Elevated Global SUMOylation in Ubc9 Transgenic Mice Protects Their Brains against Focal Cerebral Ischemic Damage

We have previously shown that a massive increase in global SUMOylation occurs during torpor in ground squirrels, and that overexpression of Ubc9 and/or SUMO-1 in cell lines and cortical neurons protects against oxygen and glucose deprivation. To examine whether increased global SUMOylation protects against ischemic brain damage, we have generated transgenic mice in which Ubc9 is expressed strongly in all tissues under the chicken β-actin promoter. Ubc9 expression levels in 10 founder lines ranged from 2 to 30 times the endogenous level, and lines that expressed Ubc9 at modestly increased levels showed robust resistance to brain ischemia compared to wild type mice. The infarction size was inversely correlated with the Ubc9 expression levels for up to five times the endogenous level. Although further increases showed no additional benefit, the Ubc9 expression level was highly correlated with global SUMO-1 conjugation levels (and SUMO-2,3 levels to a lesser extent) up to a five-fold Ubc9 increase. Most importantly, there were striking reciprocal relationships between SUMO-1 (and SUMO-2,3) conjugation levels and cerebral infarction volumes among all tested animals, suggesting that the limit in cytoprotection by global SUMOylation remains undefined. These results support efforts to further augment global protein SUMOylation in brain ischemia

The ALFALFA "Almost Darks" Campaign: Pilot VLA HI Observations of Five High Mass-to-Light Ratio Systems

We present VLA HI spectral line imaging of 5 sources discovered by ALFALFA. These targets are drawn from a larger sample of systems that were not uniquely identified with optical counterparts during ALFALFA processing, and as such have unusually high HI mass to light ratios. These candidate "Almost Dark" objects fall into 4 categories: 1) objects with nearby HI neighbors that are likely of tidal origin; 2) objects that appear to be part of a system of multiple HI sources, but which may not be tidal in origin; 3) objects isolated from nearby ALFALFA HI detections, but located near a gas-poor early-type galaxy; 4) apparently isolated sources, with no object of coincident redshift within ~400 kpc. Roughly 75% of the 200 objects without identified counterparts in the $\alpha$.40 database (Haynes et al. 2011) fall into category 1. This pilot sample contains the first five sources observed as part of a larger effort to characterize HI sources with no readily identifiable optical counterpart at single dish resolution. These objects span a range of HI mass [7.41 < log(M$_{\rm HI}$) < 9.51] and HI mass to B-band luminosity ratios (3 < M$_{\rm HI}$/L$_{\rm B}$ < 9). We compare the HI total intensity and velocity fields to SDSS optical imaging and to archival GALEX UV imaging. Four of the sources with uncertain or no optical counterpart in the ALFALFA data are identified with low surface brightness optical counterparts in SDSS imaging when compared with VLA HI intensity maps, and appear to be galaxies with clear signs of ordered rotation. One source (AGC 208602) is likely tidal in nature. We find no "dark galaxies" in this limited sample. The present observations reveal complex sources with suppressed star formation, highlighting both the observational difficulties and the necessity of synthesis follow-up observations to understand these extreme objects. (abridged)Comment: Astronomical Journal, in pres

Correction: Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

In table 3, the correlation coefficient between peak plasma cortisol and mRS at 3 months (column 4, row 5), should read 0.48, not 0 [1]

Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation.

Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain

Prevalensi Labioschisis Di Rsup. Prof. Dr. R. D. Kandou Manado Periode Januari 2011 – Oktober 2012

: Cleft lip or labioschisis is an inherited disorder that can occur on the lips to the ceiling. Cleft lip is a disruption in the face of growth since the fourth week of embryonic life. Method: This research in retrospection description research for knowning prevalence cleft lip or labioschisis in surgical department RSUP. Prof. Dr. R. D. Kandou Manado, period of Januari 2011 – October 2012. Output: Prevalence of Labioschisis and Labiopalatochisis on Januari 2011 – October 2012 is 57% and 43%. Presentation for each of kind harelipped are : unilateral labioschisis 47%, bilateral labioschisis 5%, unilateral palatum of labioshisis 28%, and bilateral palatum of labioschisis 12%, submucosa 1%, and cleft palate lips 7%. Presentation according to the place of defect : right 18%, left 57%, bilateral 25%, and status not complete 54%. Presentation according to age for doing operation : 0-4 years 73%, 5-9 years 10%, 10-14 years 7%, and >15 years 10%. Presentation labioschisis according to sex : Man 58%, and women 42%. Presentation labioschisis according to etiology : genetic factor 25%, environment factor 62%, and unknown factor 13%. Presentation of labioschisis that be surgery 93%, and not surgery 7%. Presentation of labioschisis according to complication surgery : bleeding post surgery 1%, secunder infection 4%, dehisensi/establish scar 4%, and not complication 91%. Conclusion: Prevalence labioschisis still decrease in each year, kind of labioschisis that large is unilateral labioschisis and localization defect is often on left edge. Labioschisis is happen more to man. Factor that to cause labioschisis between : genetic factor, environment factor and unknown factor. Labioschisis is often more to surgery 0-4 years old

Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

BACKGROUND: Cerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome. METHODS: Thirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume. RESULTS: Peak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures. CONCLUSIONS: These data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome

Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming.

Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.This work was supported by the Intramural Research Program of the NINDS/NIH and a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust – MRC Cambridge Stem Cell Institute. Additionally, JDB is supported by a NIH-OxCam Fellowship and FAG is supported by a scholarship from the Gates Cambridge Trust. The authors wish to acknowledge the assistance of Dr. Yan Li of the NINDS/NIH Proteomics Core

Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke

Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies

INTRODUCTION: Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization. However, for some patients, reperfusion may exacerbate the injury initially caused by ischemia, producing a so-called “cerebral reperfusion injury”. Multiple pathological processes are involved in this injury, including leukocyte infiltration, platelet and complement activation, postischemic hyperperfusion, and breakdown of the blood–brain barrier. METHODS/RESULTS AND CONCLUSIONS: Magnetic resonance imaging (MRI) can provide extensive information on this process of injury, and may have a role in the future in stratifying patients’ risk for reperfusion injury following recanalization. Moreover, different MRI modalities can be used to investigate the various mechanisms of reperfusion injury. Antileukocyte antibodies, brain cooling and conditioned blood reperfusion are potential therapeutic strategies for lessening or eliminating reperfusion injury, and interventionalists may play a role in the future in using some of these therapies in combination with thrombolysis or embolectomy. The present review summarizes the mechanisms of reperfusion injury and focuses on the way each of those mechanisms can be evaluated by different MRI modalities. The potential therapeutic strategies are also discussed