsible for autoimmunity including experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Retinoic acid-related orphan receptor γ t (RORγt) is the critical transcription factor that controls the differentiation of Th17 cells. However, little is known about the transcriptional cofactors for RORγt in the regulation of Th17 differentiation.

TCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage-Specific Manner.

T cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell-mediated Th17 responses by inhibiting IL-17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the molecular mechanisms responsible for TCF-1-regulated IL-17 gene expression are. In this study, we showed that conditional deletion of TCF-1 at the early but not later CD4CD8 double-positive stage in mice enhanced Th17 differentiation and aggravated experimental autoimmune encephalomyelitis, which correlates with abnormally high IL-17 expression.

SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORγt activity in a PKC-θ-dependent manner.

Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORγt) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORγt in vivo to promote the functional dominance of RORγt over Foxp3 and thus establishing an unopposed Th17 differentiation program.

A two-amino-acid substitution in the transcription factor RORγt disrupts its function in T17 differentiation but not in thymocyte development.

The transcription factor RORγt regulates differentiation of the T17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents T17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγt) that 'preferentially' disrupted T17 differentiation but not thymocyte development.

Regulation of Th17 Differentiation by IKKα-Dependent and -Independent Phosphorylation of RORγt.

Transcription factor retinoid acid-related orphan receptor (ROR)γt transcriptionally regulates the genes required for differentiation of Th17 cells that mediate both protective and pathogenic immunity. However, little is known about the function of posttranslational modifications in the regulation of RORγt activity. Mass spectrometric analysis of immunoprecipitated RORγt from Th17 cells identified multiple phosphorylation sites.

A unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks.

It is well established that the gene expression patterns are substantially altered in cardiac hypertrophy and heart failure, however, less is known about the reasons behind such global differences. MicroRNAs (miRNAs) are short non-coding RNAs that can target multiple molecules to regulate wide array of proteins in diverse pathways. The goal of the study was to profile alterations in miRNA expression using end-stage human heart failure samples with an aim to build signaling network pathways using predicted targets for the altered miRNA and to determine nodal molecules regulating individual networks.

Ubiquitination of RORγt at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment.

The transcription factor retinoid acid-related orphan receptor γ t (RORγt) directs the differentiation of Th17 cells. Th17 cells mediate pathological immune responses responsible for autoimmune diseases, including psoriasis and multiple sclerosis. Previous studies focused on RORγt target genes and their function in Th17 differentiation.

Inhalation exposure or body burden? Better way of estimating risk--An application of PBPK model.

We aim to establish a new way for estimating the risk from internal dose or body burden due to exposure of benzene in human subject utilizing physiologically based pharmacokinetic (PBPK) model. We also intend to verify its applicability on human subjects exposed to different levels of benzene. We estimated personal inhalation exposure of benzene for two occupational groups namely petrol pump workers and car drivers with respect to a control group, only environmentally exposed.

Gβγ-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor α-induced cardiac β-adrenergic receptor dysfunction.

Background: Proinflammatory cytokine tumor necrosis factor-α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known.

Methods And Results: Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling βAR desensitization independent of sympathetic overdrive.

Restoration of IFNγR subunit assembly, IFNγ signaling and parasite clearance in Leishmania donovani infected macrophages: role of membrane cholesterol.

Despite the presence of significant levels of systemic Interferon gamma (IFNγ), the host protective cytokine, Kala-azar patients display high parasite load with downregulated IFNγ signaling in Leishmania donovani (LD) infected macrophages (LD-MØs); the cause of such aberrant phenomenon is unknown. Here we reveal for the first time the mechanistic basis of impaired IFNγ signaling in parasitized murine macrophages. Our study clearly shows that in LD-MØs IFNγ receptor (IFNγR) expression and their ligand-affinity remained unaltered.

Inhibition of nuclear factor κB regresses cardiac hypertrophy by modulating the expression of extracellular matrix and adhesion molecules.

Myocardial remodeling denotes a chronic pathological condition of dysfunctional myocardium that occurs in cardiac hypertrophy (CH) and heart failure (HF). Reactive oxygen species (ROS) are major initiators of excessive collagen and fibronectin deposition in cardiac fibrosis. Increased production of ROS and nuclear factor κB (NF-κB) activation provide a strong link between oxidative stress and extracellular matrix (ECM) remodeling in cardiac hypertrophy.

Protease corin expression and activity in failing hearts.

Atrial and brain natriuretic peptides (ANP and BNP) regulate blood pressure and cardiac function. In patients with heart failure (HF), plasma levels of pro-ANP and pro-BNP, the precursor forms of ANP and BNP, are highly elevated, but the mechanism underlying the apparent deficiency in natriuretic peptide processing is unclear. Corin is a cardiac protease that activates natriuretic peptides.

Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure.

Aims: Cardiac-specific overexpression of myotrophin (myo) protein in transgenic (myo-Tg) mice results in hypertrophy at 4 weeks that progresses to heart failure (HF) by 36 weeks. Gene profiling showed that p53 expression increases as hypertrophy worsens to HF, suggesting that p53 may influence myo-induced HF. We aimed to define how the p53 signalling cascade affects the spectrum of cardiac hypertrophy (CH)/HF.

Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure.

Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice.

Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes.

Background: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established.

Methods And Results: We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF] View Article and Find Full Text PDF