Synergistic Biomedical Potential and Molecular Docking Analyses of Coumarin-Triazole Hybrids as Tyrosinase Inhibitors: Design, Synthesis, In Vitro Profiling, and In Silico Studies.

The tyrosinase enzyme has a vital role in the browning of vegetables and fruits and the biosynthesis of melanin. In this work, we synthesized a diverse library of coumarin-triazole hybrids, and these compounds were characterized by using suitable analytical techniques. Our research work extends beyond the synthetic effort to explore the therapeutic potential of these compounds. We put the synthesized compounds through meticulous in vitro screening against the tyrosinase enzyme, and these coumarin derivatives evinced good IC50 values in the range of 0.339 ± 0.25 µM to 14.06 ± 0.92 µM. In the library of synthesized compounds, six compounds were found to be more potent than standard ascorbic acid (IC50 = 11.5 ± 1.00), and among them, 17e and 17f, being the most active, exhibited remarkable anti-tyrosinase potential, with IC50 values of 0.339 ± 0.25 µM and 3.148 ± 0.23 µM, respectively. Furthermore, an in silico modeling study was carried out to determine the key interactions of these compounds with the tyrosinase protein (PDB ID: 2Y9X) and thus to authenticate our experimental findings. The quantitative SAR studies exhibited a good correlation between the synthesized derivatives of coumarin and their anti-tyrosinase activity. The docking studies verified the experimental results, and ligand 17e showed good interaction with the core residues of tyrosinase. This study not only expands the field of coumarin-triazole hybrid synthesis but also provides valuable insights for the development of novel tyrosinase inhibitors.

Innovative intuitionistic fuzzy fairly aggregation operators with linear programming based decision-making approach.

Intuitionistic fuzzy set (InFS) theory represents a paradigm change in handling strategic planning challenges, one of the most important issues in the physical realm. Aggregation operators (AOs) have a big part to play in making decisions, especially when there are many things to think about. When there isn't enough information, it's hard to come up with good accretion solutions. This article aims to establish innovative operational rules and AOs in an intuitionistic fuzzy enviroment. To accomplish this aim, we establish novel operational laws that utilize the notion of proportional distribution to provide a neutral or fairly remedy for InFSs. Furthermore, using suggested fairly AOs with evaluations from multiple "decision-makers" (DMs) and partial weight details under InFS, a fairly "multi-criteria decision-makin" (MCDM) method is constructed. A linear programming model is used to figure out the weights of criteria when only some of the information is known. In addition, a rigorous implementation of the proposed method is provided to illustrate the efficacy of the proposed AOs.

Influence of bio fabricated manganese oxide nanoparticles for effective callogenesis of Moringa oleifera Lam.

The use of nanoscale fertilizers to boost crop output has increased in recent years. Nanoparticles (NPs) can stimulate the biosynthesis of bioactive compounds in plants. It is the first report on biosynthesized manganese oxide nanoparticles (MnO-NPs) that mediate in-vitro callus induction of Moringa oleifera. To achieve better biocompatibility the leaf extract of Syzygium cumini was used to synthesize MnO-NPs. Scanning electron microscope SEM revealed spherical shaped morphology of MnO-NPs with an average diameter of 36 ± 0.3 nm. Energy-dispersive X-ray spectroscopy (EDX) depicted the formation of pure MnO-NPs. X-ray diffraction (XRD) and Fourier Transform Infrared (FTIR) authenticate the crystalline structure. UV-visible absorption spectroscopy depicted the activity of MnO-NPs under visible light. The biosynthesized MnO-NPs were concentration-dependent and revealed promising results in callus induction of Moringa oleifera. It was found that MnO-NPs enhance callus production of Moringa oleifera and keep the callus infection free by providing an optimum environment for rapid growth and development. Therefore MnO-NPs synthesized through the green process can be utilized in tissue culture studies. This study concludes that MnO is one of the essential plant nutrients that have tailored nutritive properties at a nano scale.

Stuttering related and psychosocial predictors of impact of stuttering.

OBJECTIVE: To investigate the psychosocial factors having an impact on persons with a stuttering problem. Methods: The correlation study was conducted from October 2016 to February 2018 at hospitals, speech clinics and educational institutes of Lahore. The sample comprised of young adults aged 16-30 years of either gender with stuttering problem. Data was collected using Stuttering Severity Instrument-4, Social Interaction Anxiety Scale-Urdu, Big Five Measure-20, Overall Assessment of the Speaker's Experience of Stuttering and the Urdu version of the shortened form of the Coping Orientation to Problems Experienced inventory. Data was analysed using SPSS 23. RESULTS: Of the 78 subjects, 66(84.6 %) were males and 12 (15.4 %) were females. There were 21(27%) subjects aged 16-19 years and 57(73%) with age range of 20-30 years. The overall mean age was 21.96±3.89 years. Mean age of onset was 4.59±1.29 years, while gradual onset and progressive stuttering was reported by 74(94.9 %). The Bilingual users 49(63%) reported to have frequent stuttering. Among the 43(55.1%) who had received treatment, 30(38%) received speech therapy and 26(33.3%) reported dissatisfaction. Stuttering severity and social anxiety were significantly positively correlated with all domains of impact of stuttering (p<0.05). Age, and duration were negatively correlated with day-to-day communication (p<0.05) and previous speech treatment showed negative association with impact on general knowledge about stuttering (p<0.05). Avoidance coping strategy had a significant relationship with all domains of impact (p<0.05). CONCLUSIONS: Severity of stuttering and social anxiety were found to have repercussions on people who stuttered, while avoidance coping was practised more to deal with the negative impact on reactions toward stuttering and quality of life.

Environmental variables drive plant species composition and distribution in the moist temperate forests of Northwestern Himalaya, Pakistan.

By assessing plant species composition and distribution in biodiversity hotspots influenced by environmental gradients, we greatly advance our understanding of the local plant community and how environmental factors are affecting these communities. This is a proxy for determining how climate change influences plant communities in mountainous regions ("space-for-time" substitution). We evaluated plant species composition and distribution, and how and which environmental variables drive the plant communities in moist temperate zone of Manoor valley of Northwestern Himalaya, Pakistan. During four consecutive years (2015-2018), we sampled 30 sampling sites, measuring 21 environmental variables, and recording all plant species present in an altitudinal variable range of 1932-3168 m.a.s.l. We used different multivariate analyses to identify potential plant communities, and to evaluate the relative importance of each environmental variable in the species composition and distribution. Finally, we also evaluated diversity patterns, by comparing diversity indices and beta diversity processes. We found that (i) the moist temperate zone in this region can be divided in four different major plant communities; (ii) each plant community has a specific set of environmental drivers; (iii) there is a significant variation in plant species composition between communities, in which six species contributed most to the plant composition dissimilarity; (iv) there is a significant difference of the four diversity indices between communities; and (v) community structure is twice more influenced by the spatial turnover of species than by the species loss. Overall, we showed that altitudinal gradients offer an important range of different environmental variables, highlighting the existence of micro-climates that drive the structure and composition of plant species in each micro-region. Each plant community along the altitudinal gradient is influenced by a set of environmental variables, which lead to the presence of indicator species in each micro-region.

Understanding eating and drinking behaviours in Pakistani university students: A conceptual model through qualitative enquiry.

Excess weight in Pakistan's university students is on the rise and is driven by their maladaptive eating behaviours. Practitioners in Pakistan have adopted Western conceptual models to understand obesogenic eating behaviours. However, these models provide incomplete explanations as they miss important culturally specific determinants for such eating behaviours. The goals of this study were two-fold: first, to explore Pakistani university students' perception of their obesity-related eating behaviours and attitudes; second, to develop a culturally sensitive model of obesogenic eating behaviours in university students from Pakistan. Semi-structured interviews were used with twenty-four Pakistani university students who were categorised as obese using the Body Mass Index according to Asia-Specific cut-offs. Interviews were transcribed, translated, and then analysed through a Grounded Theory methodology. Six major categories emerged from interviews: (1) Obesogenic Eating Habits (Social Eating, Emotional Eating, and Eating Whatever and Whenever You Want); (2) Beliefs about Food in the Culture; (3) Neither Too Fat nor Too Thin body belief (4) Student Life Attitudes; (5) Student Stressors; (6) Inconsistent Weight-Control Strategies. A model was developed with cultural beliefs about food, attitudes towards student-life, and stressors as important determinants of students' obesogenic eating habits, while inconsistent weight-control strategies contributed to further weight gain. The findings highlight the importance of identifying culturally specific determinants of eating behaviours among university students in Pakistan. This emerging model can be used to guide the development of future quantitative and also longitudinal studies aimed at identifying targets for therapeutic interventions to manage obesogenic eating behaviours in Pakistani university students.

Handling traumatic experiences in facially disfigured female burn survivors.

BACKGROUND: This research deals with the impact of resilience, perceived stigmatization, social comfort and coping strategies on quality of life among female burn survivors with facial disfigurement, man many of which are found in Asian countries. METHODS: Using cross-sectional research design, female burn survivors with severe facial disfigurement (N = 100) were drawn by using purposive sampling strategy from a public sector hospital and an organization working in Lahore, Pakistan. Perceived Stigmatization Questionnaire (PSQ) (Lawrence et al., 2006), Social Comfort Questionnaire (SCQ) (Lawrence et al., 2006), State-Trait Resilience Scale, Coping with Burns Questionnaire (CBQ) (Willebrand et al., 2001) and World Health Organization Quality of Life Brief Questionnaire (WHOQOL-BREF Questionnaire; World Health Organization, 2014) were used for assessment. RESULTS: The analyses showed a significant positive relationship among resilience, coping with burns and social comfort. A significant negative relationship was found between perceived stigmatization and coping with burns, resilience and social comfort. All these variables were tested for differentiation on the basis of survivor's age (less vs. more than 30 years), occupation (housewife vs. gainfully employed), education (less vs. more than matriculation), social status (low vs. middle class), family system (nuclear vs. joint), siblings (yes vs. no), residence (living in home vs. shelter home) and psychological help received or not after the burn injury. Results indicate a mixed type of phenomenon among variable's differentiation. Path analysis through AMOS resulted into a model showing no direct relationship of quality of life with coping with burns, perceived stigmatization and resilience; however, social comfort mediates the relationship between quality of life and coping with burns, perceived stigmatization and resilience. CONCLUSION: It is found that quality of life is dependent on coping with burns, perceived stigmatization and resilience through social comfort. The findings hold implications for the mental health professionals and rehabilitation service providers to emphasize on the restorative strategy for burn survivors to elevate their social comfort, to assist them in handling their injuries and develop a curative plan to support them in their coping skills.

Cognitive behaviour therapy with compulsive hoarding: a single case study.

The current case study used cognitive behaviour treatment (CBT) for the management of a 35-year-old, married man who presented with complaint of compulsive hoarding. The complaint of compulsive hoarding (excessive acquisition, difficulty in discarding saved material and cluttering) was accompanied by feeling of anger, sad mood, low confidence, decreased sleep and appetite, poor problem solving ability, indecisiveness and interpersonal conflicts. The study was approved by the institutional research committee (Departmental Doctoral Programme Committee) and followed by the university research committee (Advance Studies and Review Board) as academic requirement for the duration of 2013-2020. Written consent was also taken from the individual to publish the results of the case. Twenty-eight CBT sessions of one-hour duration were conducted, over a period of six months. Management plan mainly comprised decision-making techniques, cognitive restructuring, behavioural experiments, problem solving and social skills training. The individual was assessed on pre, mid, post and follow up levels. Assessment showed significant decrease in the symptoms. The present case report will help clinicians dealing with individuals with compulsive hoarding and its associated features, effectively with CBT.

Obsessive Compulsive Disorder: Frequency and Gender Estimates.

OBJECTIVE: Frequency data on mental disorders is a crucial requirement for primary, secondary and tertiary prevention. However, such local data is sparse. The study aimed to estimate frequency and gender differences of Obsessive Compulsive Disorder (OCD) in clinical population. METHOD: Retrospective data of adult patients (18 years and above) reported in Out Patient Departments (OPD) of four teaching hospitals and a private clinic was collected. Successive three years record was consulted using OPD registers. Gender difference in frequency of OCD was estimated. RESULTS: Altogether 90119 patients were registered in five psychiatric settings in major cities of Punjab during three year period. As information was missing for over one third of the registered patients, hence analysis was carried out on valid cases only i.e. 59220 (65.8% of the total number of patients registered). It was revealed that the estimated frequency of OCD is 4.1%. There was no significant gender difference revealed in frequency of OCD (P>.05). CONCLUSION: Frequency of OCD implicate the need for early detection and intervention of the disorder. Further, it elucidates the importance of community based research on other mental disorders. The need for accurate record keeping which is a core element for any research related with medical or psychological issue is also highlighted.

Response of plant physiological attributes to altitudinal gradient: Plant adaptation to temperature variation in the Himalayan region.

Plants have evolved several metabolic pathways as a response to environmental stress like low temperatures. In this perspective, it is paramount to highlight physiological mechanisms of plant responses to changing environments. To determine the impact of cold stress on the physiological attributes of high altitude plant natives, i.e. Pedicularis punctata and Plantago major, we studied the protein, sugar and proline contents, as well as abscisic acid (ABA) and indoleacetic acid (IAA) in leaves collected from three different altitudinal ranges in Himalayan region of Pakistan. Leaves were collected at the initial blooming phase from each altitudinal range i.e. 2400-2500 m, 2950-3250 m and 3500-3550 m. Temperature decreases with an increase in the altitude which induces cold acclimation. Both plant species showed significant variation in the concentrations of the ecophysiological attributes evaluated at the different collection altitudes. The concentrations of all compounds except for IAA increased as temperature decreased and altitude increased. IAA showed an opposite response, that is, the concentrations of this phytohormone decreased with decreasing temperature and increasing altitude. We showed that temperature significantly affected the physiological attributes of Pedicularis punctata and Plantago major in the Himalayan region, which works as a proxy for understanding the plant responses to climate change. As per survival and risk assessment, underlying physiological mechanisms of plant response (understory plants) to changing environments (altitude and temperature ranges) revealed adaptation in the chilling environments. Further studies are needed to completely understand how the studied plants photosynthetic characteristics are affected by altitudinal gradient.

Evaluation of the efficacy of different sources of omega-3 fatty acids in polycystic ovarian syndrome (PCOS) induced rats.

The study was planned to check the beneficial effects of various sources of omega-3 fatty acids (synthetic, flaxseed oil, fish oil) on 45 Wistar female rats. The rats were divided into five groups and assigned to different diets i.e. NC (Negative control), PC (Positive control), SO (Synthetic omega-3 250mg/kg/orally/daily), FO (flaxseed oil 250mg/kg/orally/daily) and F (fish oil 250mg/kg/orally/diet). Animals fed on different diets were induced PCOS by an intramuscular (IM) injection of estradiol-valerate (4mg/rat/IM) except NC group. Results of the lipid profile indicated that F showed highest increase in HDL level (35.67±1.45), while cholesterol, LDL, triglycerides, blood glucose and body weight were reduced in all three treatment groups. In case of a hormonal profile, testosterone, luteinizing hormone (LH) and insulin levels showed a significant reduction after treatments. It can be concluded form the study that different sources of omega-3 fatty acids can be a new approach to treat the symptoms of PCOS.

Assessing and Reporting Household Chemicals as a Novel Tool to Mitigate Pesticide Residues in Spinach (Spinacia oleracea).

Non-selective use of pesticide to increase productivity leaves residues on crops. These pesticides after consumption have a detrimental effect on human health and their intake can lead to various diseases such as kidney damage, neurological disorders, cardiovascular diseases, circulatory and reproductive problems. The recent study was designed to assess the effects of household processing treatments such as acidic solutions (acidic acid and citric acid), alkaline solutions (sodium chloride and sodium carbonate) and biological solutions (radish, ginger, garlic, and lemon extracts) were evaluated for their efficiency for removal of pesticides in spinach by gas chromatography with electron capture detector (GC-ECD). The results showed that pesticide residues were sharply reduced when spinach was exposed to washing treatments. The results showed that the greatest reduction of deltamethrin, cypermethrin, chlorpyrifos and endosulfan with 10% acetic acid was (79.68 ± 0.81%), (89.99 ± 0.12%), (94.21 ± 0.02%) and (70.32 ± 0.25%), respectively of tested washing solutions. The acidic solutions were more effective than alkaline and biological extracts in the removal of pesticide residues. The average reduction in various washing solutions ranged from 10.21 to 79.68%, 22.60 to 89.48%, 22.95 to 94-21% and 11.24-70.32% for the removal of deltamethrin, cypermethrin, chlorpyrifos, and endosulfan, respectively.

Acoustic Analysis of Normal Voice Patterns in Pakistani Adults.

This study was designed to find out normative acoustic measures of adults in Pakistan. Age and gender differences in these parameters were also studied. The study variables include fundamental frequency, absolute jitter, relative jitter, relative average perturbation, 5-point period perturbation quotient perturbation quotient, jitter average absolute difference between consecutive periods, divided by the average period, shimmer local, shimmer decibel, three-point amplitude perturbation quotient, five-point amplitude perturbation quotient, average absolute difference of consecutive differences between the consecutive periods' amplitudes, and harmonics-to-noise ratio. Participants (N = 71; men = 34; women = 37) were recruited through two-stage sampling; convenience and purposive sampling. Participants were selected from students, staff, and faculty of the University of the Punjab, caretakers of the clients coming for clinical services, and researchers' friends, family, and acquaintances. Gender groups were further divided into three subgroups based on the age bands of 21-30, 31-40, and 41-50 years. After screening for health issues, the voice samples were recorded in a sound-proof acoustic laboratory by using a stand-held microphone and Praat software. Praat was also used for voice analyses. Means and standard deviations were conducted for the participants. Age and gender differences were investigated by using the two-way analysis of variance. Normative values were also measured for men and women between the age bracket of 21 and 50 years. Age differences were not significant for any variable. Gender differences were significant in fundamental frequency, absolute jitter, relative jitter, jitter period perturbation quotient, shimmer five-point amplitude perturbation quotient, and harmonics-to-noise ratio. The interaction between age and gender was significant in all the jitter measures. The interaction showed an increase in all these measures between the ages of 31 and 40 years and a decrease between the ages of 41 and 50 years in women, whereas men showed a reverse effect both in the age ranges of 31-40 and 41-50 years.

Association between breast cancer and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) gene 1595C/T SNP in a Pakistani population.

AIM OF THE STUDY: TRAIL-mediated signalling has emerged as an extensively studied biological mechanism reported to differentially induce apoptosis in cancer cells. However, overwhelmingly increasing experimentally verified data is shedding light on resistance against TRAIL-induced apoptosis in cancer cells. Moreover, genetic and epigenetic mutations also exert effects on the functionality of TRAIL and its receptors. In this study we investigated the association between breast cancer and polymorphisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in a Pakistani Population. MATERIAL AND METHODS: Genotyping for TRAIL gene 1595 C/T polymorphism was done for 363 breast cancer patients and 193 age- and sex-matched healthy controls. DNA was extracted using standard organic methods. PCR-RFLP analysis was done for C/T polymorphism at position 1595 in exon 5 of the TRAIL gene using site-specific primers and restriction enzyme. The results were statistically evaluated by SPSS14. RESULTS: In this study, CC homozygotes were 46.3% in patients and 49.7% in controls, p = 0.729 with OR value 0.8705 (95% CI: 0.6137-1.2348). CT was statistically insignificant, p = 0.837 with OR value 0.9242 (95% CI: 0.6494-1.3154). However, the minor allele or risk allele genotype TT had a higher percentage among breast cancer patients (12.1%) than in the control group (6.7%). Since there was a statistically insignificant difference (p = 0.212, OR value 1.9098 with 95% CI 1.0019 to 3.6406) of TT genotype between the two groups, the contrastingly higher percentage of TT genotype in breast cancer patients seems to be a risk factor for the disease. Moreover, the frequency of minor allele T was also found to be higher in the patients (0.329) than in the controls (0.285). CONCLUSIONS: The TRAIL gene 1595 C/T SNP has a contradictory role in cancer development in different populations. In our population group although the percentage of homozygous risk allele TT was higher in patients it was statistically non-significant. The raised T allele and TT genotype in patients may suggest its association with breast cancer in the Pakistani population.

Somatic symptoms scale: Psychometric properties in clinical and normal sample.

OBJECTIVE: To develop a Somatic Symptoms Scale based on the criteria of standard symptoms, and to examine its psychometric properties through exploratory factor analysis. METHODS: The study was conducted from January, 2010 to May, 2011 at two teaching hospitals in Lahore city and comprised female adolescents with somatic symptoms diagnosed by a psychiatrist, and an equal number of adolescents with minor physical disability. All patients were recruited from psychiatric out-door units of different hospitals. All subjects were unmarried. Translated Urdu version of the Somatic Symptoms Scale was administered to each participant individually. They were instructed to read the scale carefully and select the response that was most appropriate. The assessment procedure was done in a separate room on the hospital premises. RESULTS: There were 150 female adolescents with somatic symptoms and equal number of females with minor disability. The overall mean age was 15.50+/-1.67 years (range: 14-17 years).Exploratory factor analysis showed that the two groups were significantly different on conversion motor symptoms (p<0.001), conversion sensory symptoms (p<0.001), pain symptoms (p<0.001), hypochondriacal symptoms (p<0.001) and body dysmorphic symptoms (p<0.001). CONCLUSIONS: The Somatic Symptoms Scale was found to be a valid and reliable measure which can be used as screening instrument for non-clinical population and as a diagnostic measure in clinical population.

Gender differences among discrimination & stigma experienced by depressive patients in Pakistan.

OBJECTIVE: This study aims to examine Gender Difference in the level of Discrimination and Stigma experienced by people diagnosed with Major Depressive Disorder in Pakistan. It was hypothesized that Women diagnosed with Depression are likely to be experiencing more Discrimination and Internalized Stigma in comparison to Men. METHODS: This is a Cross Sectional Study. Thirty eight patients diagnosed with Major Depressive Disorder recruited from different Government Sector Hospitals of Lahore; were approached after obtaining informed consent. Discrimination and Stigma were measured through Discrimination and Stigma Scale and Internalized Stigma of Mental Illness Inventory respectively. RESULTS: Both Men and Women experience considerably high level of associated Stigma and Discrimination due to their Mental Illness. However, Women in comparison to Men experience significantly greater level of Internalized Stigma especially in domains of Discrimination Experience and Social Withdrawal. CONCLUSION: The findings of this study highlight the fact that people with Depression can be more benefited with psychological treatment if dealing with Stigma and Discrimination is also addressed in Intervention Plans.

TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling.

We recently reported that hNSCs (human neural stem cells) have the interesting characteristic of migration towards an intracranial glioma. However, the molecules and mechanisms responsible for tumour tropism are unclear. In the present study, we used microarray and proteomics analyses to identify a novel chemoattractant molecule, TIMP-1 (tissue inhibitor of metalloproteinase-1), secreted from human brain tumour tissues. We demonstrate that TIMP-1 significantly enhances hNSC adhesion and migration in a cell culture system. These effects were critically dependent on CD63, as shRNA-mediated ablation of CD63 expression attenuated the response. TIMP-1 significantly increased the number of FAs (focal adhesions) and cytoskeletal reorganization for cell migration in hNSCs, whereas knockdown of CD63 resulted in decreased hNSC spreading, FAs and migration, even after TIMP-1 treatment. In addition, TIMP-1 binding to CD63 activated ß1 integrin-mediated signalling through Akt and FAK phosphorylation, leading to pattern changes in distribution of vinculin and F-actin (filamentous actin). Furthermore, inactivation of ß1 integrin by use of a blocking antibody or inhibition of PI3K (phosphoinositide 3-kinase) signalling impaired the migration of hNSCs towards TIMP-1. Collectively, our results underline TIMP-1 as a novel and effective key regulator of CD63 and ß1 integrin-mediated signalling, which regulates hNSC adhesion and migration.

Nurr1 represses tyrosine hydroxylase expression via SIRT1 in human neural stem cells.

Nurr1 is an orphan nuclear receptor best known for its essential role in the development and maintenance of midbrain dopaminergic (DA) neurons. During DA neurogenesis, Nurr1 directly targets human tyrosine hydroxylase (hTH). Here we investigated this targeting to identify the molecular mechanisms by which Nurr1 regulates DA neurogenesis. We previously cloned the hTH promoter and found three consensus elements for Nurr1 binding: NBRE-A, -B, and -C. In the present study, gel retardation and luciferase assays using hTH constructs showed that Nurr1 preferentially bound to NBRE-A, through which it mediated transcriptional activity. Furthermore, Nurr1 displayed dual-function transcriptional activities depending on the cell type. In DA-like SH-SY5Y cells, Nurr1 dose-dependently stimulated hTH-3174 promoter activity by 7- to 11-fold. However, in the human neural stem cell (hNSC) line HB1.F3, Nurr1 strongly repressed transcription from the same promoter. This repression was relieved by mutation of only the NBRE-A element and by nicotinamide [an inhibitor of class III histone deacetylases (HDACs), such as SIRT1], but not by trichostatin A (an inhibitor of class I and II HDACs). SIRT1 was strongly expressed in the nucleus of HB1.F3 cells, while it was localized in the cytoplasm in SH-SY5Y cells. ChIP assays of HB1.F3 cells showed that Nurr1 overexpression significantly increased the SIRT1 occupancy of the NBRE-A hTH promoter region, while low SIRT1 levels were observed in control cells. In contrast, no significant SIRT1 recruitment was observed in SH-SY5Y cells. These results indicate that differential SIRT1 localization may be involved in hTH gene regulation. Overall, our findings suggest that Nurr1 exists in dual transcriptional complexes, including co-repressor complexes that can be remodeled to become co-activators and can fine-tune hTH gene transcription during human DA neurogenesis.

Psychoeducation and the family burden in schizophrenia: a randomized controlled trial.

BACKGROUND: The majority of patients with schizophrenia live with their relatives in Pakistan, thereby families experience a considerable burden. We aimed to study the impact of psychoeducation on the burden of schizophrenia on the family in a randomised controlled trial. METHODS: A total of 108 patients with schizophrenia and their family members from the outpatient department of a teaching hospital in Lahore, Pakistan were randomised. Both groups received psychotropic drugs but one group received psychoeducation in addition. Family burden was assessed at the time of recruitment and at 6 months post intervention. RESULTS: In all, 99 patients and their relatives completed the treatment. There was significant reduction in burden at post-intervention assessment in the psychoeducation group based on intention to treat analysis. CONCLUSION: Family psychoeducation can be an important intervention for patients with schizophrenia in Pakistan.

2-[3-(4-Methoxyphen-yl)-1-phenyl-1H-pyrazol-5-yl]phenol.

The title compound, C(22)H(18)N(2)O(2), was derived from 1-(2-hydroxy-phen-yl)-3-(4-methoxy-phen-yl)propane-1,3-dione. The central pyrazole ring forms dihedral angles of 16.83 (5), 48.97 (4) and 51.68 (4)°, respectively, with the methoxy-phenyl, phenyl and hydroxy-phenyl rings. The crystal packing is stabilized by O-H⋯N hydrogen bonding.