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1.  Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses 
Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties.
To estimate the clinical effects of zuclopenthixol acetate for the management of acute aggression or violence thought to be due to serious mental illnesses, in comparison to other drugs used to treat similar conditions.
Search methods
We searched the Cochrane Schizophrenia’s Group Trials Register (July 2011). We supplemented this by citation searching and personal contact with authors and relevant pharmaceutical companies.
Selection criteria
All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs.
Data collection and analysis
Two review authors extracted and cross-checked data independently. We calculated fixed-effect relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. We analysed by intention-to-treat. We used mean differences (MD) for continuous variables.
Main results
We found no data for the primary outcome, tranquillisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n = 40, 1 RCT, RR 0.60, 95% CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n = 134, 3 RCTs, RR 1.49, 95% CI 0.97 to 2.30) although additional use of benzodiazepines was less (n = 50, 1 RCT, RR 0.03, 95% CI 0.00 to 0.47). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n = 70, 1 RCT, RR 0.39, 95% CI 0.18 to 0.84, NNT 4, CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n = 148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74, 95% CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders (< 20%). Three studies found no difference in the proportion of people getting blurred vision/dry mouth (n = 192, 2 RCTs, RR at 24 hours 0.90, 95% CI 0.48 to 1.70). Similarly, dizziness was equally infrequent for those allocated zuclopenthixol acetate compared with haloperidol (n = 192, 2 RCTs, RR at 24 hours 1.15, 95% CI 0.46 to 2.88). There was no difference between treatments for leaving the study before completion (n = 522, RR 0.85, 95% CI 0.31 to 2.31). One study reported no difference in adverse effects and outcome scores, when high dose (50-100 mg/injection) zuclopenthixol acetate was compared with low dose (25-50 mg/injection) zuclopenthixol acetate.
Authors’ conclusions
Recommendations on the use of zuclopenthixol acetate for the management of psychiatric emergencies in preference to ‘standard’ treatment have to be viewed with caution. Most of the small trials present important methodological flaws and findings are poorly reported. This review did not find any suggestion that zuclopenthixol acetate is more or less effective in controlling aggressive acute psychosis, or in preventing adverse effects than intramuscular haloperidol, and neither seemed to have a rapid onset of action. Use of zuclopenthixol acetate may result in less numerous coercive injections and low doses of the drug may be as effective as higher doses. Well-conducted pragmatic randomised controlled trials are needed.
PMCID: PMC4175533  PMID: 22513898
Acute Disease; Aggression [*drug effects]; Antipsychotic Agents [*therapeutic use]; Benzodiazepines [therapeutic use]; Clopenthixol [*therapeutic use]; Dibenzothiazepines [therapeutic use]; Haloperidol [therapeutic use]; Psychotic Disorders [*drug therapy]; Randomized Controlled Trials as Topic; Schizophrenia [*drug therapy]; Violence [psychology]; Humans
2.  Atypical antipsychotics for people with both schizophrenia and depression 
Many people (up to 50%) with schizophrenia also have co-morbid depression. It has been suggested that new atypical antipsychotic drugs are beneficial for people with the two diagnoses.
To assess the effects of atypical antipsychotic drugs on people who have a diagnosis of both schizophrenia and depression.
Search methods
We searched the Cochrane Schizophrenia’s Group Register (to March 2006). We supplemented this by citation searching and personal contact with authors and relevant pharmaceutical companies.
Selection criteria
We included randomised clinical trials of atypical antipsychotic drugs used specifically for the treatment of people with a diagnosis of both schizophrenia and depression.
Data collection and analysis
We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).
Main results
We found 878 citations but were only able to include three studies (five reports). One trial found no significant difference between quetiapine and haloperidol for the outcome of ‘less than 50% reduction in PANSS score’ (n=180, RR 0.91 CI 0.8 to 1.0). Those allocated sulpiride had significantly lower depression scores compared with people given chlorpromazine (1 RCT, n=36, WMD CPRS −0.70 CI −1.2 to −0.2). Again, however, in the quetiapine versus haloperidol comparison, the continuous scoring did not highlight differences (1 RCT, n=180, WMD PANSS depression change −0.57 CI −1.4 to 0.30). When clozapine was compared with any other antipsychotic drug plus an antidepressant or placebo, clozapine constantly scored better on Hamilton scores (1 RCT, n=29, WMD vs antipsychotic + mianserin −5.53 CI −8.23 to −2.8; 1 RCT, n=32, WMD vs antipsychotic + meclobemide −4.35 CI −6.7 to −2.03; 1 RCT, n=33, WMD vs antipsychotic + placebo −6.35 CI −8.6 to −4.1).
Authors’ conclusions
There are too few data to guide patients, carers, clinicians or policy makers. Current practice has to be guided by evidence other than that derived from randomised trials and more trials in this important area are indicated.
PMCID: PMC4171386  PMID: 18254078
Antidepressive Agents [therapeutic use]; Antipsychotic Agents [* therapeutic use]; Chemotherapy, Adjuvant; Comorbidity; Depression [* drug therapy]; Randomized Controlled Trials as Topic; Schizophrenia [* drug therapy]; Humans
3.  Genome wide screening of RNAi factors of Sf21 cells reveal several novel pathway associated proteins 
BMC Genomics  2014;15(1):775.
RNA interference (RNAi) leads to sequence specific knock-down of gene expression and has emerged as an important tool to analyse gene functions, pathway analysis and gene therapy. Although RNAi is a conserved cellular process involving common elements and factors, species-specific differences have been observed among different eukaryotes. Identification of components for RNAi pathway is pursued intensively and successful genome-wide screens have been performed for components of RNAi pathways in various organisms. Functional comparative genomics analysis offers evolutionary insight that forms basis of discoveries of novel RNAi-factors within related organisms. Keeping in view the academic and commercial utility of insect derived cell-line from Spodoptera frugiperda, we pursued the identification and functional analysis of components of RNAi-machinery of Sf21 cell-line using genome-wide application.
The genome and transcriptome of Sf21 was assembled and annotated. In silico application of comparative genome analysis among insects allowed us to identify several RNAi factors in Sf21 line. The candidate RNAi factors from assembled genome were validated by knockdown analysis of candidate factors using the siRNA screens on the Sf21-gfp reporter cell-line. Forty two (42) potential factors were identified using the cell based assay. These include core RNAi elements including Dicer-2, Argonaute-1, Drosha, Aubergine and auxiliary modules like chromatin factors, RNA helicases, RNA processing module, signalling allied proteins and others. Phylogenetic analyses and domain architecture revealed that Spodoptera frugiperda homologs retained identity with Lepidoptera (Bombyx mori) or Coleoptera (Tribolium castaneum) sustaining an evolutionary conserved scaffold in post-transcriptional gene silencing paradigm within insects.
The database of RNAi-factors generated by whole genome association survey offers comprehensive outlook about conservation as well as specific differences of the proteins of RNAi machinery. Understanding the interior involved in different phases of gene silencing also offers impending tool for RNAi-based applications.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-775) contains supplementary material, which is available to authorized users.
PMCID: PMC4247154  PMID: 25199785
RNA interference; siRNA screening; Sf21 cells; Genome-wide screening; Insect RNAi; Spodoptera frugiperda
4.  Two Structurally Different Dienelactone Hydrolases (TfdEI and TfdEII) from Cupriavidus necator JMP134 Plasmid pJP4 Catalyse Cis- and Trans-Dienelactones with Similar Efficiency 
PLoS ONE  2014;9(7):e101801.
In this study, dienelactone hydrolases (TfdEI and TfdEII) located on plasmid pJP4 of Cupriavidus necator JMP134 were cloned, purified, characterized and three dimensional structures were predicted. tfdEI and tfdEII genes were cloned into pET21b vector and expressed in E. coli BL21(DE3). The enzymes were purified by applying ultra-membrane filtration, anion-exchange QFF and gel-filtration columns. The enzyme activity was determined by using cis-dienelactone. The three-dimensional structure of enzymes was predicted using SWISS-MODEL workspace and the biophysical properties were determined on ExPASy server. Both TfdEI and TfdEII (Mr 25 kDa) exhibited optimum activity at 37°C and pH 7.0. The enzymes retained approximately 50% of their activity after 1 h of incubation at 50°C and showed high stability against denaturing agents. The TfdEI and TfdEII hydrolysed cis-dienelactone at a rate of 0.258 and 0.182 µMs−1, with a Km value of 87 µM and 305 µM, respectively. Also, TfdEI and TfdEII hydrolysed trans-dienelactone at a rate of 0.053 µMs−1 and 0.0766 µMs−1, with a Km value of 84 µM and 178 µM, respectively. The TfdEI and TfdEII kcat/Km ratios were 0.12 µM−1s−1and 0.13 µM−1s−1 and 0.216 µM−1s−1 and 0.094 µM−1s−1 for for cis- and trans-dienelactone, respectively. The kcat/Km ratios for cis-dienelactone show that both enzymes catalyse the reaction with same efficiency even though Km value differs significantly. This is the first report to characterize and compare reaction kinetics of purified TfdEI and TfdEII from Cupriavidus necator JMP134 and may be helpful for further exploration of their catalytic mechanisms.
PMCID: PMC4108320  PMID: 25054964
5.  Loss of nuclear PTEN in HCV-infected human hepatocytes 
Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11.
The intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots of nuclear and cytoplasmic proteins. Effects of PTEN depletion were examined by comparing expression arrays of uninfected cells with either HCV-infected or vmr11-transfected cells. Target genes suggested by array analyses were validated by Western blot. The influence of nuclear PTEN deficiency on virus production was determined by quantitative analysis of HCV genomic RNA in culture media of infected hepatocytes.
Import of PTEN to the nucleus relies on the interaction of Transportin-2 and PTEN proteins; we show that depletion of Transportin-2 by HCV infection or by the introduction of vmr11 in uninfected cells results in reduced nuclear PTEN. In turn, nuclear PTEN insufficiency correlates with increased virus production and the induction of γ-H2AX, a marker of DNA double-strand breaks and genomic instability.
An HCV-derived small non-coding RNA inhibits Transportin-2 and PTEN translocation to the nucleus, suggesting a direct viral role in hepatic oncogenesis.
PMCID: PMC4114100  PMID: 25075209
HCV infection; Nuclear PTEN restriction
6.  Lower motor neuron paralysis with extensive cord atrophy in parainfectious acute transverse myelitis 
We describe a young patient of acute transverse myelitis (ATM) who developed true lower motor neuron (LMN) type flaccid paraplegia as a result of anterior horn cell damage in the region of cord inflammation that extended from conus upwards up to the D4 transverse level. We infer that flaccidity in acute phase of ATM is not always due to spinal shock and may represent true LMN paralysis particularly if the long segment myelits is severe and extending up to last spinal segment.
PMCID: PMC4162027  PMID: 25221410
Acute disseminated encephalomyelitis; acute transverse myelitis; ascending myelitis; magnetic resonance imaging; parainfectious myelitis
7.  Comparison of Protein Acetyltransferase Action of CRTAase with the Prototypes of HAT 
The Scientific World Journal  2014;2014:578956.
Our laboratory is credited for the discovery of enzymatic acetylation of protein, a phenomenon unknown till we identified an enzyme termed acetoxy drug: protein transacetylase (TAase), catalyzing the transfer of acetyl group from polyphenolic acetates to receptor proteins (RP). Later, TAase was identified as calreticulin (CR), an endoplasmic reticulum luminal protein. CR was termed calreticulin transacetylase (CRTAase). Our persistent study revealed that CR like other families of histone acetyltransferases (HATs) such as p300, Rtt109, PCAF, and ESA1, undergoes autoacetylation. The autoacetylated CR was characterized as a stable intermediate in CRTAase catalyzed protein acetylation, and similar was the case with ESA1. The autoacetylation of CR like that of HATs was found to enhance protein-protein interaction. CR like HAT-1, CBP, and p300 mediated the acylation of RP utilizing acetyl CoA and propionyl CoA as the substrates. The similarities between CRTAase and HATs in mediating protein acylation are highlighted in this review.
PMCID: PMC3932232  PMID: 24688408
8.  Hepatitis B and/or C co-infection in HIV infected patients: A study in a tertiary care centre from south India 
Background & objectives:
Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in human immunodeficiency virus (HIV) infected individuals results in increased hepatic complications. We undertook this study to evaluate the presence of HBV and HCV in HIV infected individuals attending a tertiary care centre in southern India.
A total of 120 cases with HIV infection and 120 healthy adult control subjects were included in the study. Samples were tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies by enzyme linked immunosorbent assay (ELISA) method. HBsAg and anti-HCV positive serum samples were further tested for the presence of hepatitis B e antigen (HBeAg), anti-HBe antibodies, HBV-DNA and HCV-RNA.
The most common mode of transmission was sexual promiscuity (79%), followed by spouse positivity (15%) and history of blood transfusion (6%). HBsAg and anti-HCV were positive in 18 (15%) and 10 (8.3%) HIV infected patients; the corresponding figures in healthy controls being 2 (1.6%) 0 (0%) (P<0.0001). Among HIV infected patients, presence of HBeAg and anti-HBe antibodies was seen in 33.3 and 55.5 per cent, respectively; both HBeAg and anti-HBe antibodies were negative in 11.1 per cent. HBV DNA and HCV RNA were positive in 10 of 18 and in all anti-HCV positive samples. Triple infection with HBV, HCV and HIV was seen in three patients. CD4+ T-lymphocyte count less than 200/μl was seen in 22 of 28 co-infected cases.
Interpretation & conclusions:
The findings of our study showed presence of HBV (15%) and HCV (8.3%) co-infections in HIV positive patients which was higher than that seen in HIV negative controls. Co-infection with HBV and HCV is a common problem in HIV infected patients in India. Hence, all HIV patients need to be routinely tested for markers of HBV and HCV infection.
PMCID: PMC3978987  PMID: 24521641
Co-infection; hepatitis B virus; hepatitis C virus; human immunodeficiency virus
9.  Synthesis of cobalt nanoparticles on Si (100) by swift heavy ion irradiation 
Nanoscale Research Letters  2013;8(1):433.
We report the growth and characterization of uniform-sized nanoparticles of cobalt on n-type silicon (100) substrates by swift heavy ion (SHI) irradiation. The Co thin films of 25-nm thicknesses were grown by e-beam evaporation and irradiated with two different types of ions, 45-MeV Li3+ and 100-MeV O7+ ions with fluences ranging from 1 × 1011 to 1 × 1013 ions/cm2. SHI irradiation, with the beam rastered over the area of the film, resulted in the restructuring of the film into a dense array of Co nanostructures. Surface topography studied by atomic force microscopy revealed narrowed size distributions, with particle sizes ranging from 20 to 50 nm, formed through a self-organized process. Ion fluence-dependent changes in crystallinity of the Co nanostructures were determined by glancing angle X-ray diffraction. Rutherford backscattering spectroscopy analysis showed the absence of beam-induced mixing in this system. Surface restructuring and beam-induced crystallization are the dominant effects, with the nanoparticle size and density being dependent on the ion fluence. Results are analyzed in the context of molecular dynamics calculations of electron-lattice energy transfer.
PMCID: PMC3853973  PMID: 24138985
Cobalt nanostructures; Ion irradiation; Surface restructuring; Atomic force microscopy; Thin films
10.  Isolation and characterization of a Bacillus subtilis strain that degrades endosulfan and endosulfan sulfate 
3 Biotech  2013;4(5):467-475.
Endosulfan has emerged as a major environmental menace worldwide due to  extensive usage and environmental persistence, seeking its remedial by a cheaper and efficient means. Therefore, natural resource (soil) was explored to search a potential candidate for biodegradation of endosulfan. A soil bacterium was enriched and isolated by applying a strong nutritional selection pressure, using a non-sulfur medium supplemented with endosulfan as sole source sulfur. The microbial strain was found to degrade endosulfan as well as its equally toxic metabolite endosulfan sulfate to non-toxic metabolites (endodiol and endosulfan lactone) very efficiently (up to 94.2 %) within 7 days, estimated qualitatively by thin layer chromatography and quantitatively by gas chromatography-electron capture detection methods. The isolate was characterized for its morphological, physiological, biochemical and 16S rRNA sequencing and identified as a new strain of Bacillus subtilis with strain designation AKPJ04, which was deposited with accession number Microbial Type Culture Collection and Gene Bank (MTCC) 8561, at MTCC, Institute of Microbial Technology, Chandigarh, India. The partial 16S rRNA sequence was submitted to Genbank, Maryland, USA, with the accession number EU 258611. The primary investigation for endosulfan degrading gene(s) localization suggested its location on chromosomal DNA.
Electronic supplementary material
The online version of this article (doi:10.1007/s13205-013-0176-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4162894
Biodegradation; Endosulfan; Bacillus subtilis; Characterization
11.  Assessment of hemostatic changes after crystalloid and colloid fluid preloading in trauma patients using standard coagulation parameters and thromboelastography 
Saudi Journal of Anaesthesia  2013;7(1):48-56.
The choice of an ideal fluid administered post trauma and its subsequent influence on coagulation still poses a clinical dilemma. Hence, this study was designed to assess the influence of in vivo hemodilution with various fluid preparations (4% gelatin, 6% hydoxyethyl starch (HES), Ringer's lactate, 0.9% normal saline) on coagulation using standard coagulation parameters and real-time thromboelastography (TEG) in patients undergoing elective surgery post trauma.
In a randomized, double-blind study, 100 patients of either sex and age, belonging to ASA Grades I and II, scheduled for elective surgeries were allocated into four groups of 25 each according to the type of fluid infused. Group G (4% gelatin), Group N (0.9% normal saline), Group R (Ringer's lactate), and Group H (6% HES) received preloading with 1 L of fluid according to the group. The coagulation status of the patients was assessed during perioperative period (before surgery, after fluid preloading, and at the end of the surgery) using both conventional coagulation analysis and TEG.
Statistical Analysis:
Analysis of variance (ANOVA), post hoc and Pearson Chi-square test were used.
In all the patients preloaded with gelatin, there was a significant increase in prothrombin time index (PTI; 14.88±0.90 vs. 13.78±3.01, P<0.001) and international normalized ratio (INR; 1.12±0.09 vs. 1.09±0.19, P<0.05) compared to the baseline value. An increase was observed in these parameters in the postoperative period also. In the HES group, there was statistically significant increase in PT time (15.70±1.51 vs. 13.74±0.75, P=0.01) and INR (1.20±0.15 vs. 1.03±0.17, P<0.001) as compared to the baseline. In the intergroup comparisons, the patients preloaded with HES had a significant increase in INR (1.20±0.15 vs. 1.12±0.09, P=0.04) and reaction time (R time; 6.84±2.55 min vs. 4.79±1.77 min, P=0.02) as compared to the gelatin group. The fall in coagulation time (k time; 2.16±0.98 vs. 3.94±2.6, P=0.02), rise in maximum amplitude (MA; 61.94±14.08 vs. 50.11±14.10, P=0.04), and rise in A20 (56.17±14.66 vs. 43.11±14.24, P=0.05) were more in patients preloaded with RL as compared to the HES group. 100% patients in the gelatin group, 84.2% patients in the NS group, 94.4% patients in the RL group, and 66.7% patients in the HES group had hypocoagulable (R time > 14 min) state in the postoperative period.
Crystalloids are optimal volume expanders in trauma, with RL having beneficial effects on coagulation system (decrease in k time and increase in MA and A20). Among the colloids, HES 6% (130/0.4) affects coagulation parameters (increase in PTI, INR, R time, k time) more than gelatin. Trial registration (protocol number-IEC/NP-189/2011).
PMCID: PMC3657925  PMID: 23717233
Colloids; crystalloids; thromboelastography; trauma
12.  Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens 
AIDS Research and Human Retroviruses  2011;27(10):1099-1109.
The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.
PMCID: PMC3482873  PMID: 21406030
13.  Production of HIV Particles Is Regulated by Altering Sub-Cellular Localization and Dynamics of Rev Induced by Double-Strand RNA Binding Protein 
PLoS ONE  2011;6(2):e16686.
Human immunodeficiency virus (HIV)-1 encoded Rev is essential for export from the nucleus to the cytoplasm, of unspliced and singly spliced transcripts coding for structural and nonstructural viral proteins. This process is spatially and temporally coordinated resulting from the interactions between cellular and viral proteins. Here we examined the effects of the sub-cellular localization and dynamics of Rev on the efficiency of nucleocytoplasmic transport of HIV-1 Gag transcripts and virus particle production. Using confocal microscopy and fluorescence recovery after bleaching (FRAP), we report that NF90ctv, a cellular protein involved in Rev function, alters both the sub-cellular localization and dynamics of Rev in vivo, which drastically affects the accumulation of the viral protein p24. The CRM1–dependent nuclear export of Gag mRNA linked to the Rev Response Element (RRE) is dependent on specific domains of the NF90ctv protein. Taken together, our results demonstrate that the appropriate intracellular localization and dynamics of Rev could regulate Gag assembly and HIV-1 replication.
PMCID: PMC3043055  PMID: 21364984
14.  Delayed presentation of spinal cord trauma 
PMCID: PMC3123003  PMID: 21716836
15.  Zuclopenthixol Dihydrochloride for Schizophrenia 
Schizophrenia Bulletin  2009;35(5):855-856.
PMCID: PMC2728825  PMID: 19661197
16.  Atypical Antipsychotics for People With Both Schizophrenia and Depression 
Schizophrenia Bulletin  2009;35(2):297-298.
PMCID: PMC2659320  PMID: 19244590
17.  Antipsychotic Medication for Childhood-Onset Schizophrenia 
Schizophrenia Bulletin  2007;33(5):1082-1083.
PMCID: PMC2632357  PMID: 17670793
cochrane; childhood onset; schizophrenia
18.  RNA interference: a multifaceted innate antiviral defense 
Retrovirology  2008;5:17.
The RNA interference mechanism utilizes short RNA duplexes to either suppress or induce target gene expression. Post-transcriptional regulation mediated by microRNA is an integral component of innate antiviral defense. The magnitude and the efficiency of viral restriction guided by RNA-based defenses, as well as the full physiological implication of host-pathogen engagement, constitute exciting areas of investigation in the biology of non-coding RNAs.
PMCID: PMC2259359  PMID: 18241347
19.  Modulation of RANTES expression by HCV core protein in liver derived cell lines 
BMC Gastroenterology  2007;7:21.
Hepatitis C virus (HCV) infection is associated with high percentage of chronicity which implies the ability of the virus to evade or modulate host cell immune system. Modulation of chemokines, such as RANTES may be part of the virus induced pathogenicity. We examined the effect of core and structural proteins of HCV on RANTES expression in two liver derived cell lines, HepG2 and Chang Liver (CHL).
HepG2 and Chang Liver (CHL) cell lines were established and selected for constitutive expression of HCV core and structural genes. Flow cytometry and quantitative RT-PCR analysis were performed to examine the effect of HCV core protein on RANTES expression. Luciferase analysis after RANTES-Luc-promoter transfection of established cell lines was assayed by luminometer measurements (RLU) of RANTES promoter activity. IRF-1 and IRF-7 expression was then examined by immunoblotting analysis.
Results of flow cytometry and RT-PCR analysis indicated that RANTES is differentially regulated by HCV core protein in the two cell lines examined as its expression was inhibited in HepG2 cells, by a reduction of RANTES promoter activity. Conversely, RANTES protein and mRNA were induced by the core protein in CHL cells, through the induction of the promoter.
Since HCV genome modulates IRF-1 and IRF-7 in replicon system and IRF-1, IRF-3 and IRF-7 have been reported to regulate RANTES promoter in various cell systems, analysis of the mechanism underlying RANTES modulation by the core protein revealed that IRF-1 expression was induced in HepG2 cells by the core protein, whereas in CHL cells it was expressed at a very low level that was not influenced by transfection with the core protein construct. This suggested that IRF-1 level may mediate the expression of RANTES in cell lines of liver origin. The effect of the core protein on RANTES promoter was countered by co-transfection with NF90, a double-stranded-RNA binding protein that activates some interferon response genes and acts as a component of cell defense against viral infection.
HCV core protein have opposite effects on the expression of RANTES in different cell types in vitro, possibly reflecting a similar scenario in different microenvironments in vivo.
PMCID: PMC1913921  PMID: 17565659
20.  Nuclear Factor 90(NF90) targeted to TAR RNA inhibits transcriptional activation of HIV-1 
Retrovirology  2007;4:41.
Examination of host cell-based inhibitors of HIV-1 transcription may be important for attenuating viral replication. We describe properties of a cellular double-stranded RNA binding protein with intrinsic affinity for HIV-1 TAR RNA that interferes with Tat/TAR interaction and inhibits viral gene expression.
Utilizing TAR affinity fractionation, North-Western blotting, and mobility-shift assays, we show that the C-terminal variant of nuclear factor 90 (NF90ctv) with strong affinity for the TAR RNA, competes with Tat/TAR interaction in vitro. Analysis of the effect of NF90ctv-TAR RNA interaction in vivo showed significant inhibition of Tat-transactivation of HIV-1 LTR in cells expressing NF90ctv, as well as changes in histone H3 lysine-4 and lysine-9 methylation of HIV chromatin that are consistent with the epigenetic changes in transcriptionally repressed gene.
Structural integrity of the TAR element is crucial in HIV-1 gene expression. Our results show that perturbation Tat/TAR RNA interaction by the dsRNA binding protein is sufficient to inhibit transcriptional activation of HIV-1.
PMCID: PMC1910605  PMID: 17565699
21.  The silent defense: Micro-RNA directed defense against HIV-1 replication 
Retrovirology  2007;4:26.
MicroRNAs play critical role in regulating gene expression. MicroRNA profile of particular cell type bears the signature of cell type specific gene expression. Given that viral pathogens replicate by evading host defenses, research is now focused on the miRNA-regulated genes that critically regulate HIV-1 propagation in human host cells.
PMCID: PMC1865552  PMID: 17430590
22.  Nuclear Factor 90, a cellular dsRNA binding protein inhibits the HIV Rev-export function 
Retrovirology  2006;3:83.
The HIV Rev protein is known to facilitate export of incompletely spliced and unspliced viral transcripts to the cytoplasm, a necessary step in virus life cycle. The Rev-mediated nucleo-cytoplasmic transport of nascent viral transcripts, dependents on interaction of Rev with the RRE RNA structural element present in the target RNAs. The C-terminal variant of dsRNA-binding nuclear protein 90 (NF90ctv) has been shown to markedly attenuate viral replication in stably transduced HIV-1 target cell line. Here we examined a mechanism of interference of viral life cycle involving Rev-NF90ctv interaction.
Since Rev:RRE complex formations depend on protein:RNA and protein:protein interactions, we investigated whether the expression of NF90ctv might interfere with Rev-mediated export of RRE-containing transcripts. When HeLa cells expressed both NF90ctv and Rev protein, we observed that NF90ctv inhibited the Rev-mediated RNA transport. In particular, three regions of NF90ctv protein are involved in blocking Rev function. Moreover, interaction of NF90ctv with the RRE RNA resulted in the expression of a reporter protein coding sequences linked to the RRE structure. Moreover, Rev influenced the subcellular localization of NF90ctv, and this process is leptomycin B sensitive.
The dsRNA binding protein, NF90ctv competes with HIV Rev function at two levels, by competitive protein:protein interaction involving Rev binding to specific domains of NF90ctv, as well as by its binding to the RRE-RNA structure. Our results are consistent with a model of Rev-mediated HIV-1 RNA export that envisions Rev-multimerization, a process interrupted by NF90ctv.
PMCID: PMC1713252  PMID: 17125513
23.  Coordination of Transcription Factor Phosphorylation and Histone Methylation by the P-TEFb Kinase during Human Immunodeficiency Virus Type 1 Transcription 
Journal of Virology  2004;78(24):13522-13533.
The human immunodeficiency virus type 1 (HIV-1) Tat protein recruits positive transcription elongation factor b (P-TEFb) to the transactivation response (TAR) RNA structure to facilitate formation of processive transcription elongation complexes (TECs). Here we examine the role of the Tat/TAR-specified cyclin-dependent kinase 9 (CDK9) kinase activity in regulation of HIV-1 transcription elongation and histone methylation. In HIV-1 TECs, P-TEFb phosphorylates the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) and the transcription elongation factors SPT5 and Tat-SF1 in a Tat/TAR-dependent manner. Using in vivo chromatin immunoprecipitation analysis, we demonstrate the following distinct properties of the HIV-1 transcription complexes. First, the RNAP II CTD is phosphorylated at Ser 2 and Ser 5 near the promoter and at downstream coding regions. Second, the stable association of SPT5 with the TECs is dependent upon P-TEFb kinase activity. Third, P-TEFb kinase activity is critical for the induction of methylation of histone H3 at lysine 4 and lysine 36 on HIV-1 genes. Flavopiridol, a potent P-TEFb kinase inhibitor, inhibits CTD phosphorylation, stable SPT5 binding, and histone methylation, suggesting that its potent antiviral activity is due to its ability to inhibit several critical and unique steps in HIV-1 transcription elongation.
PMCID: PMC533906  PMID: 15564463
24.  Restriction of Human Immunodeficiency Virus Type 1 Rev Function in Murine A9 Cells Involves the Rev C-Terminal Domain 
Journal of Virology  2003;77(5):3084-3090.
The human immunodeficiency virus type 1 (HIV-1) Rev and human T-cell leukemia virus type 1 (HTLV-1) Rex proteins are essential for the expression of viral structural proteins and productive infection. Both contain a nuclear export signal (NES) in their C-terminal domain and a nuclear localization signal (NLS) in their N-terminal domain. The NES and NLS are necessary for shuttling between nucleus and cytoplasm and are therefore indispensable for the transport of unspliced and singly spliced viral transcripts. HIV-1 Rev function is restricted in A9 cells, a murine fibroblast cell line, whereas HTLV-1 Rex is functional in these cells. Immunofluorescence studies with RevGFP fusion protein demonstrate normal import and export of Rev in A9 cells. To ascertain which domains of Rev are necessary for the restriction of Rev function in A9 cells, we studied a chimeric construct in which the NES domain of Rev was exchanged with Rex C-terminal amino acids 79 to 95, the Rev1-79/Rex79-95 chimera, which restored Rev function in A9 cells. In addition, overexpression of a truncated Rev containing the Rev C-terminal domain in the presence of wild-type Rev, led to restoration of Rev function in A9 cells. These results suggest that the C-terminal domain of HIV-1 Rev plays an important role in restricting Rev function in murine cells.
PMCID: PMC149738  PMID: 12584334
25.  Cell Cycle-Regulated Transcription by the Human Immunodeficiency Virus Type 1 Tat Transactivator 
Journal of Virology  2000;74(2):652-660.
Cyclin-dependent kinases are required for the Tat-dependent transition from abortive to productive elongation. Further, the human immunodeficiency virus type 1 (HIV-1) Vpr protein prevents proliferation of infected cells by arresting them in the G2 phase of the cell cycle. These findings suggest that the life cycle of the virus may be integrally related to the cell cycle. We now demonstrate by in vitro transcription analysis that Tat-dependent transcription takes place in a cell cycle-dependent manner. Remarkably, Tat activates gene expression in two distinct stages of the cell cycle. Tat-dependent long terminal repeat activation is observed in G1. This activation is TAR dependent and requires a functional Sp1 binding site. A second phase of transactivation by Tat is observed in G2 and is TAR independent. This later phase of transcription is enhanced by a natural cell cycle blocker of HIV-1, vpr, which arrests infected cells at the G2/M boundary. These studies link the HIV-1 Tat protein to cell cycle-specific biological functions.
PMCID: PMC111584  PMID: 10623726

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