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Psoriasis is a predominantly Th17 cell-driven chronic autoinflammatory skin disorder. Brevilin A, a natural sesquiterpene lactone extracted from Centipeda minima, has been used as a traditional oriental medicine for allergic diseases for centuries. However, the effects of brevilin A on psoriasis have yet to be established. In this study, we investigated brevilin A to elucidate its potential effects on T cell activities in psoriasis, in animal models and patients. An imiquimod (IMQ)-induced psoriasis-like dermatitis murine model was utilized. Experimental mice were administered different doses of brevilin A (5, 10, 20 mg/kg respectively) for a duration of 5 days. Cutaneous manifestations were measured daily. Under hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC), acanthosis and proinflammatory cytokine expression in the dorsal skin of mice were detected. Enzyme-linked immunosorbent assay (ELISA) was used for the measurement of IL-17A levels in serum samples. Naïve CD4+ T cells, isolated from mice spleen and lymph nodes and from peripheral blood mononuclear cells (PBMCs) of psoriatic patients, were used to evaluate the effects of brevilin A on Th17 differentiation. In brevilin A-treated mice, brevilin A significantly reduced skin redness and scaling; acanthosis as well as IL-6, IL-17A, and ki-67 expressions were downregulated in the dorsal skin, and serum levels of IL-17A were lowered. Brevilin A also inhibited Th17 differentiation. In conclusion, brevilin A demonstrated significant capability in ameliorating skin inflammation in IMQ-induced psoriasis-like dermatitis and could modulate Th17 differentiation. Therefore, brevilin A is potentially pharmacologically effective in the treatment of psoriasis.

B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.

Psoriasis is a recurrent inflammatory skin disease characterized by redness and scaly skin lesions with itchy or painful sensations. Forsythoside A, one of the main active compounds isolated from the fruit of Forsythia suspensa, has been widely applied to treat inflammatory diseases in the clinical use of traditional oriental medicine. However, the effect of forsythoside A on psoriasis remains unclear. This study aimed to explore the therapeutic effects and immune regulation of forsythoside A on psoriasis. C57BL/6 mice were divided into six groups and treated with imiquimod cream on their shaved back skin to induce psoriasis-like dermatitis. Different doses of forsythoside A (5 mg/kg, 10 mg/kg, or 20 mg/kg) were administered to the respective treatment groups. Skin redness, scaling, and ear thickness were measured; keratinocyte proliferation and inflammatory cytokine expression were detected by hematoxylin–eosin and immunohistochemical staining. Th17 cells in the inguinal lymph nodes were detected by flow cytometric analysis. IL-17A levels were measured using ELISA. The results showed that forsythoside A relieved psoriatic skin symptoms such as skin redness, thickness, scaling, and reduced epidermal thickening. The expression of IL-6, IL-17, and Ki-67 was downregulated in the forsythoside-A-treated groups. Th17 cell expression in inguinal lymph nodes and IL-17A secretion was suppressed by forsythoside A. In conclusion, forsythoside A was found to alleviate imiquimod-induced psoriasis-like dermatitis in mice by suppressing Th17 development and IL-17A secretion. These findings demonstrate the feasibility of forsythoside A in treating human psoriasis.

PVDF membranes were prepared with nonsolvent-induced phase separation, using solvents with various dipole moments, including HMPA, NMP, DMAc and TEP. Both the fraction of the polar crystalline phase and the water permeability of the prepared membrane increased monotonously with an increasing solvent dipole moment. FTIR/ATR analyses were conducted at the surfaces of the cast films during membrane formation to provide information on if the solvents were present as the PVDF crystallized. The results reveal that, with HMPA, NMP or DMAc being used to dissolve PVDF, a solvent with a higher dipole moment resulted in a lower solvent removal rate from the cast film, because the viscosity of the casting solution was higher. The lower solvent removal rate allowed a higher solvent concentration on the surface of the cast film, leading to a more porous surface and longer solvent-governed crystallization. Because of its low polarity, TEP induced non-polar crystals and had a low affinity for water, accounting for the low water permeability and the low fraction of polar crystals with TEP as the solvent. The results provide insight into how the membrane structure on a molecular scale (related to the crystalline phase) and nanoscale (related to water permeability) was related to and influenced by solvent polarity and its removal rate during membrane formation.

T-cell acute lymphoblastic leukemia (T-ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T-cell progenitors. Conventional treatments for T-ALL fail to prevent or cure the disease, with a high-risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T-ALL. Niclosamide, a traditional oral anti-helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T-ALL. Here, the present study aimed to investigate the anti-leukemia effects of niclosamide on T-ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T-ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T-ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T-ALL cells treated with niclosamide, changes in apoptosis- and autophagy-related proteins were analyzed by western blotting. In addition, in an in vivo model, T-ALL xenograft mice were used to study the anti-leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF-CEM T-ALL cells in both a dose- and time-dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF-CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase-3 and LC3B, while downregulated those of Bcl-2 and p62, in a dose-dependent manner in both Jurkat and CCRF-CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T-ALL xenograft mice by activating cleaved caspase-3 and LC3B. We conclude that niclosamide plays an anti-leukemia role, and that it represents a novel approach for the treatment of T-ALL.

The incidence of colon cancer continues to increase annually, and it is the leading cause of cancer-associated mortality worldwide. Altering cell metabolism and inducing autophagic cell death have recently emerged as novel strategies in preventing tumor growth. Autophagy plays an essential role in energy production by degrading damaged cellular components and is also associated with tumor proliferation suppression. Itraconazole is an FDA-approved drug used as an antifungal medication and has been reported to induce autophagic cell death in breast cancer. However, the effects of itraconazole on cell metabolism and induction of apoptosis in colon cancer remain unclear. The present study analyzed extensive data from patients diagnosed with colon cancer using itraconazole between January 2011 and December 2015, from the Taiwanese National Health Insurance Research Database. The underlying molecular mechanisms of itraconazole in autophagy-induced cell death were also investigated. The results demonstrated that the 5-year survival rate was significantly higher in patients with colon cancer who received itraconazole treatment. In addition, itraconazole decreased the viability and cell colony formation, and induced cleaved caspase-3 expression and G1 cell cycle arrest of COLO 205 and HCT 116 cells. Notably, itraconazole induced autophagy by enhancing LC3B and p62 expression. Following LC3 knockdown, the viability of itraconazole-treated COLO 205 and HCT 116 cells notably improved. Taken together, the results of the present study suggest that itraconazole may have a beneficial effect on patients with colon cancer, and its underlying molecular mechanisms may be associated with the induction of autophagic cell death.

The purposes of this study were to investigate whether the presence of silane in universal adhesives affects the functions of 10-methacryloyloxydecyl dihydrogen phosphate (MDP) and adhesion to zirconia.Two silane-containing universal adhesives (Scotchbond Universal (SBU) and Clearfil Universal-Bond (CUB)) and two silane-free adhesives (All-Bond Universal (ABU) and SE-Bond primer (SE)) were individually applied on zirconia disks. Time-of-flight secondary-ion-mass-spectrometry (ToF-SIMS) examined the distributions of MDP- and silane-related ions, as well as evidence of zirconium phosphate (ZrP) compounds, on the surface and interfacial regions using a depth profiling mode. The hydrophilicity and resin wettability of the treated zirconia were examined using a contact angle test. For the shear bond strength (SBS) test, the zirconia disks were air-blasted, treated with the assigned adhesives, and bonded with pre-cured composite cylinders using a resin cement. These resin-zirconia assemblies received a bond test after 24-h storage.Both SBU and CUB exhibited silane-related ions and ZrOThe silane content may cause hydroxylation of zirconia and affect MDP adsorption. An acidic pH accelerated the condensation of silanol. The bond performance of the MDP-based adhesive could be influenced by the silane content and other components.

Epidemiological studies have reported that elderly patients with metabolic syndrome (MetS) are significantly more likely to develop neuronal degenerative diseases than those without MetS. Our previous study showed that patients with MetS had significantly higher levels of negatively charged very low density lipoproteins (VLDLs) in the plasma than healthy controls. Highly electronegative VLDL is a key risk factor for endothelial dysfunction and atrial fibrillation. However, the impact of negatively charged VLDL in brain immunity remains unclear. In this study, VLDLs were isolated from normal healthy (nVLDL) individuals or patients with MetS (metVLDL). Primary astroglia and microglia mixed cell cultures as well as microglial-enriched cultures were used to test the effects of VLDLs. Microglia/astroglia activation as evidenced by their morphological changes and production of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), were assessed by immunofluorescence staining and ELISA, respectively. Our results showed that metVLDLs mainly act on the microglia, and not the astroglia, with low concentration (0.05–0.5 μg/mL) inducing cell morphological changes and decreased cellular processes in the microglia. However, nVLDL treatment at these concentrations had no effects on microglia and astroglia. Most importantly, TNF-α and PGE2 levels significantly increased in the microglia treated with metVLDL via a dose-dependent manner. Together, our data indicate that metVLDLs can contribute to MetS-associated brain disorders through microglia activation and neuroinflammation.

The combinations of alumina particle air abrasion (AA) and a 10-methacryloyloxyidecyl-dihyidrogenphosphate (MDP) primer and a tribochemical silica coating (TSC) and a silane–base primer are contemporary pre-cementation treatments for zirconia restorations for bonding with resin cements. However, the stability of zirconia resists the mechanical or chemical preparations. The purpose of this study was to develop an atmospheric-pressure oxygen plasma (OP)-aided silicatization method to enhance the adhesion of resin cements to zirconia. Zirconia discs were prepared to receive surface treatments of different combinations: (1) AA or TSC (2) with or without OP treatment, and (3) a chemical primer (no primer, silane, or a silane–MDP mixture). The surface morphology, hydrophilicity, and chemical compositions were characterized, and the resin–zirconia bond strengths were examined either after 24 h or a thermocycling test. The results indicated that the OP treatment after the TSC facilitated the homogeneous distribution of silane and crosslinking of silica particles, and effectively improved the hydrophilicity. The OP increased the O and Si and reduced the C elemental contents, while the combination of TSC, OP, and silane induced SiOx generation. Among the groups, only the TSC-OP–silane treatment effectively enhanced the bond strength and maintained the adhesion after thermocycling. With these results, the OP aided the silicatization protocol effectively, generated silane crosslinking, and resulted in superior resin–zirconia bond strength and durability compared to the current treatments.

Background: Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an excessive number of immature lymphocytes, including immature precursors of both B- and T cells. ALL affects children more often than adults. Immature lymphocytes lead to arrested differentiation and proliferation of cells. Its conventional treatments involve medication with dexamethasone, vincristine, and other anticancer drugs. Although the current first-line drugs can achieve effective treatment, they still cannot prevent the recurrence of some patients with ALL. Treatments have high risk of recurrence especially after the first remission. Currently, novel therapies to treat ALL are in need. Autophagy and apoptosis play important roles in regulating cancer development. Autophagy involves degradation of proteins and organelles, and apoptosis leads to cell death. These phenomena are crucial in cancer progression. Past studies reported that many potential anticancer agents regulate intracellular signaling pathways. Methods: The authors discuss the recent research findings on the role of autophagy and apoptosis in ALL. Results: The autophagy and apoptosis are widely used in the treatment of ALL. Most studies showed that many agents regulate autophagy and apoptosis in ALL cell models, clinical trials, and ALL animal models. Conclusions: In summary, activating autophagy and apoptosis pathways are the main strategies for ALL treatments. For ALL, combining new drugs with traditional chemotherapy and glucocorticoids treatments can achieve the greatest therapeutic effect by activating autophagy and apoptosis.

Hydrophobic alumina hollow fiber membranes were first used for sucrose concentration in a vacuum membrane distillation (VMD) system. The alumina hollow fiber membranes were prepared using the combined phase inversion and sintering method and then grafted with FAS to impart hydrophobicity. The as-prepared hydrophobic alumina hollow fiber membrane had a high mechanical strength of 191 MPa, a high water contact angle of 140° and a high liquid entry pressure of water of 5.0 bar. Fifty-two hydrophobic alumina hollow fibers were packed into a shell-and-tube module. To evaluate the sucrose concentration performance of the prepared membrane module, the effects of various parameters on the permeate flux, such as the feed flow rate, temperature, vacuum pressure and concentration, were investigated in the VMD system. In the batch sucrose concentration tests, an 8 L 10°Brix sucrose solution was successfully concentrated to 50°Brix by removing 6.4 L of water using the VMD system. At a feed flow rate of 5 L/min and temperature of 70 °C, the permeate flux remained as high as 35.1 and 19.0 kg/m2 h when the sucrose solution was concentrated to 10°Brix and 50°Brix. Furthermore, the permeate flux could be recovered in a new concentration cycle after the membrane module was washed with pure water. The results revealed that the hydrophobic alumina hollow fiber membranes are promising and feasible for concentration processes in a VMD system.

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p

The environmental impacts of brine disposal from seawater desalination plants and wastewater treatment plants represent a subject of growing concern; thus, determining the potential applicability of zero liquid discharge (ZLD) for water treatment is crucial. Membrane-based technologies are a potentially attractive strategy that can be used to reach this goal. Recent studies have highlighted that integrating a series of membrane processes is a viable approach to achieving ZLD for industrial use. However, a relatively limited number of reports have been published on the challenging problems encountered with ZLD approaches. Here, we provide a review of membrane processes that may be used in ZLD approaches and describe their problems as well as potential solutions and innovative technologies for improving their performance. Furthermore, the energy consumption of the different approaches is calculated and analyzed because it represents a major contributor to the total cost, and investments in innovative technologies are discussed. Finally, the prospects for membrane-based ZLD and further research are highlighted.

Background: Different drug dependencies may have unique genetic vulnerabilities. Changes in serotonin availability and function have been linked to addiction. We investigated whether 2 serotonergic polymorphisms, TPH1 A218C (rs1800532) and 5-HTT-linked promoter region (5-HTTLPR) (rs25531), are differently associated with alcohol or opiate dependence. Methods: Alcohol-dependent patients (n = 292), opiate-dependent patients (n = 309), and healthy controls (n = 301) were recruited from the Han Chinese population in Taiwan. Genotypes of TPH1 A218C and 5-HTTLPR polymorphisms were analyzed using a polymerase chain reaction with restriction fragment length polymorphism. Results: The genotype frequencies of the TPH1 A218C polymorphisms were not significantly different in the 3 groups. The genotype frequencies of the 5-HTTLPR S+ (S/S, S/LG, LG/LG) polymorphisms were significantly higher in opiate-dependent patients (χ2 = 8.77, p = 0.01), but not after controlling for the covariates of age, gender, and interaction effect in logistic regression analysis. Moreover, there was a significant interaction between the TPH1 A218C A/C and 5-HTTLPR S+ gene polymorphisms in opiate-dependent (OR 2.72, p = 0.01), but not in alcohol-dependent patients. Conclusions: Our data suggested that there may be a differential genetic vulnerability in serotonergic genes for alcohol and opiate addiction. However, replications of our findings are still needed.

Search is a central visual function. Most of what is known about search derives from experiments where subjects view 2D displays on computer monitors. In the natural world, however, search involves movement of the body in large-scale spatial contexts, and it is unclear how this might affect search strategies. In this experiment, we explore the nature of memory representations developed when searching in an immersive virtual environment. By manipulating target location, we demonstrate that search depends on episodic spatial memory as well as learnt spatial priors. Subjects rapidly learned the large-scale structure of the space, with shorter paths and less head rotation to find targets. These results suggest that spatial memory of the global structure allows a search strategy that involves efficient attention allocation based on the relevance of scene regions. Thus spatial memory may allow less energetically costly search strategies., We would like to thank the support from grants NIH EY05729 and PSI2013-43742. M.P.A. supported by a UAM-Banco Santander Inter-University Cooperation Project and by a “José Castillejo” International Mobility Grant (Ministerio de Educación, Cultura y Deporte, Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de I + D + i 2008–2011)

Huntington's disease (HD) is a genetic and neurodegenerative disease, leading to motor and cognitive dysfunction in HD patients. At cellular level, this disease is caused by the accumulation of mutant huntingtin (HTT) in different cells, and finally results in the dysfunction of different cells. To clean these mutant proteins, ubiquitin-proteasome system (UPS) and autophagy system are two critical pathways in the brain; however, little is known in other peripheral tissues. As mutant HTT affects different tissues progressively and might influence the UPS and autophagy pathways at early stages, we attempted to examine two clearance systems in HD models before the onset. Here, in vitro results showed that the accumulation of UPS signals with time was observed obviously in neuroblastoma and kidney cells, not in other cells. In HD transgenic mice, we observed the impairment of UPS, but not autophagy, over time in the cortex and striatum. In heart and muscle tissues, disturbance of autophagy was observed, whereas dysfunction of UPS was displayed in liver and lung. These results suggest that two protein clearance pathways are disturbed differentially in different tissues before the onset of HD, and enhancement of protein clearance at early stages might provide a potential stratagem to alleviate the progression of HD.

The standard treatment regimen for patients diagnosed with non-small cell lung cancer (NSCLC) with locally advanced stage III disease is concurrent chemoradiotherapy (CCRT). This study investigated the molecular effects of vinca alkaloid vinorelbine (VNR)-based CCRT. We reviewed the records of 68 patients with stage III NSCLC: 42 patients received VNR-based CCRT, and 26 were treated with radiation alone. Human lung adenocarcinoma cells were used in this study to investigate the molecular effects of glucosylceramide synthase inhibition on VNR-based CCRT. There was response rate of 66.7% with CCRT, which was better than the response rate observed with radiation alone (30.8%; P

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder characterized by dysregulation of various genes. Recently, microRNAs (miRNAs) have been reported to be involved in this dysregulation, suggesting that manipulation of appropriate miRNA regulation may have a therapeutic benefit. Here, we report the beneficial effects of miR-196a (miR196a) on HD in cell, transgenic mouse models, and human induced pluripotent stem cells derived from one individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT and pathological aggregates, accompanying the overexpression of miR-196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR-196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathological progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR-196a also decreased HTT expression and pathological aggregates when HD-iPSCs were differentiated into the neuronal stage. Mechanisms of miR-196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, cAMP response element-binding protein pathway, and several neuronal regulatory pathways in vivo. Taken together, these results show that manipulating miR-196a provides beneficial effects in HD, suggesting the potential therapeutical role of miR-196a in HD.

Patients with bipolar II disorder (BDII) have a higher prevalence rate of metabolic disturbance. Whether BDII itself, in addition to its current standard treatment, is a risk factor for metabolic syndrome warrants additional study. The dopamine receptor D3 (DRD3) gene, one of the candidate genes for BDII, is also involved in the dopaminergic system. We investigated whether it is related to changes in the metabolic indices of patients with BDII given 12 weeks of standard treatment. Patients with a first diagnosis of BDII (n = 117) were recruited. Metabolic profiles (cholesterol, triglycerides, fasting serum glucose, body mass index) were measured at baseline and at 2, 8, and 12 weeks. The genotype of the DRD3 Ser9Gly polymorphism (rs6280) was determined. Multiple linear regressions with generalized estimating equation methods were used. Seventy-six (65.0%) patients completed the 12-week intervention. Significant differences in triglyceride change were associated with the DRD3 Ser9Gly genotype (P = 0.03). Patients with the Ser/Ser genotype had significantly smaller triglyceride increases and a lower risk of developing metabolic syndrome than did those with the Ser/Gly+Gly/Gly genotype. However, the associations between the DRD3 Ser9Gly polymorphism with changes in triglyceride level become nonsignificant after correcting for multiple comparisons. We conclude that the DRD3 Ser9Gly polymorphism is nominally associated with changes in triglycerides and metabolic syndrome after 12 weeks of standard BDII treatment.

Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naïve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-α, transforming growth factor [TGF]-β1, interleukin [IL]-6, IL-8 and IL-1β) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P

Objective: Emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder. To investigate biological markers of cytokines and brain-derived neurotrophic factor between bipolar I, bipolar II, and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and, more specifically, provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar II disorder patients from a biological marker perspective. Methods: We enrolled patients with bipolar I disorder (n=234), bipolar II disorder (n=260), other specified bipolar disorder with short duration hypomania (n=243), and healthy controls (n=140). Their clinical symptoms were rated using the Hamilton Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokine (tumor necrosis factor-α, C-reactive protein, transforming growth factor-β1, and interleukin-8) and brain-derived neurotrophic factor levels were measured in each group. Multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain-derived neurotrophic factor levels among the groups. Results: Multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant ( P

1Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2Institute of Behavioral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3Institute of Allied Health Sciences, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan 4Addiction Research Center, National Cheng Kung University, Tainan, Taiwan 5Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 6Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan *Correspondence author: Ru-Band Lu, Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, E-mail: rblu@mail.ncku.edu.tw

Huntington's disease (HD) is a genetically neurodegenerative disease, affecting the central nervous system and leading to mental and motor dysfunctions. To date, there is no cure for HD; as a result, HD patients gradually suffer devastating symptoms, such as chorea, weight loss, depression and mood swings, until death. According to previous studies, the exon 1 region of the huntingtin (HTT) gene with expanded CAG trinucleotide repeats plays a critical role in causing HD. In vitro studies using exon 1 of HTT fused with green fluorescent protein (GFP) gene have facilitated discovering several mechanisms of HD. However, whether this chimera construct exerts similar functions in vivo is still not clear. Here, we report the generation of transgenic mice carrying GFP fused with mutant HTT exon 1 containing 84 CAG trinucleotide repeats, and the evaluation of phenotypes via molecular, neuropathological and behavioral analyses. Results show that these transgenic mice not only displayed neuropathological characteristics, observed either by green fluorescent signals or by immunohistochemical staining, but also progressively developed pathological and behavioral symptoms of HD. Most interestingly, these transgenic mice showed significantly differential expression levels of nuclear aggregates between cortex and striatum regions, highly mimicking selective expression of mutant HTT in HD patients. To the best of our knowledge, this is the first report showing different nuclear diffusion profiling in mouse models with transgenic mice carrying the exon 1 region of mutant HTT. Our model will be beneficial for tracing the expression of mutant HTT and accelerating the understanding of selective pathological progression in HD.

Patients with post-traumatic stress disorder (PTSD) frequently complain of having sleep disturbances, such as insomnia and rapid eye movement (REM) sleep abnormality. Cannabidiol (CBD), a psycho-inactive constituent of marijuana, reduces physiological non-REM (NREM) sleep and REM sleep in normal rats, in addition to generating its anxiolytic effect. However, the effects of CBD on anxiety-induced sleep disturbances remain unclear. Because anxiety progression is caused by persistent stress for a period of time, we employed the repeated combination tests (RCT) consisting of a 50-min open field (OF) and a subsequent 10-min elevated plus-maze (EPM) for four consecutive days to simulate the development of anxiety. Time spent in the centre arena of OF and during open arms of the EPM was substantially decreased in latter days of RCT, suggesting the habituation, which potentially lessens anxiety-mediated behavioural responses, was not observed in current tests. CBD microinjected into the central nucleus of amygdala (CeA) significantly enhanced time spent in centre arena of OF, increased time during the open arms and decreased frequency of entry to the enclosed arms of EPM, further confirming its anxiolytic effect. The decrease of NREM sleep during the first hour and the suppression of REM sleep during hours 4-10 after the RCT represent the similar clinical observations (e.g. insomnia and REM sleep interruption) in PTSD patients. CBD efficiently blocked anxiety-induced REM sleep suppression, but had little effect on the alteration of NREM sleep. Conclusively, CBD may block anxiety-induced REM sleep alteration via its anxiolytic effect, rather than via sleep regulation per se. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Aim of the study Baicalin is an active compound originating from the root of Scutellaria baicalensis Georgi, which has been used for anti-inflammation, anti-bacteria, anti-hypertension, anti-allergy and sedation since ancient China, though the neuronal mechanisms involved in the sedative effect is still unclear. Baicalin possesses the ability to decrease the expression of pro-inflammatory cytokines and nuclear factor (NF)-κB activity. Furthermore, baicalin has demonstrated an anxiolytic-like effect via activation of γ-aminobutyric acid-A (GABA A ) receptors. Pro-inflammatory cytokines (e.g. interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α) and the GABAergic system promote sleep. This study was designed to determine whether the GABA A receptor activation and/or the suppression of pro-inflammatory cytokines mediate(s) baicalin-induced sleep alterations. Materials and methods Baicalin was intracerebroventricularly (ICV) administered 20 min either prior to the beginning of the light period or before the onset of the dark period. Electroencephalogram (EEG) and gross body movement were acquired for sleep analysis. Pharmacological blockade of IL-1 and GABA A receptors were employed to elucidate the involvements of IL-1 and GABA A receptors in baicalin-induced sleep alterations. IL-1β concentrations obtained after baicalin administration in several distinct brain regions were determined by ELISA. Results ICV administration of baicalin decreased slow wave sleep (SWS) during the first 2 h of the light period. Rapid eye movement sleep (REMS) was not altered. The blockade of IL-1β-induced SWS enhancement by baicalin suggests that the antagonism of IL-1 receptors is involved in baicalin-induced SWS decrement during the light period. However, IL-1β concentrations during the light period were not altered after baicalin administration. In contrast, baicalin increased both SWS and REMS during hours 8–10 of the dark (active) period when baicalin was administered at the beginning of the dark period, and its effects were blocked by the GABA A receptor antagonist bicuculline. Conclusion Baicalin exhibits biphasic effects on sleep–wake regulation; the decrease of SWS during the light period and increases of SWS and REMS during the dark period. Inhibition of IL-1 action and enhancement of GABA A receptor activity may mediate baicalin's effects during the light and dark period, respectively.

Microsomal prostaglandin E synthase-1 (mPGES-1) has been regarded as an attractive drug for inflammation-related diseases. In search of new mPGES-1 inhibitors, we performed virtual screening using our traditional Chinese medicine and natural products database (http://tcm.cmu.edu.tw/) and constructed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) using a training set of 30 experimentally tested mPGES-1 inhibitors. The CoMFA and CoMSIA models derived were statistically significant with cross-validated coefficient values of 0.808 for CoMFA and 0.829 for CoMSIA and non-cross-validated coefficient values of 0.829 for CoMFA and 0.980 for CoMSIA. Docking and de novo evolution design gave three top derivatives, 2-O-caffeoyl tartaric acid-Evo_2, glucogallin-Evo_1 and 3-O-feruloylquinic acid-Evo_7 that have higher binding affinities than the control, glutathione. These three derivatives have interactions with Arg70, Arg73, Arg110, Arg126 and Arg38, which ...

A facile and practical protocol was developed for the synthesis of glycosyl iodides using AlI3 generated in situ from cheap aluminum metal and molecular iodine. Furthermore, in combination with iodine-catalyzed per-O-acetylation, sequential synthesis of per-acetylated glycosyl iodides, per-acetylated thioglycosides, selenoglycoside, and O-glycosides from unprotected reducing sugars was also achieved with complete diastereocontrol in a one-pot version. Supplemental material is available for this article. Go to the publisher's online edition of Journal of Carbohydrate Chemistry to view the free supplemental file.

The present investigation revealed how the morphology and crystalline forms of a poly(vinylidene fluoride) (PVDF) membrane, prepared by using the vapor-induced phase separation (VIPS) method, were affected by the temperature at which PVDF was dissolved to form the casting solution. The results showed that there existed an important transition dissolution temperature, being referred to as the “critical dissolution temperature”, across which the morphology and crystalline forms of membranes drastically changed. With a dissolution temperature above the critical dissolution temperature, the prepared membranes were composed of nodules and the size of nodules decreased as the dissolution temperature decreased. And, with a dissolution temperature below the critical, membranes with lacy (bi-continuous) structure were obtained. In addition, the α-crystalline form of PVDF grew faster than the β-form when the dissolution temperature was below the critical, and the β-form became faster and dominant as the dissolution temperature increased to be above the critical. The existence of the critical dissolution temperature was observed for all the three solvents used in the present study, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), and N,M-dimethylformamide (DMF), indicating that the phenomena are general and not limited to a specific solvent. Also, it was observed that the two PVDF/NMP solutions, prepared with dissolution temperatures above and below the critical temperature, responded in different ways when water was added into the solutions. Though both solutions gelled, the solution with higher dissolution temperature started the gelation with a crystallization-initiation gelling process, while the other with a non-crystallization-initiation gelling. We propose that the competition between the two gelling processes play an important role in determining the PVDF membrane morphology and crystalline polymorphs, and the dissolution temperature can change the competition. And the critical dissolution temperature can be interpreted as a dissolution temperature across which the dominant gelling process switched.

A systematic study investigating the effect of membrane material and morphology on the filtration-cycle based on performance of three microfiltration membranes employed for filtering feed solution of Bovine Serum Albumin with yeast suspension has been carried out in dead-end filtration mode. The effects of operating conditions, like feed solution pH, transmembrane pressure (TMP), and membrane cleaning methods have been studied to establish a possible relationship with membrane fouling and to reduce the fouling that occurs during filtration. It was found that filtration resistance increases for the selected membranes with an increase in pH of the feed solution. An increase in TMP increases the permeate flux; however, the effect is not linear due to cake compression at higher TMP. The performance based on the filtration cycle is evaluated, and potential cleaning solutions to restore the permeate flux of filtration after several filtration cycles are identified. Scanning electron microscopy images demonstrate the experimental findings. The expanded polytetrafluoroethylene membrane flushed with caustic soda solution is found to be the most suitable and efficient membrane for microfiltration without significant reduction in flux and protein transmission, even after several filtration cycles.

Protein separation mechanisms by a crossflow ultrafiltration membrane process are investigated using interfacial phenomena analysis of protein–protein and protein–membrane interactions. Varying operating conditions are used and membrane morphological parameters like hydrophilicity and hydrophobicity obtained from contact angle measurement. A single protein solution of bovine serum albumin (BSA) or ovalbumin (OV) or lysozyme (LY) is used in each filtration study case under various operating conditions, such as pH, ionic strength, and different polyethersulfone (PES) membranes with varying surface hydrophobicity and hydrophilicity. Under these conditions analyse of protein–membrane interfacial phenomena and protein separation filtration mechanisms are undertaken. Results indicate that electrostatic forces play an important role in protein deposition on the membrane surface and the rate of protein transmission across the membrane. Findings show that, at the proteins isoelectric point (pI), a hydrophobic membrane causes severe protein adsorption to the membrane surface, allowing a very small percentage of protein to be transported to the permeate side.

Different drug dependencies may have unique genetic vulnerabilities. Changes in serotonin availability and function have been linked to addiction. We investigated whether 2 serotonergic polymorphisms, TPH1 A218C (rs1800532) and 5-HTT-linked promoter region (5-HTTLPR) (rs25531), are differently associated with alcohol or opiate dependence.Alcohol-dependent patients (n = 292), opiate-dependent patients (n = 309), and healthy controls (n = 301) were recruited from the Han Chinese population in Taiwan. Genotypes of TPH1 A218C and 5-HTTLPR polymorphisms were analyzed using a polymerase chain reaction with restriction fragment length polymorphism.The genotype frequencies of the TPH1 A218C polymorphisms were not significantly different in the 3 groups. The genotype frequencies of the 5-HTTLPR S+ (S/S, S/LG, LG/LG) polymorphisms were significantly higher in opiate-dependent patients (x03C7;2 = 8.77, p = 0.01), but not after controlling for the covariates of age, gender, and interaction effect in logistic regression analysis. Moreover, there was a significant interaction between the TPH1 A218C A/C and 5-HTTLPR S+ gene polymorphisms in opiate-dependent (OR 2.72, p = 0.01), but not in alcohol-dependent patients.Our data suggested that there may be a differential genetic vulnerability in serotonergic genes for alcohol and opiate addiction. However, replications of our findings are still needed.

Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor α, nitric oxide, prostaglandin E2 and interleukin 1β). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages.