Complex Interplay Between MAZR and Runx3 Regulates the Generation of Cytotoxic T Lymphocyte and Memory T Cells

The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8(+) T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs in vitro. However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made in vitro, the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8 alpha, Granzyme B and perforin in vivo. Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools

A highly efficient and sustainable catalyst system for terminal epoxy-carboxylic acid ring opening reactions

The nucleophilic ring opening of epoxides by carboxylic acids is an indispensable transformation for materials science and coating technologies. Due to this industrial significance, improvements in operational energy consumption and catalyst sustainability are highly desirable for this transformation. Herein, an efficient, environmentally benign and non-toxic halide free cooperative catalyst system based on an iron(III) benzoate complex and guanidinium carbonate is reported. The novel catalyst system shows improved activity over onium halide catalysts under neat conditions and in several solvents, including anisole and nBuOAc. Detailed mechanistic studies using FeCl3/DMAP as a catalyst revealed the importance of a carboxylate bridged cationic trinuclear μ3-oxo iron cluster and guanidinium carbonate or DMAP as a carboxylate reservoir due to its superior activity.</p

Influence of aging and menopause in determining vertebral and distal forearm bone loss in adult healthy women

In order to assess the relative influence of aging and menopause in determining the decrease of bone mass in adult women, two groups of normal subjects were examined in this retrospective, cross-sectional study. In group A, bone mineral density (BMD) was evaluated at spine (L2-L4) by dual X-ray absorptiometry (DXA) (Hologic QDR-1000); in group B, BMD was measured at the distal forearm by single photon absorptiometry (SPA) (Osteometer DT 100). Both groups were further divided into two subgroups: A1 and B1 included women with the same postmenopausal, but different chronological age; A2 and B2 included women with the same chronological, but different postmenopausal age. BMD and BMI-corrected BMD (cBMD) were plotted versus age and years since menopause, respectively. Mathematical analysis of the correlation curves between BMD and chronological age showed that the decrease of BMD is very similar at spine and forearm, and is better fitted by a quadratic function. Age-related fractional bone diminution shows a progressive increase with aging (at spine: -0.38%/year at 45 years, -0.81%/year at 50, -1.3%/year at 55 and -1.9%/year at 60. At forearm: -0.5%/year at 50 years, -1.1%/year at 55 and -1.68%/year at 60). On the other hand, menopause-related BMD decrement is very evident during the first year since menopause (at spine: -8.1%/year; at forearm: -3.4%/year), and progressively decreases, according to a logarithmic function. Ten years later, yearly diminution of BMD is below 1%/year and 0.4%/year at spine and forearm, respectively. At this time, age contributes to determine bone loss for 2/3 and menopause for 1/3

Vascular endothelial Tissue Factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.

AIMS Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular tissue factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo. METHODS AND RESULTS In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2,989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral center, TMAO levels were associated with an increased incident (3 yr) risk for major adverse cardiovascular events (MACE, myocardial infarction, stroke or death) [4th quartile(Q4) versus Q1 adjusted hazard ratio(95% confidence interval) HR(95%CI), 1.73(1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR(95%CI) 1.75(1.25-2.44), n = 2,793). Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 yr) MACE risk in the multi-site Swiss Acute Coronary Syndromes (ACS) Cohort, focusing on the subset (n = 1,469) on chronic dual anti-platelet therapy during follow-up [adjusted HR(95% CI) 1.70(1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA lyase inhibitor (fluoromethylcholine, FMC). CONCLUSIONS Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA lyase. TRANSLATIONAL PERSPECTIVE The pro-thrombotic effects of the gut microbial TMAO pathway are shown to extend beyond enhancement of platelet responsiveness and include heightened vascular Tissue Factor(TF). In clinical studies, TMAO is shown to predict event risk in patients in the presence of anti-platelet drugs. In animal studies, TMAO elevation is shown to promote vascular endothelial TF expression and a TF-dependent pro-thrombotic effect. Pharmacological targeting of gut microbial choline TMA lyase reduced host TMAO, vascular TF and abrogated the pro-thrombotic TMAO-associated phenotype. These studies suggest inhibiting the TMAO pathway may be a rational target for reducing residual risk in patients on antiplatelet therapy