We have reported that lesion of the organum vasculosum of the lamina terminalis (OVLT) has no effect on basal levels of mean arterial pressure (MAP) but abolishes the hypertensive effects of angiotensin II (AngII) in rats consuming a normal-salt diet. These results suggest that the OVLT does not contribute to regulation of MAP under conditions of normal salt intake, but it is an important brain site for the hypertensive actions of AngII. The OVLT has been proposed as a major sodium sensor in the brain and the hypertensive effects of AngII are exacerbated by high-salt intake. Therefore, the objective of this study was to investigate the role of the OVLT during AngII-induced hypertension in rats fed a high-salt diet. Male Sprague-Dawley rats underwent sham (Sham; n = 9) or OVLT lesion (OVLTx; n = 8) surgery and were placed on a high-salt (2% NaCl) diet. MAP was measured by radio telemetry during three control days, 10 days of AngII infusion (10 ng/kg/min, i.v.), and a 3-day recovery period. MAP was significantly lower in OVLTx (97 ± 2 mmHg) compared to Sham (106 ± 1 mmHg) rats during the control period (P < 0.05). Moreover, the chronic pressor response to AngII was markedly attenuated in OVLTx rats. MAP increased 58 ± 3 mmHg in Sham rats by Day 10 of AngII compared to a 40 ± 7 mmHg increase in OVLTx rats (P < 0.05). We conclude that (1) the OVLT regulates the basal levels of MAP in rats consuming a high-salt and (2) the OVLT is an important brain site of action for the pathogenesis of AngII-salt hypertension in the rat. Supported by HL076312.

Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D). Pharmacological inhibition of Janus tyrosine kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-(49-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD41 T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4 1 CD25 1 FoxP3 1 phenotype. They secreted decreased amounts of IL-10, IL-4 and interferon (IFN)-c compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor (TGF)-b secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4 1 FoxP3 1 Tregs, while generating an elevated numbers of CD4 1 FoxP3 2 TGF-b-secreting T cells. In conclusion, our data suggest an induction of TGF-b-secreting CD4 1 T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.

The incidence of autoimmune Type 1 diabetes (T1D) has been steadily rising in developed countries. Although the exact cause of T1D remains elusive, it is known that both genetics and environmental factors play a role in its immunopathogenesis. Whereas a positive association between p,p 0 -DDE, a DDT metabolite, and Type 2 diabetes (T2D) has been well established, its role in T1D development in an experimental animal model has never been elucidated. This study seeks to investigate the effects of DDE exposure on the development of T1D in a NOD mouse model. As T1D is a T-cell-mediated disease, the underlying mechanism of DDE action on T-cells was studied in vitro and, in the context of acute and chronic DDE exposure, in vivo by investigating lymphocytes' viability, proliferation, their subsets and cytokine profiles. Chronic high-dose DDE treatment, initiated in pre-diabetic 8-week-old NOD females administered twice weekly intraperitoneally with 50 mg/kg DDE, significantly increased diabetes incidence and augmented disease severity in treated animals. Whereas T-cell proliferation and cell viability in the spleens of treated mice were not affected, diabetogenic action of chronic DDE exposure was associated with a decrease in regulatory T-cells and a suppression of secretion of protective cytokines, such as IL-4 and IL-10. Interestingly, an acute high-dose in vivo treatment of 8-week-old NOD males with 100 mg DDE/kg, administered intraperitoneally every other day over a period of 10 days, increased T-cell proliferation and potentiated pro-inflammatory and T H 1-type cytokine secretion, without affecting the splenocytes viability and the T-cell subpopulations. These results confirm that high-dose DDE treatments affect the immune system, in particularly T-cell function. In conclusion, this study shows for the first time that high-dose chronic DDE exposure exhibits a diabetogenic potential, with an underlying immunomodulatory mechanism of action, in the development of T1D in an experimental mouse NOD model.

Transcription occurs ubiquitously throughout non-coding parts of the genome, including at repetitive a-satellite DNA elements which comprise the majority of human centromeres. The function of temporally regulated centromeric transcription, and transcripts, is consequently a topic of intense investigation. In this study, we use high throughput approaches to identify and describe lncRNAs associated with the centromere specific histone variant CENP-A that arise from the transcription of specific centromeres at early G1, which we then show are physically associated with centromeres, and which are functionally necessary for accurate chromosome segregation. Targeted depletion of one such centromeric RNA, which originates from a single centromere, is sufficient to increase the frequency of chromosome segregation defects. These data support the emerging paradigm of the necessity of centromere-specific lncRNAs in the integrity of faithful chromosome segregation.

We have recently shown that lesion of the organum vasculosum of the lamina terminalis (OVLT) abolishes the hypertensive effects of chronic angiotensin II (AngII) in rats consuming a normal salt diet (0.4% NaCl). While these results support the idea that the OVLT plays an important role in AngII‐induced hypertension, the OVLT has also been suggested as a major sodium sensor in the brain, and the hypertensive effects of AngII are exacerbated by high salt intake. The objective of this study was to investigate the role of the OVLT during AngII‐induced hypertension concurrent with a high salt diet. Male Sprague‐Dawley rats underwent sham (OVLTsham; n = 7) or OVLT lesion (OVLTx; n = 5) and were placed on a high salt (2% NaCl) diet. Mean arterial pressure (MAP) was measured by radio telemetry during 3 control days, 10‐days of AngII infusion (10 ng/kg/min, iv), and a 3‐day recovery period. MAP was not different between groups during the 3 day control period. However, by day 7 of AngII, MAP was higher in sham (158 ± 3 mmHg) compared to OVLTx rats (147 ± 3 mmHg) and remained higher throughout AngII infusion. MAP returned to control levels in both groups during the recovery period. These results suggest that the OVLT contributes to AngII‐salt hypertension in the rat. Supported by HL076312.