Fighting Against the Clock: Circadian Disruption and Parkinson's Disease.

Circadian disruption is being increasingly recognized as a critical factor in the development and progression of Parkinson's disease (PD). This review aims to provide an in-depth overview of the relationship between circadian disruption and PD by exploring the molecular, cellular, and behavioral aspects of this interaction. This review will include a comprehensive understanding of how the clock gene system and transcription-translation feedback loops function and how they are diminished in PD. The article also discusses the role of clock genes in the regulation of circadian rhythms, as well as the impact of clock gene dysregulation on mitochondrial function, oxidative stress, and neuroinflammation, including the microbiota-gut-brain axis, which have all been proposed as being crucial mechanisms in the pathophysiology of PD. Finally, this review highlights potential therapeutic strategies targeting the clock gene system and circadian rhythm for the treatment of PD.

Endovascular thrombectomy for basilar-artery occlusion: A meta-analysis with trial sequential analysis.

Background and purpose: Basilar-artery occlusion (BAO) usually accounts for devastating neurologic sequelae, poor prognosis, and even death. While endovascular thrombectomy (EVT) is the most successful treatment for anterior circulation stroke with large vessel occlusion, its effectiveness in treating acute BAO is still debatable. Our aim is to compare the efficacy and safety between EVT and conservative medical treatment (CMT) in BAO. Methods: Up until May 2022, relevant literature was gathered using searches in Embase, PubMed, and the Cochrane Library. The primary outcomes were defined as good functional outcome (modified Rankin Scale 0-2) and favorable functional outcome (modified Rankin Scale 0-3) at 3 months between EVT and CMT groups. The secondary outcomes included mortality at 3 months, symptomatic intracerebral hemorrhage (ICH), and any ICH. Results: Eight studies involving 3733 patients with BAO were enrolled 2573 individuals underwent EVT, and the remaining 1160 patients received CMT. Compared with CMT, EVT achieved more favorable functional outcome (odds ratio (OR) 1.26, 95% CI 1.03-1.55, I2 = 54%, p = 0.05) in BAO. The good functional outcome showed a similar tendency (OR 1.23, 95% CI 0.97-1.57, I2 = 63%, p = 0.02) as well. EVT decreased mortality at 3 months (OR 0.81, 95% CI 0.70-0.93, I2 = 31 %, p = 0.19), although having a tendency to cause symptomatic ICH (OR 2.91, 95% CI 1.38-6.18, I2 = 22 %, p = 0.27). Conclusions: EVT in BAO provides superior functional outcomes and less mortality compared with CMT. Even though EVT has the propensity to cause symptomatic ICH, EVT nevertheless improved posterior circulation stroke.

Biodegradable Oxide Neuromorphic Transistors for Neuromorphic Computing and Anxiety Disorder Emulation.

Brain-inspired neuromorphic computing and portable intelligent electronic products have received increasing attention. In the present work, nanocellulose-gated indium tin oxide neuromorphic transistors are fabricated. The device exhibits good electrical performance. Short-term synaptic plasticities were mimicked, including excitatory postsynaptic current, paired-pulse facilitation, and dynamic high-pass synaptic filtering. Interestingly, an effective linear synaptic weight updating strategy was adopted, resulting in an excellent recognition accuracy of ∼92.93% for the Modified National Institute of Standard and Technology database adopting a two-layer multilayer perceptron neural network. Moreover, with unique interfacial protonic coupling, anxiety disorder behavior was conceptually emulated, exhibiting "neurosensitization", "primary and secondary fear", and "fear-adrenaline secretion-exacerbated fear". Finally, the neuromorphic transistors could be dissolved in water, demonstrating potential in "green" electronics. These findings indicate that the proposed oxide neuromorphic transistors would have potential as implantable chips for nerve health diagnosis, neural prostheses, and brain-machine interfaces.

Case report: Steroid-responsive acute chorea as first presentation of the coexistence of Moyamoya and Graves' disease.

Background: Chorea is a movement disorder characterized by abrupt, rapid, and uncontrollable, random movements from one part of the body to another with motor impersistence. Sporadic chorea is rarely caused by either thyrotoxicosis or Moyamoya disease (MMD). Methods and results: In this case report, we describe a female patient with chorea with the rare coexistence of Graves' disease and Moyamoya disease. Tc-99m ethyl cysteinate dimer (ECD) brain perfusion single-photon emission computed tomography (SPECT) showed mild to moderate hypoperfusion in bilateral frontal and left temporal regions. After administering dexamethasone 20 mg for 5 days, her choreic movement symptoms recovered rapidly. Conclusion: Although uncommon, thyrotoxicosis and Moyamoya disease can co-occur, especially in Asian female adults. Excessive thyroid hormones contribute to the dysregulation of neurotransmitters in basal ganglia-thalamocortical circuits. Moyamoya disease is responsible for ischemic changes affecting the excitatory-inhibitory circuits between the basal ganglia and the neocortex. Under a state of coexistence, thyrotoxicosis exaggerates cerebral metabolism, aggravating the impaired cerebral perfusion induced by Moyamoya disease. Moreover, inflammatory reactions caused by thyroid autoantibodies may also promote the progression of Moyamoya disease. In our experience, treatment with steroids may not only synergize the anti-thyroid effect but may also be a way to modulate the neurotransmitters within the basal ganglia or restore cerebral perfusion. We suggest that evaluation of the thyroid function status in Moyamoya disease is essential.

Recent advances in neuromorphic transistors for artificial perception applications: FOCUS ISSUE REVIEW.

Conventional von Neumann architecture is insufficient in establishing artificial intelligence (AI) in terms of energy efficiency, computing in memory and dynamic learning. Delightedly, rapid developments in neuromorphic computing provide a new paradigm to solve this dilemma. Furthermore, neuromorphic devices that can realize synaptic plasticity and neuromorphic function have extraordinary significance for neuromorphic system. A three-terminal neuromorphic transistor is one of the typical representatives. In addition, human body has five senses, including vision, touch, auditory sense, olfactory sense and gustatory sense, providing abundant information for brain. Inspired by the human perception system, developments in artificial perception system will give new vitality to intelligent robots. This review discusses the operation mechanism, function and application of neuromorphic transistors. The latest progresses in artificial perception systems based on neuromorphic transistors are provided. Finally, the opportunities and challenges of artificial perception systems are summarized.

The Role of Nondiabetic Hyperglycemia in Critically Ill Patients with Acute Ischemic Stroke.

In this study, we aim to elucidate the association between nondiabetic hyperglycemia and the short-term prognosis of critically ill patients with acute ischemic stroke. We extracted data using the Medical Information Mart for Intensive Care IV from 2008 to 2019. The primary outcomes were set as intensive care units (ICU) and in-hospital mortality. We developed a Cox proportional hazards model to determine the nonlinear association between serum glucose levels and primary outcomes. Of the 1086 patients included, 236 patients had hyperglycemia. Patients with hyperglycemia were associated with higher ages, female gender, higher Charlson Comorbidity Index scores, and higher Acute Physiology Score III scores. After propensity score matching, 222 pairs remained. The hyperglycemia group had a significantly higher ICU mortality (17.6% vs. 10.8%; p = 0.041). Meanwhile, no significant differences in ICU length of stay (5.2 vs. 5.2; p = 0.910), in-hospital mortality (26.6% vs. 18.9%, p = 0.054), and hospital length of stay (10.0 vs. 9.1; p = 0.404) were observed between the two groups. The Kaplan-Meier curves for ICU and in-hospital survival before matching suggested significant differences; however, after matching, they failed to prove any disparity. Non-diabetic patients with acute ischemic stroke have poor clinical characteristic while encountering hyperglycemic events; therefore, careful monitoring in the acute phase is still required.

Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity.

Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKIα, an essential regulator of spinogenesis. CaMKK1/CaMKIα signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor ßPIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKIα/ßPIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.

Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study.

BACKGROUND: The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan. METHOD: 2616 patients aged 20 years or older with newly diagnosed psoriasis during 2004-2008 and 10,464 participants without psoriasis were identified. Both groups were followed up until the diagnoses of CFS were made at the end of 2011. RESULTS: The relationship between psoriasis and the subsequent risk of CFS was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 2.27 and 3.58 per 1000 person-years among the non-psoriasis and psoriasis populations, respectively (adjusted hazard ratio [HR] = 1.48, with 95% confidence interval [CI] 1.07-2.06). In the stratified analysis, the psoriasis group were consistently associated with a higher risk of CFS in male sex (HR = 2.05, 95% CI 1.31-3.20) and age group of ≥ 60 years old (HR = 2.32, 95% CI 1.33-4.06). In addition, we discovered that the significantly increased risk of CFS among psoriasis patients is attenuated after they receive phototherapy and/or immunomodulatory drugs. CONCLUSIONS: The data from this population-based retrospective cohort study revealed that psoriasis is associated with an elevated risk of subsequent CFS, which is differentiated by sex and age.

Excessive nNOS/NO/AMPK signaling activation mediated by the blockage of the CBS/H2S system contributes to oxygen­glucose deprivation­induced endoplasmic reticulum stress in PC12 cells.

Hypoxic­ischemia stress causes severe brain injury, leading to death and disability worldwide. Although it has been reported that endoplasmic reticulum (ER) stress is an essential step in the progression of hypoxia or ischemia­induced brain injury, the underlying molecular mechanisms are and have not yet been fully elucidated. Accumulating evidence has indicated that both nitric oxide (NO) and hydrogen sulfide (H2S) play an important role in the development of cerebral ischemic injury. In the present study, we aimed to investigate the effect of the association between NO signaling and the cystathionine ß­synthase (CBS)/H2S system on ER stress in a cell model of cerebral hypoxia­ischemia injury. We found that oxygen­glucose deprivation (OGD) markedly increased the NO level and neuronal NO synthase (nNOS) activity. 3­Bromo­7­nitroindazole (3­Br­7­NI), a relatively selective nNOS inhibitor, abolished the OGD­induced inhibition of cell viability and the increased expression of ER stress­related proteins, including glucose­regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase­12 in PC12 cells, indicating the contribution of excessive nNOS/NO signaling to OGD­induced ER stress. Furthermore, we found that OGD increased the phosphorylated AMP­activated protein kinase (p­AMPK)/AMPK ratio, and the AMPK activator, 5­aminoimidazole­4­carboxamide­1­ß­D­ribofuranoside (AICAR), attenuated the effects on OGD­induced ER stress, suggesting that OGD­induced NO overproduction results in AMPK activation in PC12 cells. We also found that OGD induced the downregulation of the CBS/H2S system, as indicated by the decreased H2S level in the culture supernatant and CBS activity in PC12 cells. In addition, we found that treatment with NaHS (a H2S donor) or S­adenosyl­L­methionine (SAM, a CBS agonist) mitigated OGD­induced ER stress, as well as the NO level, nNOS activity and AMPK phosphorylation in PC12 cells. On the whole, these results suggest that the inhibition of the CBS/H2S system, which facilitated excessive nNOS/NO/AMPK activation, contributes to OGD­induced ER stress.

Heteromers of µ opioid and dopamine D1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

BACKGROUND AND PURPOSE: Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear. EXPERIMENTAL APPROACH: Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization. KEY RESULTS: The dopamine D1 receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of µ opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D1 receptor knockout (KO) mice, suggesting that SCH23390 modified µ receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of µ receptor-D1 receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited µ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D1 or µ receptor KO mice and thus unable to form µ receptor-D1 receptor heterodimers, failed to show locomotor sensitization to morphine. CONCLUSION AND IMPLICATIONS: Our results suggest that µ receptor-D1 receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.

Preliminary application of laparoscopic technique in treatment of upper urinary calculi / 中国内镜杂志

Objective To evaluate the reasonable individual program for upper urinary tract calculi in minimally invasive treatment. Methods From January 2013 to June 2016, 147 patients (sides) with upper urinary calculi who had some characteristics received laparoscopic nehprectomy or corresponding surgical treatment. The number of cases of postoperative stagnation, the average hospitalization time and the average cost of treatment were compared with those of 147 patients (lateral) who underwent PCNL and URSL with the similarity, shape and load of stones before June 2016, respectively. Results The removal rate of stage I was 100.00％ (147/147) in laparoscopic group, which was significantly higher than that in PCNL and URSL group (91.84％, 135/147), the difference was statistically significant (P = 0.001); Laparoscopic group postoperative blood transfusion (0/147) and interventional hemostasis (0/147) were significantly lower in 6 cases (6/147) and 4 cases (4/147) in PCNL and URSL groups,the differences were statistically significant (P = 0.013, P = 0.044). There was no postoperative severe infection in laparoscopic group (0/147), which has no significant difference (P = 0.156) in postoperative severe infection between PCNL and URSL group (2/147). There were 9 cases of 134 cases of postoperative (9/134) fever at ≥ 38℃ in laparoscopic group, which was significantly lower than that in PCNL and URSL group (28/147), the difference was statistically significant (P = 0.002); Laparoscopic group of postoperative urinary tract stenosis in 3 cases (3/114), which was significantly lower than that of PCNL and URSL group (9/101), the difference was statistically significant (P = 0.045). The average length of stay in laparoscopic group was (10.12 ± 0.29) d, which was significantly lower (P = 0.011) than that in PCNL and URSL group (13.97 ± 0.38) days. The average cost of treatment in laparoscopic group (12541.84 ± 181.54) yuan was significantly lower than that in PCNL and URSL group (18124.65 ± 302.32) yuan, the difference was statistically significant (P = 0.018). Conclusion In some cases, when the upper urinary tract calcuci are suitable for 'cut out', the use of laparoscopic treatment is more secure; when there is a need for surgical treatment of complications, can be treated simultaneously. Laparoscopic technique is one of the important methods of minimally invasive treatment for upper urinary calculi.

Antimicrobial susceptibility and clinical outcomes of Candida parapsilosis bloodstream infections in a tertiary teaching hospital in Northern Taiwan.

BACKGROUND: Candida parapsilosis is an emerging non-albicans Candida that is associated with central line-associated infection. C. parapsilosis has higher minimal inhibitory concentration to echinocandin than Candida albicans, and the effects of echinocandin on C. parapsilosis are ambiguous. Therefore, in this study, we aimed to investigate the susceptibility and the correlation between incidence and drug consumption. METHODS: This retrospective study was conducted in a tertiary teaching hospital in northern Taiwan between 2008 and 2012. The Candida species distribution, the correlation between the use of antifungal agents and the incidence of C. parapsilosis bloodstream infection, demographic information, clinical characteristics, mortality rate, and in vitro susceptibility of C. parapsilosis were analyzed. RESULTS: A total of 77 episodes from 77 patients were included for analysis. The overall 90-day mortality rate was 41.6%. The incidence of C. parapsilosis bloodstream infection showed a moderate positive correlation with the increased defined daily dose of echinocandin. The risk factors associated with mortality included malignancy or a metastatic tumor. Multivariate logistical regression analysis showed that patients with malignancy had higher odds ratios in terms of mortality. The rate of C. parapsilosis resistance to fluconazole was 3%, whereas the susceptibility rate was 95.5%. CONCLUSION: Underlying comorbidity and malignancy were factors leading to death in patients with C. parapsilosis bloodstream infection. Catheter removal did not influence the mortality rate. The survival rate of patients receiving echinocandin was lower than the group receiving fluconazole. Fluconazole remains the drug of choice to treat C. parapsilosis bloodstream infections.

Dorsal hippocampal NMDA receptor blockade impairs extinction of naloxone-precipitated conditioned place aversion in acute morphine-treated rats by suppressing ERK and CREB phosphorylation in the basolateral amygdala.

BACKGROUND AND PURPOSE: Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying the loss (extinction) of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction. EXPERIMENTAL APPROACH: Naloxone-induced conditioned place aversion (CPA) of Sprague-Dawley rats was used to measure conditioned aversion. An NMDA receptor antagonist and MAPK kinase inhibitor were applied through intracranial injections. The phosphorylation of ERK and cAMP response element-binding protein (CREB) was detected using Western blot. KEY RESULTS: The extinction of CPA behaviour increased the phosphorylation of ERK and CREB in the dorsal hippocampus (DH) and basolateral amygdala (BLA), but not in the central amygdala (CeA). Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuated ERK and CREB phosphorylation in the BLA and impaired the extinction of CPA behaviour. Although intra-DH injections of AP-5 attenuated extinction training-induced activation of the ERK-CREB pathway in the BLA, intra-BLA injection of AP5 had no effect on extinction training-induced activation of the ERK-CREB pathway in the DH. CONCLUSIONS AND IMPLICATIONS: These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behaviour and that the DH, via a direct or indirect pathway, modulates the activity of ERK and CREB in the BLA through activation of NMDA receptors after extinction training. Understanding the mechanisms underlying the extinction of conditioned aversion could facilitate the treatment of drug addiction. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Clinical characteristics of children and adults hospitalized for influenza virus infection.

BACKGROUND/PURPOSE: Influenza infection has different clinical presentations and outcomes in children and adults, and bacterial coinfection is associated with significantly higher morbidity and mortality. This study compared the clinical features in children and adults hospitalized for influenza virus infection and the role of concomitant bacteremia. METHODS: A retrospective observational cohort study was conducted by a review of medical records of all consecutive patients admitted for influenza infection between April 1, 2009 and February 28, 2011. RESULTS: Of the 1203 patients, 76.2% were children, and ranged in age from 1 month to 99 years, with a mortality of 3.1% for adults; no children died. Pneumonia, acute respiratory distress syndrome, acute respiratory failure, septic shock, and cardiovascular complications were more common in adults. Bacteremia was more common in adults than in children (3.5% vs. 0.4%). C-reactive protein (CRP) > 4 mg/dL and a longer hospital stay occurred more often in children with bacteremia than in the group without bacteremia. In adults with bacteremia, acute respiratory failure, septic shock, and cardiovascular complications were more common, with a mortality of 50% versus 1.4% compared with those without bacteremia, and thrombocytopenia and increased CRP were independent risk factors. Using receiver operating characteristic analysis, CRP ≥ 14 mg/dL had a sensitivity of 90.0% and a specificity of 80.0%. CONCLUSION: Influenza infection in adults is associated with increased risk of complications, bacteremia, and mortality compared with that in children. Bacteremia in adults with influenza is associated with increased complications and mortality; thrombocytopenia and elevated CRP levels could identify those at risk.

Oncogenic fibulin-5 promotes nasopharyngeal carcinoma cell metastasis through the FLJ10540/AKT pathway and correlates with poor prognosis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential and locoregional recurrence, although the molecular alterations that are driving NPC metastasis remain unclear at this time. This study aimed to examine the expression of fibulin-5 in NPC, correlate the results with clinicopathological variables and survival, and to investigate the role of fibulin-5 in human NPC cell lines. MATERIAL AND METHODS: Standard semi-quantitative-RT-PCR, quantitative-RT-PCR, immunoblotting, and immunohistochemistry were used to investigate the mRNA and protein expression profiles of fibulin-5 in normal and NPC tissues. Immunohistochemistry of fibulin-5 was correlated with clinicopathological characteristics by univariate analyses. NPC cells overexpressing fibulin-5 or fibulin-5-siRNA cells were generated by stable transfection to characterize the molecular mechanisms of fibulin-5-elicited cell growth and metastasis. RESULTS: Our results demonstrated that fibulin-5 overexpression in NPC specimens and significantly correlated with advanced tumor metastasis indicating a poor 5-year overall survival. Fibulin-5 was mainly expressed in the nucleus in human NPC specimens and cell lines. Functionally, fibulin-5 overexpression yielded fast growth in NPC cells. In addition, fibulin-5 promotes cell metastasis in NPC cells through increased FLJ10540 and phosphor-AKT activity. In contrast, siRNA depletion of fibulin-5 suppressed FLJ10540 expression and phosphor-AKT activity. Suppression of either fibulin-5 or FLJ10540 can cause significant inhibition with regards to cell motility in NPC cells. Finally, immunohistochemical analysis of human aggressive NPC specimens showed a significant and positive correlation between fibulin-5 and FLJ10540 expression. CONCLUSION: Higher fibulin-5 expression is not only an important indicator of poor survival, but also contributes to the development of new therapeutic strategies in the FLJ10540/AKT pathway for NPC treatment.

Extinction of aversive memories associated with morphine withdrawal requires ERK-mediated epigenetic regulation of brain-derived neurotrophic factor transcription in the rat ventromedial prefrontal cortex.

Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner.

FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is well-known for its highly metastatic characteristics, but little is known of its molecular mechanisms. New biomarkers that predict clinical outcome, in particular the ability of the primary tumor to develop metastatic tumors are urgently needed. The aim of this study is to investigate the role of FLJ10540 in human NPC development. METHODS: A bioinformatics approach was used to explore the potentially important regulatory genes involved in the growth/metastasis control of NPC. FLJ10540 was chosen for this study. Two co-expression strategies from NPC microarray were employed to identify the relationship between FLJ10540 and osteopontin. Quantitative-RT-PCR, immunoblotting, and immunohistochemistry analysis were used to investigate the mRNA and protein expression profiles of FLJ10540 and osteopontin in the normal and NPC tissues to confirm microarray results. TW01 and Hone1 NPC cells with overexpression FLJ10540 or siRNA to repress endogenous FLJ10540 were generated by stable transfection to further elucidate the molecular mechanisms of FLJ10540-elicited cell growth and metastasis under osteopontin stimulation. RESULTS: We found that osteopontin expression exhibited a positive correlation with FLJ10540 in NPC microarray. We also demonstrated comprehensively that FLJ10540 and osteopontin were not only overexpressed in NPC specimens, but also significantly correlated with advanced tumor and lymph node-metastasis stages, and had a poor 5-year survival rate, respectively. Stimulation of NPC parental cells with osteopontin results in an increase in FLJ10540 mRNA and protein expressions. Functionally, FLJ10540 transfectant alone, or stimulated with osteopontin, exhibited fast growth and increased metastasis as compared to vehicle control with or without osteopontin stimulation. Conversely, knockdown of FLJ10540 by siRNA results in the suppression of NPC cell growth and motility. Treatment with anti-CD44 antibodies in NPC parental cells not only resulted in a decrease of FLJ10540 protein, but also affected the abilities of FLJ10540-elicited cell growth and motility in osteopontin stimulated-NPC cells. CONCLUSIONS: These findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.

58-kDa microspherule protein (MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates p53/p21 senescence pathway.

The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated ß-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties.

A 1.72µW, 23.2fj/conversion step successive approach ADC for bio-medical signal acquisition.

This paper presents a successive approach register (SAR) analog-to-digital converter (ADC) with a novel hybrid digital-to-analog converter (DAC) architecture: half junction splitting (J.S.) and half binary weighted capacitor DAC. This DAC maintains low power consumption of J.S. DAC and the high signal-to-noise plus distortion ratio (SNDR) of binary weighted capacitor DAC. The power dissipation of the circuit is 1.72 µW, SNDR 59.17 dB, spurious free dynamic range (SFDR) 73.39 dB, and the FOM 23.2 fj/conversion step with 0.9 V supply voltage. The proposed circuit is fabricated in TSMC 0.18 µm 1P6M CMOS process technology.