Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Coxiella endosymbiont of Rhipicephalus microplus modulates tick physiology with a major impact in blood feeding capacity

In the past decade, metagenomics studies exploring tick microbiota have revealed widespread interactions between bacteria and arthropods, including symbiotic interactions. Functional studies showed that obligate endosymbionts contribute to tick biology, affecting reproductive fitness and molting. Understanding the molecular basis of the interaction between ticks and their mutualist endosymbionts may help to develop control methods based on microbiome manipulation. Previously, we showed that Rhipicephalus microplus larvae with reduced levels of Coxiella endosymbiont of R. microplus (CERM) were arrested at the metanymph life stage (partially engorged nymph) and did not molt into adults. In this study, we performed a transcriptomic differential analysis of the R. microplus metanymph in the presence and absence of its mutualist endosymbiont. The lack of CERM resulted in an altered expression profile of transcripts from several functional categories. Gene products such as DA-P36, protease inhibitors, metalloproteases, and evasins, which are involved in blood feeding capacity, were underexpressed in CERM-free metanymphs. Disregulation in genes related to extracellular matrix remodeling was also observed in the absence of the symbiont. Taken together, the observed alterations in gene expression may explain the blockage of development at the metanymph stage and reveal a novel physiological aspect of the symbiont-tick-vertebrate host interaction

Control of magnetic anisotropy by orbital hybridization in (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattice

The asymmetry of chemical nature at the hetero-structural interface offers an unique opportunity to design desirable electronic structure by controlling charge transfer and orbital hybridization across the interface. However, the control of hetero-interface remains a daunting task. Here, we report the modulation of interfacial coupling of (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattices by manipulating the periodic thickness with n unit cells of SrTiO3 and n unit cells La0.67Sr0.33MnO3. The easy axis of magnetic anisotropy rotates from in-plane (n = 10) to out-of-plane (n = 2) orientation at 150 K. Transmission electron microscopy reveals enlarged tetragonal ratio > 1 with breaking of volume conservation around the (La0.67Sr0.33MnO3)n/(SrTiO3)n interface, and electronic charge transfer from Mn to Ti 3d orbitals across the interface. Orbital hybridization accompanying the charge transfer results in preferred occupancy of 3d3z2-r2 orbital at the interface, which induces a stronger electronic hopping integral along the out-of-plane direction and corresponding out-of-plane magnetic easy axis for n = 2. We demonstrate that interfacial orbital hybridization in superlattices of strongly correlated oxides may be a promising approach to tailor electronic and magnetic properties in device applications

Measurement of the Ge 70 (n,γ) cross section up to 300 keV at the CERN n-TOF facility

©2019 American Physical Society.Neutron capture data on intermediate mass nuclei are of key importance to nucleosynthesis in the weak component of the slow neutron capture processes, which occurs in massive stars. The (n,γ) cross section on Ge70, which is mainly produced in the s process, was measured at the neutron time-of-flight facility n-TOF at CERN. Resonance capture kernels were determined up to 40 keV neutron energy and average cross sections up to 300 keV. Stellar cross sections were calculated from kT=5 keV to kT=100 keV and are in very good agreement with a previous measurement by Walter and Beer (1985) and recent evaluations. Average cross sections are in agreement with Walter and Beer (1985) over most of the neutron energy range covered, while they are systematically smaller for neutron energies above 150 keV. We have calculated isotopic abundances produced in s-process environments in a 25 solar mass star for two initial metallicities (below solar and close to solar). While the low metallicity model reproduces best the solar system germanium isotopic abundances, the close to solar model shows a good global match to solar system abundances in the range of mass numbers A=60-80.Peer reviewedFinal Published versio

Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - N-TOF

The 238U fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The 238U fission cross section has been measured relative to the 235U fission cross section at CERN - n-TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit

Thrombopoietin Receptor Agonists for Severe Thrombocytopenia after Allogeneic Stem Cell Transplantation : Experience of the Spanish Group of Hematopoietic Stem Cell Transplant

Persistent thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Romiplostim and eltrombopag are the currently available thrombopoietin receptor agonists (TPO-RAs), and some studies with very small numbers of cases have reported their potential efficacy in the allo-SCT setting. The present retrospective study evaluated the safety and efficacy of TPO-RAs in 86 patients with persistent thrombocytopenia after allo-HSCT. Sixteen patients (19%) had isolated thrombocytopenia (PT), and 71 (82%) had secondary failure of platelet recovery (SFPR). TPO-RA therapy was started at a median of 127 days (range, 27 to 1177 days) after allo-SCT. The median initial and maximum administered doses were 50 mg/day (range, 25 to 150 mg/day) and 75 mg/day (range, 25 to 150 mg/day), respectively, for eltrombopag and 1 µg/kg (range, 1 to 7 µg/kg) and 5 µg/kg (range, 1 to 10 µg/kg), respectively, for romiplostin. The median platelet count before initiation of TPO-RA therapy was 14,000/µL (range, 1000 to 57,000/µL). Platelet recovery to ≥50,000/µL without transfusion support was achieved in 72% of patients at a median time of 66 days (range, 2 to 247 days). Eighty-one percent of the patients had a decreased number of megakaryocytes before treatment, showing a slower response to therapy (P =.011). The median duration of treatment was 62 days (range, 7 to 700 days). Grade 3-4 adverse events (hepatic and asthenia) were observed in only 2% of the patients. At last follow-up, 81% of patients had discontinued TPO-RAs and maintained response, and 71% were alive. To our knowledge, this is the largest series analyzing the use of TPO-RAs after allo-SCT reported to date. Our results support the efficacy and safety in this new setting. Further prospective trials are needed to increase the level of evidence and to identify predictors of response