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.

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.

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.

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.

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.

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.

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.

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.

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.

Interaction between human papillomavirus type 5 E2 and polo-like kinase 1.

The E2 protein of the papillomavirus plays an essential role in the viral life cycle. Through a yeast two-hybrid screening, human polo-like kinase 1 was found to interact with human papillomavirus type 5 E2. Further characterization identified that the domains responsible for the interaction are the transactivation domain of HPV-5 E2 and the sequence between the kinase and the polo box domains of Plk1. In vivo, Plk1 and HPV-5 E2 are colocalized at the nuclear speckles. In the skin epithelium not infected with epidermodysplasia verruciformis associated HPVs, Plk1 is expressed in the stratum basale, indicating that the Plk1-HPV-5 E2 interaction likely occurs in the keratinocytes at the basal layer of the epithelium upon infection of HPV-5. Both HPV-5 E2 and Plk1 also interact with the E2 binding domain of Brd4. The E2 binding domain of Brd4 is phosphorylated by Plk1 in vitro, and this phosphorylation event is blocked by the presence of HPV-5 E2. Hence, these findings suggest the possibility that the cellular function of Brd4 is de-regulated by forming a complex with HPV-5 E2 in the infected epithelial cells.

Clinical experiences of pulmonary and bloodstream nocardiosis in two tertiary care hospitals in northern Taiwan, 2000-2004.

BACKGROUND AND PURPOSE: Nocardia is an uncommon pathogen in humans, and most patients with nocardiosis are immunocompromised, with variable etiologies. To understand the incidence, clinical characteristics, treatment and outcome of pulmonary and bloodstream nocardiosis, we conducted a retrospective study in two tertiary care hospitals in northern Taiwan. METHODS: We reviewed laboratory culture reports and clinical records of 29 adult patients with lower respiratory tract or bloodstream nocardiosis (21 and 8 patients, respectively) in two tertiary care hospitals, over a period of 5 years. The risk factors, clinical manifestations, response to therapy, outcome and recurrence rate were compared between these two groups. RESULTS: The most common underlying conditions in pulmonary nocardiosis were chronic lung disease and long-term steroid usage. For nocardemia, underlying malignancy and steroid administration are common. Fourteen of 21 patients with pulmonary nocardiosis ever transferred to an intensive care unit and 9 of them had concomitant infection. In patients with and without coexisting isolates during hospital course, the mean days from admission to specific therapy for nocardiosis were 26.4 and 11.9 days, respectively. Patients with nocardemia showed great variation in clinical manifestations and disease severity; central venous catheter implantation was noted in 6 of them. Only one patient with nocardemia had documented recurrence. Twenty four patients were treated with antimicrobials (trimethoprim-sulfamethoxazole, 83%; imipenem or meropenem, 25%). Treatment failure occurred in 7 of 20 patients treated with trimethoprim-sulfamethoxazole alone or in combination. CONCLUSIONS: Pulmonary or disseminated nocardiosis is rare but may be fatal as an opportunistic infection in an immunocompromised host with chronic lung disease, underlying malignancy or long-term steroid usage. The significance of primary nocardemia needs careful evaluation. Concomitant infection was the probable predisposing factor for intensive care unit admission for pulmonary nocardiosis in our study (p=0.019) and might obscure the isolation of nocardiae organisms and delay effective treatment. For critical patients with nocardiae infection, initial therapy with a combination antimicrobial regimen is recommended.

Up-regulation of fibroblast growth factor 3 is associated with tumor metastasis and recurrence in human hepatocellular carcinoma.

Recently, we established a hepatocellular carcinoma (HCC) cell line (named H4-M) from a metastatic HCC tumor. In H4-M, a marker chromosome containing a homogeneously staining region (hsr) was identified by cytogenetic analysis. The hsr was characterized by chromosome microdissection and the result showed that the hsr was composed of DNA sequence from 11q13. Oncogenes CCND1 and FGF3 were localized within the complicon and overexpressions of CCND1 and FGF3 were confirmed by Northern blot analysis. Clinical significance of FGF3 overexpression was studied by immunohistochemistry (IHC) using an HCC tissue microarray (TMA) containing 60 pairs of primary/metastatic HCCs and 30 pairs of primary/recurrent HCCs. TMA study showed that overexpression of FGF3 was significantly associated with HCC metastasis and recurrence (p<0.01), suggesting that up-regulation of FGF3 may play an important role in HCC metastasis and recurrence.

Fournier's gangrene: ten-year experience in a medical center in northern Taiwan.

BACKGROUND AND PURPOSE: Fournier's gangrene is a life-threatening infection. The mortality is still high despite the rapid advancement of modern intensive care and surgical technique. In this study, we present our institution's recent experience with a large series of patients with Fournier's gangrene. METHODS: A retrospective chart review was performed including 44 consecutive patients with Fournier's gangrene over a 10-year period. RESULTS: The 44 cases comprised 39 males and 5 females, with a mean age of 55.5 years. The mean duration of hospitalization was 27.9 days. Overall mortality was 22.7%. Diabetes mellitus, hypertension, chronic liver disease, liver cirrhosis and chronic renal insufficiency were the 5 leading predisposing factors. Liver cirrhosis was highly related to mortality (p=0.009). The etiologic origin of the gangrene was colorectal, urological and dermatological in 52.3%, 25.0%, and 11.4% of patients, respectively. The most common isolated pathogens were Escherichia coli, Bacteroides fragilis, Klebsiella pneumoniae, Enterococcus spp., and Proteus mirabilis. There were a total of 74 debridements. Other related surgical procedures were reconstruction surgery (n = 18), colostomy (2), cystostomy (1), vasectomy (1), orchiectomy (1) and penectomy (1). Major complications of Fournier's gangrene, including respiratory failure, renal failure, septic shock, hepatic failure and disseminated intravascular coagulopathy, were significantly to mortality (p<0.05). CONCLUSIONS: Early diagnosis, intensive medical care (aggressive resuscitation and broad-spectrum antibiotics), and prompt and repeated surgical intervention are the mainstays of treatment. Liver cirrhosis in particular is a poor prognostic factor. Reconstructive surgery should also be a consideration once the acute condition has improved. Patients with comorbid condition, serious infection, and major complications should be treated carefully and aggressively.

[Effects of sapindoside on blood pressure and vasoactive substance in renovascular hypertension rat].

OBJECTIVE: To observe the effects of sapindoside on blood pressure, Ang II, Ald, ET in the blood plasma and NO in the serum in renovascular hypertension rat. METHOD: The 2K1C (2 kidney 1 clap) hypertensive model rats were used and drugs had been given by ig. for 5 weeks. The blood pressure was measured at the 1, 3, 7, 14, 21, 28, 35 day after drug. At the end of 5th weeks, the Ang II, Ald, ET in the blood plasma and NO in the serum were measured. RESULT: Sapindoside (H, M and L) by ig. for 5 weeks could significantly lower the blood pressure, increase the levels of NO in the serum, reduce the concentration of Ang II, Ald, ET in the blood plasma. CONCLUSION: Sapindoside plays an important role in decreasing the blood pressure of renovascular hypertension rat.

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.

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.