Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex. UL82 also impaired the recruitment of TBK1 and IRF3 to the STING complex. The levels of downstream antiviral genes induced by UL82-deficient HCMV were higher than those induced by wild-type HCMV. Conversely, wild-type HCMV replicated more efficiently than the UL82-deficient mutant. These findings reveal an important mechanism of immune evasion by HCMV.

The goal of this study was to determine whether changes in cardiac metabolism in Type 2 diabetes are associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty (ZDF) and lean control rats were isolated and perfused with glucose, lactate, pyruvate, and palmitate. The rates of glucose, lactate, pyruvate, and palmitate oxidation rates and glycolysis were determined during baseline perfusion and low-flow ischemia (LFI; 0.3 ml/min for 30 min) and after LFI and reperfusion. Under all conditions, ATP synthesis from palmitate was increased and synthesis from lactate was decreased in the ZDF group, whereas the contribution from glucose was unchanged. During baseline perfusion, the rate of glycolysis was lower in the ZDF group; however, during LFI and reperfusion, there were no differences between groups. Despite these metabolic shifts, there were no differences in oxygen consumption or ATP production rates between the groups under any perfusion conditions. Cardiac function was slightly depressed before LFI in the ZDF group, but during reperfusion, function was improved relative to the control group despite the increased dependence on fatty acids for energy production. These data suggest that in this model of diabetes, the shift from carbohydrates to fatty acids for oxidative energy production did not increase myocardial oxygen consumption and was not associated with impaired response to ischemia and reperfusion. contractile dysfunction; ischemia; nuclear magnetic resonance spectroscopy; carbohydrate metabolism DIABETES IS LINKED TO OBESITY, dyslipidemia, and hypertension (16,34,40,41), all of which are independent risk factors for cardiovascular disease (33,34,43); however, there is growing evidence to support the existence of a specific diabetic cardiomyopathy that is independent of other risk factors for heart disease (8 -11, 14, 21, 39, 42-44, 47, 48, 51). One of the earliest changes that occurs after the onset of experimentally induced diabetes is in the regulation of cardiac metabolism, typically characterized by increased fatty acid oxidation and decreased carbohydrate use (9). It has been suggested (26) that this shift in metabolism may play a role in the development of diabetic cardiomyopathy, which leads to both impaired contractile function as well as increased susceptibility to ischemic injury. For example, Belke et al. (2) found that increasing GLUT4 expression in hearts from diabetic db/db mice not only reversed the metabolic defects but also normalized cardiac function. However, treatment with a peroxisome proliferatoractivated receptor-␥ agonist in the same animal model of diabetes normalized the changes in cardiac metabolism, but contractile function remained depressed (5). Thus the potential role of altered substrate utilization in the development of cardiac dysfunction in diabetes remains to be determined.The increase in cardiac fatty acid utilization that occurs with diabetes is proposed to be detrimental because fatty acids are less-efficient fuels that...

Reductionist approaches based on 3D fibers reveal that single-cell migration along fibers is driven by lateral actin-based waves for various cell types.

The aim of this study was to determine whether the transition from insulin resistance to hyperglycemia in a model of type 2 diabetes leads to intrinsic changes in the myocardium that increase the sensitivity to ischemic injury. Hearts from 6-, 12-, and 24-wk-old lean (Control) and obese Zucker diabetic fatty (ZDF) rats were isolated, perfused, and subjected to 30 min of low-flow ischemia (LFI) and 60 min of reperfusion. At 6 wk, ZDF animals were insulin resistant but not hyperglycemic. By 12 wk, the ZDF group was hyperglycemic and became progressively worse by 24 wk. In spontaneously beating hearts rate-pressure product (RPP) was depressed in the ZDF groups compared with age-matched Controls, primarily due to lower heart rate. Pacing significantly increased RPP in all ZDF groups; however, this was accompanied by a significant decrease in left ventricular developed pressure. There was also greater contracture during LFI in the ZDF groups compared with the Control group; surprisingly, however, functional recovery upon reperfusion was significantly higher in the diabetic 12- and 24-wk ZDF groups compared with age-matched Control groups and the 6-wk ZDF group. This improvement in recovery in the ZDF diabetic groups was independent of substrate availability, severity of ischemia, and duration of diabetes. These data demonstrate that, although the development of type 2 diabetes leads to progressive contractile and metabolic abnormalities during normoxia and LFI, it was not associated with increased susceptibility to ischemic injury.