The truncated disk from Suzaku data of GX 339-4 in the extreme very high state

We report on the geometry of accretion disk and high energy coronae in the strong Comptonization state (the very high/steep power law/hard intermediate state) based on a Suzaku observation of the famous Galactic black hole GX 339-4. These data were taken just before the peak of the 2006-2007 outburst, and the average X-ray luminosity in the 0.7-200 keV band is estimated to be 2.9E38 erg/s for a distance of 8 kpc. We fit the spectrum with both simple (independent disk and corona) and sophisticated (energetically coupled disk and corona) models, but all fits imply that the underlying optically thick disk is truncated significantly before the innermost stable circular orbit around the black hole. We show this directly by a comparison with similarly broadband data from a disk dominated spectrum at almost the same luminosity observed by XMM-Newton and RXTE 3 days after the Suzaku observation. During the Suzaku observation, the QPO frequency changes from 4.3 Hz to 5.5 Hz, while the spectrum softens. The energetically coupled model gives a corresponding 5+/- 8 % decrease in derived inner radius of the disk. While this is not significant, it is consistent with the predicted change in QPO frequency from Lense-Thirring precession of the hot flow interior to the disk and/or a deformation mode of this flow, as a higher QPO frequency implies a smaller size scale for the corona. This is consistent with the truncated disk extending further inwards towards the black hole.Comment: Accepted to ApJ, 41 pages, 9 figures, 3 table

Neural Degeneration in the Retina of the Streptozotocin-Induced Type 1 Diabetes Model

Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis

IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis

Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163(+) eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy

Effect of branched-chain amino acid supplementation on the oxidized/reduced state of plasma albumin in rats with chronic liver disease

We examined whether continuous supplementation with branched-chain amino acids phosphorylates ribosomal protein S6, a downstream effector of mammalian target of rapamycin, and improves hypoalbuminemia of rats with chronic liver disease. Sprague-Dawley rats were fed a casein diet (control group) or a branched-chain amino acid-supplemented casein diet (branched-chain amino acid group) for 11 weeks with repeated injections of carbon tetrachloride. Throughout this experimental period, no significant difference in plasma albumin concentration was seen between groups. The percentage of reduced albumin within total plasma albumin gradually decreased in both control and branched-chain amino acid groups. After 11 weeks with supplementation, phosphorylation of ribosomal protein S6 was significantly increased in the liver of rats in the branched-chain amino acid group compared with the control group. Furthermore, the percentage of reduced albumin within total albumin was significantly higher in the branched-chain amino acid group than in the control group. These results indicate that continuous supplementation with branched-chain amino acids in rats with chronic liver disease induces phosphorylation of hepatic ribosomal protein S6 and attenuates decreases in the percentage of reduced albumin, although levels of plasma albumin are not increased

SIRT6 Is Required for Normal Retinal Function

The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod and cone photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin

Neuroprotective response after photodynamic therapy: Role of vascular endothelial growth factor

Background: Anti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood. Methods: We assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively. Results: At both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis. Conclusion: Cytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective

Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called “dysplasia-like atypia” (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence

Expression of nampt in hippocampal and cortical excitatory neurons is critical for cognitive function

Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(−/−) mice). CaMKIIαNampt(−/−) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2–3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation