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Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. In response to stress, autophagy is induced and may either contribute to cell death or serve as a cell survival mechan...
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Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. In response to stress, autophagy is induced and may either contribute to cell death or serve as a cell survival mechanism. Very little is known about autophagy in renal pathophysiology. This study examined autophagy and its pathological role in renal cell injury using in vitro and in vivo models of ischemia-reperfusion. We found that hypoxia (1% O2) induced autophagy in cultured renal proximal tubular cells. Blockade of autophagy by 3-methyladenine or small-interfering RNA knockdown of Beclin-1 and ATG5 (two key autophagic genes) sensitized the tubular cells to hypoxia-induced apoptosis. In an in vitro model of ischemia-reperfusion, autophagy was not induced by anoxic (0% O2) incubation in glucose-free buffer, but was induced during subsequent recovery/reperfusion period. In this model, suppression of autophagy also enhanced apoptosis. In vivo, autophagy was induced in kidney tissues during renal ischemia-reperfusion in mice. Autophagy was not obvious during the ischemia period, but was significantly enhanced during reperfusion. Inhibition of autophagy by chloroquine and 3-methyladenine worsened renal ischemia/reperfusion injury, as indicated by renal function, histology, and tubular apoptosis. Together, the results demonstrated autophagy induction during hypoxic and ischemic renal injury. Under these pathological conditions, autophagy may provide a protective mechanism for cell survival.
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Scientists engaged in drug discovery and development face many critical issues along the road to identifying the best drug candidates to bring forward for testing in patients. In neuroscience, these challenges can involve particul...
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Scientists engaged in drug discovery and development face many critical issues along the road to identifying the best drug candidates to bring forward for testing in patients. In neuroscience, these challenges can involve particularly demanding questions regarding target engagement, the predict ability of endpoints in animal models, new disease model validation, CNS penetration, and the identification of pharmacodynamic markers. For neurological conditions such as Alzheimer's disease, clinical trials of novel drugs that may modify the course of disease, rather than targeting specific symptoms, add extra layers of complexity. Major studies designed to track the course of a disease increasingly depend on noninvasive, translational imaging. In this brief review, we highlight examples of the new wave of neuroimaging studies that engender useful biomarkers of disease for translational research.
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Primordial germ cells (PGCs) in Xenopus are specified through the inheritance of germ plasm. During gastrulation, PGCs remain totipotent while surrounding cells in the vegetal mass become committed to endoderm through the action o...
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Primordial germ cells (PGCs) in Xenopus are specified through the inheritance of germ plasm. During gastrulation, PGCs remain totipotent while surrounding cells in the vegetal mass become committed to endoderm through the action of the vegetal localized maternal transcription factor VegT. We find that although PGCs contain maternal VegT RNA, they do not express its downstream targets at the mid-blastula transition (MBT). Transcriptional repression in PGCs correlates with the failure to phosphorylate serine 2 in the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAPII). As serine 5 is phosphorylated, these results are consistent with a block after the initiation step but before the elongation step of RNAPII-based transcription. Repression of PGC gene expression occurs despite an apparently permissive chromatin environment. Phosphorylation of CTD-serine 2 and expression of zygotic mRNAs in PGCs are first detected at neurula, some 10 hours after MBT, indicating that transcription is significantly delayed in the germ cell lineage. Significantly, Oct-91, a POU subclass V transcription factor related to mammalian Oct3/4, is among the earliest zygotic transcripts detected in PGCs and is a likely mediator of pluripotency. Our findings suggest that PGCs are unable to respond to maternally inherited endoderm determinants because RNAPII activity is transiently blocked while these determinants are present. Our results in a vertebrate system further support the concept that one strategy used repeatedly during evolution for preserving the germline is RNAPII repression.
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Prostaglandin E(2) (PGE(2)) is a well-known mediator of beta-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE(2)-induced pancreatic bet...
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Prostaglandin E(2) (PGE(2)) is a well-known mediator of beta-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE(2)-induced pancreatic beta-cell dysfunction. The aim of this study was to further dissect the signaling pathway of this process in pancreatic beta-cell line HIT-T15 cells and primary mouse islets. We found that PGE(2) time-dependently increased the c-Jun N-terminal kinase (JNK) pathway activity. JNK inhibition by the JNK-specific inhibitor SP600125 reversed PGE(2)-inhibited glucose-stimulated insulin secretion (GSIS). PGE(2) induced dephosphorylation of Akt and FOXO1, leading to nuclear localization and transactivation of FOXO1. Activation of FOXO1 induced nuclear exclusion but had no obvious effect on the whole-cell protein level of pancreatic and duodenal homeobox 1 (PDX1). However, these effects were all attenuated by JNK inhibition. Furthermore, adenovirus-mediated overexpression of dominant-negative (DN)-FOXO1 abolished whereas constitutively active (CA)-FOXO1 mimicked the effects of PGE(2) on GSIS in isolated mouse islets. In addition, we demonstrated that DN-JNK1 but not DN-JNK2 or CA-Akt abolished the PGE(2)-induced AP-1 luciferase reporter activity, whereas DN-JNK1 and CA-Akt but not DN-JNK2 reversed the effect of PGE(2) on FOXO1 transcriptional activity, and overexpression of DN-JNK1 rescued PGE(2)-impaired GSIS in mouse islets. Our results revealed that activation of the JNK is involved in PGE(2)-induced beta-cell dysfunction. PGE(2)-mediated JNK1 activation, through dephosphorylation of Akt and FOXO1, leads to nuclear accumulation of FOXO1 and nucleocytoplasmic shuttling of PDX1, finally resulting in defective GSIS in pancreatic beta-cells.
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Megalocytivirus is a newly defined piscine iridovirus and has been shown to be an important causative agent of viral diseases in fish. Here, a new megalocytivirus strain, designated SKIV-ZJ07, was isolated from spotted knifejaw (O...
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Megalocytivirus is a newly defined piscine iridovirus and has been shown to be an important causative agent of viral diseases in fish. Here, a new megalocytivirus strain, designated SKIV-ZJ07, was isolated from spotted knifejaw (Oplegnathus punctatus) using a mandarinfish fry cell line (MFF-1). Phylogenetic analysis of the major capsid protein and ATPase genes showed that SKIV-ZJ07 was most similar to the orange-spotted grouper iridovirus (OSGIV) from China and a U1 strain red sea bream iridovirus (RSIV-U1) from Japan. SKIV-ZJ07 was purified and the major viral proteins were identified using one-dimensional gel electrophoresis mass spectrometry (1-DE-MS) analysis. Twenty proteins were found to match proteins derived from rock sea bream iridovirus (RBIV), OSGIV and infectious spleen and kidney necrosis virus (ISKNV). Among these, 19 proteins had not been previously identified as virion-associated proteins in megalocytivirus. Challenge tests showed that SKIV-ZJ07 was highly virulent in mandarinfish. Infected fish displayed typical histopathological symptoms of ISKNV-infected fish and died, indicating that the mandarinfish is an ideal model for further study of megalocytivirus-host interactions, molecular mechanisms of viral infection and pathogenesis. Interestingly, large numbers of regular paracrystalline SKIV-ZJ07 virion arrays were observed in both SKIV-infected MFF-1 cells and mandarinfish tissues by transmission electron microscopy (TEM), which is unusual for megalocytivirus under artificial infection conditions. Taken together, the results presented here provide new insight into the pathology of megalocytivirus infection.
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Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. OBJECTIVE: To evaluate the effect of food of varying fat content on the pharmacokinetics and tol...
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Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. OBJECTIVE: To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of gabapentin enacarbil. METHODS, MATERIALS AND SUBJECTS: A randomized, open-label, crossover study of 1,200 mg gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 - 300 kcal total, approximately 6% from fat), moderate-fat (500 - 600 kcal total, approximately 30% from fat) or high-fat meals (1,000 kcal total, approximately 50% from fat), separated by a washout period of >or= 5 days. RESULTS: Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of gabapentin from gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC(inf)) in fed conditions were 23% (low-fat meal), 31% (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t(max), but a trend for delayed gabapentin enacarbil absorption was seen in t(max) ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. CONCLUSION: Administration of gabapentin enacarbil with food enhanced gabapentin exposure compared with fasted conditions, regardless of the fat or caloric content, and gabapentin enacarbil was generally well tolerated.
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BACKGROUND: The prevalence of cigarette smoking in China is high. Surgery provides an excellent opportunity for patients to quit smoking, and anesthesiologists can play an important role in tobacco control. However, little is know...
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BACKGROUND: The prevalence of cigarette smoking in China is high. Surgery provides an excellent opportunity for patients to quit smoking, and anesthesiologists can play an important role in tobacco control. However, little is known about the practices, knowledge, and attitudes of Chinese anesthesiologists regarding perioperative tobacco interventions. METHODS: Chinese anesthesiologists were surveyed at a national meeting in 2009, with written questionnaires distributed to 800 practicing anesthesiologists. RESULTS: The survey response rate was 60.3%, and 10% of respondents themselves smoked cigarettes. Most (73%) of them frequently or almost always asked about smoking status; 51% advised about the health risk of tobacco use; and 60% advised patients to quit. Compared with nonsmokers, smokers were significantly less likely to advise about the health risks of smoking and quitting. A high proportion of respondents had accurate perceptions of perioperative and long-term health risks of smoking. Although most respondents agreed that advising patients to quit is the responsibility of anesthesiologists and the perioperative period is a good time to help patients quit smoking, few knew how to counsel about smoking or help patients get the help they needed to quit. Nonetheless, most of the respondents were willing to learn about perioperative interventions and spend an extra 5 min to help patients quit smoking. CONCLUSIONS: Given their adequate knowledge of health risks of smoking, strong perception of responsibilities, and willingness to participate in tobacco control, Chinese anesthesiologists are poised to play a significant role in tobacco control in China that could improve perioperative outcomes and promote long-term health.
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Linear transceiver designs are investigated for distributed two-way relaying networks, which aim at minimising the Weighted Mean Square Error (WMSE) of data detections. The forwarding matrices at relays and equalization matrices a...
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Linear transceiver designs are investigated for distributed two-way relaying networks, which aim at minimising the Weighted Mean Square Error (WMSE) of data detections. The forwarding matrices at relays and equalization matrices at destinations are jointly optimised. To overcome the challenging limitations introduced by individual power constraints, a Semi-Definite Relaxation (SDR) called element-wise relaxation is proposed, which can transform the original optimization problem into a standard convex optimization problem. In this research, two-way relaying is understood from a pure signal processing perspective which can potentially simplify the theoretical analysis. Finally, simulation results are used for assessing the performance advantage of the proposed algorithm.
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Antigen-specific memory T cells (Tms) are essential in the immune surveillance of residual and metastatic tumors. Activation of Tms requires designing vaccines based on tumor rejection antigens, which are often not available to ca...
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Antigen-specific memory T cells (Tms) are essential in the immune surveillance of residual and metastatic tumors. Activation of Tms requires designing vaccines based on tumor rejection antigens, which are often not available to cancer patients. Therefore, it is desirable to have a general applicable approach to activate Tms without extensive knowledge of tumor antigens. Here, we report that activation of antigen-specific Tms could be achieved by the administration of agonistic anti-CD137 monoclonal antibody without additional tumor vaccination, leading to the prevention of recurrence and metastases after surgical resection of primary tumors in mouse models. By reconstitution with CD137-deficient Tms, we demonstrate that expression of CD137 on antigen-specific Tms is only partially required for the effect of anti-CD137 antibody. Other host cells, including those from hematopoietic and nonhematopoietic origins, are also important because ablation of CD137 from these cells partially but significantly eliminates antitumor effect of anti-CD137 antibody. Our findings implicate a potential new approach to prevent recurrence and metastases in cancer patients.
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BACKGROUND: The prognosis of patients with metastasized thyroid carcinoma is not optimistic, necessitating the search for new treatment options. AIM: Beneficial effects of retinoic acid (RA) have been suggested in thyroid cancer d...
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BACKGROUND: The prognosis of patients with metastasized thyroid carcinoma is not optimistic, necessitating the search for new treatment options. AIM: Beneficial effects of retinoic acid (RA) have been suggested in thyroid cancer differentiation and the present study was performed to investigate the anti-metastatic potential of RA in respect of important determinants of metastatic behavior in thyroid carcinoma, focusing on the role of invasion-associated proteins. MATERIALS AND METHODS: Differentiated thyroid carcinoma cell lines FTC- 133 and XTC.UC1, and anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with alltrans- RA (ATRA) or the solvent ethanol. Invasion and adhesion potency in vitro was studied by transwell experiment and short-term adhesion assay. The involvement of invasion-associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), matrix metalloproteinase-2 (MMP-2) and E-cadherin, were investigated by semi-quantitative RT-PCR and Western blot. RESULTS: In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines, with the most significant effect in anaplastic cancer cells. Short-term adhesion assay suggested that ATRA increases cancer cell adhesion to extracellular matrix (ECM) in C643, HTH74 and XTC.UC1, probably through a transcriptional and translational regulation of some attachment molecules. RT-PCR andWestern blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-cadherin was increased, whereas the MMP-2 expression was not significantly down-regulated in ATRA-treated group. In ATRA-treated FTC-133 and XTC.UC1 cell lines, MMP-2 expression was decreased, but no significant changes in uPA and E-cadherin expression were observed. CONCLUSIONS: The present study demonstrates the influence of ATRA on both important determinants of metastatic behavior ("de-adhesion" and proteolysis) in thyroid carcinoma cell lines, especially in anaplastic cancer cells. These findings may add to the explanations for beneficial effects of RA in the treatment of metastatic thyroid carcinomas.
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