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Material selection is a complex process that involves selecting the best material for a given application. It is a critical process in engineering, and the importance of selecting the right material for the job cannot be overstated. Multi-criteria decision-making (MCDM) is an important tool that can be used to help engineers make informed decisions about material selection. The logistic function can be extended using the soft-max function, which is widely used in stochastic classification methods like neural nets, soft-max extrapolation, linear differential analysis, and Naïve Bayes detectors. This has inspired researchers to develop soft-max-based fuzzy aggregation operators (AOs) for q-rung orthopair fuzzy sets (q-ROPFS) and to propose an MCDM approach based on these AOs. To test the effectiveness of this approach, the researchers applied it to a practical problem using q-rung orthopair fuzzy data and conducted a numerical example to validate the suggested procedures.

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.

The creation of sustainable artificial tropical forests is of utmost importance for addressing critical environmental issues like deforestation, habitat loss, and climate change. This research paper presents an innovative approach that considers ecological, socioeconomic, and technological factors. The proposed approach integrates multi-criteria decision-making (MCDM) methods that take into account the preferences and opinions of stakeholders. To analyze the various criteria involved, cubic picture fuzzy numbers (CPFNs) are utilized. To ensure fairness in evaluating CPFNs, the study focuses on developing operational laws and aggregation operators that promote neutrality and fairness. Specifically, the paper introduces the “cubic picture fuzzy fairly weighted average (CPFFWA) operator” and the “cubic picture fuzzy fairly ordered weighted averaging (CPFFOWA) operator.” By considering stakeholders and prioritizing their long-term sustainability and resilience, this approach proves to be highly valuable for policymakers, forest managers, and other relevant parties. This research avenue bridges the gap in current literature where limited exploration of fairly aggregation operators in tandem with picture fuzzy sets within tropical forest contexts exists. Ultimately, the research strives to contribute to the practical management of these vital ecosystems, fostering environmental conservation and sustainability through a cross-disciplinary approach amalgamating ecology, fuzzy logic, decision theory, and environmental science.

This article introduces a novel paradigm for enhancing the administration of decisions regarding sustainable energy planning. This is achieved by deploying novel spherical fuzzy aggregation operators that have been meticulously tailored to address the inherent complexities of uncertainty and imprecision prevalent in energy planning datasets. These operators vastly increase the precision and efficacy of decision-making processes, thereby transforming the entire sustainable energy landscape. This study focuses predominantly on the complex domain of multi-attribute decision-making (MADM), in which the interplay of parameters is characterized by a discernible hierarchy of importance. This method generates aggregation operators based on the assignment of non-negative real values to clearly defined priority echelons, a framework known as priority degrees. This effort results in the development of two notable prioritized operators: the “spherical fuzzy prioritized averaging operator with priority degrees” and the “spherical fuzzy prioritized geometric operator with priority degrees”. The efficacy of these conceptual frameworks is vividly demonstrated through the application of extensive case studies, in which observable results clearly demonstrate their superiority over conventional methodologies. The empirical findings unequivocally demonstrate the superiority of the proposed operators, resonating with substantial performance and efficiency improvements. This study not only adds a seminal dimension to the field of sustainable energy management but also reveals a revolutionary application of spherical fuzzy aggregation operators at the forefront of effective decision-making paradigms. The seamless fusion of theoretical innovation and practical utility outlines a path forward, with transformative prospects and far-reaching implications for the sustainable energy landscape.

People in economically advantaged nations tend to evaluate their life as more positive overall and report greater well-being than people in less advantaged nations. But how does positivity manifest in the daily life experiences of individuals around the world? The present study asked 15,244 college students from 62 nations, in 42 languages, to describe a situation they experienced the previous day using the Riverside Situational Q-sort (RSQ). Using expert ratings, the overall positivity of each situation was calculated for both nations and individuals. The positivity of the average situation in each nation was strongly related to the economic development of the nation as measured by the Human Development Index (HDI). For individuals’ daily experiences, the economic status of their nation also predicted the positivity of their experience, even more than their family socioeconomic status. Further analyses revealed the specific characteristics of the average situations for higher HDI nations that make their experiences more positive. Higher HDI was associated with situational experiences involving humor, socializing with others, and the potential to express emotions and fantasies. Lower HDI was associated with an increase in the presence of threats, blame, and hostility, as well as situational experiences consisting of family, religion, and money. Despite the increase in a few negative situational characteristics in lower HDI countries, the overall average experience still ranged from neutral to slightly positive, rather than negative, suggesting that greater HDI may not necessarily increase positive experiences but rather decrease negative experiences. The results illustrate how national economic status influences the lives of individuals even within a single instance of daily life, with large and powerful consequences when accumulated across individuals within each nation.

Objective: To investigate the speech sound errors and literacy skills in children with orofacial clefts (cleft palate& cleft lip and palate). Study Design: Comparative cross-sectional study. Place and Duration of Study: Centre for Clinical Psychology, University of the Punjab, Lahore, from Mar 2016 to Feb 2017. Methodology: A sample of 42 participants (cleft lip & palate: n=18 and cleft palate: n=24) was collected. Two stage sampling strategy was used. Each child was individually screened through Slosson intelligence test revised checklist of orofacial cleft and diagnostic statistical Manual-V checklist. Then children were provided with assessment measures which included demographic informational questionnaire, community developed VPI Screener, word list for articulation and phonological processes, annual status of education report (ASER) and curriculum-based measurement (Written Expression). Manual SODA (substitution, omission, distortion and addition) analysis was done to know about the type of speech sound errors. Results: Independent sample t-test was used to compare the differences of speech sound errors (52.11 ± 25.08), (47.29 ± 25.38), reading skills (3.67 ± 1.14), (3.75 ± 1.26) and writing skills (14.61 ± 13.49), (25.14 ± 29.16) in cleft lip & palate and cleft palate respectively, indicated that there were no differences; with p-value: p=0.54, 0.83, 0.13. Conclusion: Results indicated no significant differences in speech sound errors, reading, writing skills and resonance between children with cleft lip & palate and cleft palate.

Introduction: Aplastic anemia is a syndrome of bone marrow failure comprising of peripheral pancytopenia and marrow hypoplasia. Recently, research has shown papaya leaf juice to increase blood cells counts. Aims & Objectives: This research was planned to investigate the effect of papaya leaf juice on blood cell counts in busulfan induced myelosuppressed mice. Place and duration of study: Post Graduate Medical Institute, Lahore from September 2015 to December 2015. Material &Methods: This animal experimental study comprised of 36 adult healthy Swiss albino mice weighing 30-35 g, divided randomly into three equal groups. Busulfan was given orally (14mg/kg) to induce myelosuppression to busulfan group and Carica papaya+ busulfan group on 8 occasions over a period of 23 days. Carica papaya leaf juice (10ml/kg) was given to the Carica papaya+ busulfan group daily for 23 days to observe its role in preventing myelosuppression. Normal group was given distilled water in an equivalent amount. One day after the final dose of busulfan and Carica papaya, the animals were sampled for blood cell counts. Data was analyzed using SPSS version 20. A p-value < 0.05 and below was considered as significant. Results: The Carica papaya leaf juice not only prevented significant fall in hemoglobin (10.86 ± 1.455 g/dl), RBC (9.54 ± 0.954× 106/mm3) and platelet count (958.92 ± 176.22 x103/mm3) vs (9.70 ± 0.904,11.24 ± 0.952 g/dl), RBC count (6.5025 ± 1.43,10.43 ± 0.234× 106/mm3) and platelet count (627.83 ± 151.63, 3881.08 ± 83.13 x103/mm3) in busulfan group but also kept them close to normal range. Total leukocyte count in C.papaya treated group improved significantly to 8116.67± 1540.85/mm3 vs (4516.67±789.51, 6666.67±798.10/mm3) busulfan treated and normal groups respectively. Conclusion: The Carica papaya leaf juice possesses significant myeloprotective activity. It may be a good candidate for prevention of chemotherapy induced pancytopenia

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 was comprised of young adults aged 16-30 years of either gender with development 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

Children, adolescents, and adults who stutter widely experience anxiety and avoid social situations; hence stuttering negatively affects their quality of life (Yaruss & Quesal, 2004). The study aims to investigate the relation between social anxiety, stigma perception, and quality of life among individuals who stutter and to examine if stigma perception mediates between social anxiety and quality of life. Participants of aged 11- 25 years (Mage =18.83, SD = 4.74, N = 117) were recruited using purposive and snowball sampling technique. Participants were screened based on dysfluency using DSM-5 (2013) stuttering criteria. Results revealed significant association between social anxiety, stigma perception, and quality of life. Mediation analysis also showed that stigma perception partially mediated the relation between social anxiety and quality of life in individuals who stutter. Furthermore, significant age differences were found in social anxiety and quality of life in individuals who stutter. The study concluded that stigma perception partially mediates the relationship between social anxiety and quality of life; therefore, social anxiety and perceived stigma need to be reduced to enhance stuttering individuals’ quality of life. Results highlight the importance of multidisciplinary approach in the management of stuttering.

BACKGROUND & OBJECTIVE: Mental health is playing an important role in our daily life. Now a days depression is the second most common illness in the world. Online social networking is one of the risk factors to mental illness, and objective is to determine the usage of social networking sites (SNS) and level of depression among undergraduate students. METHODOLOGY: This cross-sectional study was conducted at Sindh Agriculture University Tandojam- Sindh with simple random sampling through self-administrated questionnaires. Sample size was calculated on a prevalence rate of 50%, students ranging from 17-28 years, using SNS were included while those having any chronic illness were excluded. Ethical approval was obtained from Health Services Academy Islamabad, anonymity confidentiality, and privacy was assured. SPSS version 20.0 was used, and chi-square was applied to find the association. RESULTS: Out of 212 students, the respondents consisted mainly of male students n=165 (77.8%), among them, 52 (24.5%) students were of age 19 years and 76 (35.8%) were in first-year class. Results reveal that the frequently used SNS was Facebook 169 (79.7%). The students using these sites for more than 4 years were 28 (13.2%). Among the SNS users, 142(67%) were having moderate depression, while 9 (4.2%) had severe depression. Male students have more online friends (p

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.

Due to insufficient healthcare facilities for the fight against cancer, a large percentage of individuals die. Utilizing computational tools inside the health and medical system helps to minimize fatalities. Timely cancer detection enhances the likelihood of effective therapy. Cancer risk assessment is important for legal and regulatory reasons, for cancer prevention, and to avoid the risks. The approach for assessing cancer risk based on the q-rung orthopair fuzzy set (q-ROFS) is described. The technique is predicated on a multifactor evaluation of the likelihood of a cancerous. q-ROFS is a robust approach for modeling uncertainties in multicriteria decision making (MCDM). The combinative distance-based assessment (CODAS) technique integrates two separate approaches, namely the “simple additive weighting” (SAW) method and the “weighted product method (WPM)”. In this study, the CODAS approach is extended to the q-rung orthopair fuzzy framework with application to cancer risk assessment. Additionally, the symmetry of the optimal decision in cancer risk assessment is carried out by a comparison analysis of the suggested model with some existing models.

Nowadays, there is an ever-increasing diversity of materials available, each with its own set of features, capabilities, benefits, and drawbacks. There is no single definitive criteria for selecting the perfect biomedical material; designers and engineers must consider a vast array of distinct biomedical material selection qualities. The goal of this study is to establish fairly operational rules and aggregation operators (AOs) in a linear Diophantine fuzzy context. To achieve this goal, we devised innovative operational principles that make use of the notion of proportional distribution to provide an equitable or fair aggregate for linear Diophantine fuzzy numbers (LDFNs). Furthermore, a multi-criteria decision-making (MCDM) approach is built by combining recommended fairly AOs with evaluations from multiple decision-makers (DMs) and partial weight information under the linear Diophantine fuzzy paradigm. The weights of the criterion are determined using incomplete data with the help of a linear programming model. The enhanced technique might be used in the selection of compounds in a variety of applications, including biomedical programmes where the chemicals used in prostheses must have qualities similar to those of human tissues. The approach presented for the femoral component of the hip joint prosthesis may be used by orthopaedists and practitioners who will choose bio-materials. This is due to the fact that biomedical materials are employed in many sections of the human body for various functions.

Due to the fact that there is no symmetry in the division of cancer cells, it is important to consider this asymmetrical behavior. Because of this heterogeneity during any therapy, not every cancer cell that is killed only is abolished, which is sensitive to the particular treatment chosen. Mathematical models that describe these pathways are critical for predicting cancer cell proliferation behavior. The literature on the mathematical modeling of cancer onset, growth, and metastasis is extensive. Both deterministic and stochastic factors were used to develop mathematical models to mimic the development rate of cancer cells. We focus on the cell’s heterogeneity in our model so that the cells generally responsible for spreading cancer, which are called stem cells, can be killed. Aggregation operators (AOs) play an important role in decision making, especially when there are several competing factors. A key issue in the case of uncertain data is to develop appropriate solutions for the aggregation process. We presented two novel Einstein AOs: q-rung picture fuzzy dynamic Einstein weighted averaging (q-RPFDEWA) operator and q-rung picture fuzzy dynamic Einstein weighted geometric (q-RPFDEWG) operator. Several enticing aspects of these AOs are thoroughly discussed. Furthermore, we provide a method for dealing with multi-period decision-making (MPDM) issues by applying optimal solutions. A numerical example is presented to explain how the recommended technique can be used in cancer therapy assessment. Authenticity analysis is also presented to demonstrate the efficacy of the proposed technique. The suggested AOs and decision-making methodologies are generally applicable in real-world multi-stage and dynamic decision analysis.

The concept of m-polar spherical fuzzy sets (mPSFS) is a combination of m-polar fuzzy sets (mPFS) and spherical fuzzy sets (SFS). An mPSFS is an optimal strategy for addressing multipolarity and fuzziness in terms of ordered triples of positive membership grades (PMGs), negative membership grades (NMGs), and neutral grades (NGs). In this study, the innovative concept of m-polar spherical fuzzy topology (mPSF-topology) is proposed for data analysis and information aggregation. We look into the characteristics and results of mPSF-topology with the help of several examples. Topological structures on mPSFSs help with both the development of new artificial intelligence (AI) tools for different domain strategies and the study of different kinds of uncertainty in everyday life problems. These strategies make it possible to recognise and look into a situation early on, which helps professionals to reduce certain risks. In order to address various group decision-making issues in the m-polar spherical fuzzy domain, one suggestion has been to apply an extended linear assignment model (LAM) along with the SIR method known as superiority and inferiority ranking methodology in order to analyze road accident issues and dispute resolution. In addition, we examine the symmetry of optimal decision and perform a comparative study between the research carried out using the suggested methodology and several existing methods.

The current research was carried out to characterize the phytosociology of the forests of one of Pakistan’s most valuable tree species (Deodar) across its native range. In this context, our main hypothesis was that, along the altitudinal gradient, we would find different plant communities that would be driven by different environmental variables (climatic, edaphic, and physiographic). Therefore, to assess the vegetation structure of the pure Deodar forests of the unexplored Manoor Valley (Northwestern Himalaya), Pakistan, frequent field visits were carried out during different seasons of 2015–2018. Ecological methods: Line transects sampling (23 stands) and phytosociological attributes were evaluated in relation to geographical and environmental variables. Various statistical software applications (i.e., PCORD, RStudio 4.0, and R 3.6.1) were used to examine all of the gathered data of plant species and environmental variables. A total of three different plant communities (Cedrus–Isodon–Cynodon, Cedrus–Cynodon–Dryopteris, and Sambucus–Cedrus–Desmodium) were identified by grouping 162 species and 23 stands in pure Deodar forests under the influence of geographic, slope, edaphic, and climatic variables, ranging from 1580.8 to 2373.8 m. The altitude (1936–2373 m), slope angle (25–85°), sandy (29–48%) and loamy soil texture, wind speed (1.45 ms−1), and temperature (25.8 °C) all had a strong influence on the Sambucus–Cedrus–Desmodium community. In contrast with this, the Cedrus–Cynodon–Dryopteris community showed a positively significant relationship with the northeastern slope, silty (32–58%) and sandy (15.8–55%) loamy soil texture, and barometric pressure (814.3 pa). Nonetheless, the Cedrus–Isodon–Cynodon community revealed a significant positive association with the northeastern to southwestern slope, pH (6.3), wet bulb (19.7), and dew point (17.7). We found significant differences (p < 0.001) among the three communities found in the pure Deodar forests in the four diversity indexes. The Sambucus–Cedrus–Desmodium community has the maximum number of plants (129 species), Shannon’s diversity (H’ = 3.7), and Simpson’s dominance (0.98) values among the recorded communities. The Pielou’s evenness index value was led by the Cedrus–Isodon–Cynodon community (0.97). Beta diversity showed a dissimilarity lower than 50% among the three communities. Simple term effects in the canonical correspondence analysis model revealed significant (p < 0.05) differences in altitude, slope angle, slope (southeastern), and wind speed variables. The present investigation sheds light on vegetation pattern and species contribution as a function of environmental gradients and provides a baseline for future studies.

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. Continuous...

The present research was carried out to observe the comparative effectiveness of different chemical treatments in combination with simultaneous thermal treatment on soluble (SDF) and insoluble dietary fiber (IDF) ratio to improve functional properties of barley. For this purpose, two varieties of barley, i.e., Haider-93 and Jau-87 were assessed for chemical composition, mineral, non-starch polysaccharides, and dietary fiber contents through respective methods. Two varieties were chemically treated through acid, alkaline, and consecutive acid–alkaline treatments in combination with thermal treatment. Results of chemical composition revealed that Jau-87 was higher in moisture (11.4%), crude fat (2.67%), and crude fiber (4.70%), whereas Haider-93 exhibited higher ash (2.56%) and crude protein content (12.7%). Moreover, barley is a rich source of potassium ranging from 4.77 to 5.07 g/kg. Likewise, main non-starch polysaccharides in barley were arabinoxylan (3.60–3.77%) and beta-glucan (3.65–3.67%). Furthermore, barley contains more IDF (12.00–12.40 g/100 g dm) than SDF (4.73–5.70 g/100 g dm). Additionally, modification of SDF (23.68%) and IDF (11.69%) ratio through acid treatment was nonsignificant, while acid–alkaline treatment showed highly significant results, i.e., 771.46% increased in SDF and 53.39% decreased in IDF. It is concluded that chemical treatments alone or in combination with pressure cooking increased SDF. However, simultaneous effect of acid and alkaline treatment most effectively increased the solubility of barley.

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.

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.

This study was designed to evaluate the antioxidant potential of Loranthus pulverulentus. Stem bark, leaves, and seeds of Loranthus pulverulentus were extracted in methanol:water (90 : 10) and partitioned with n-hexane, chloroform, ethyl acetate, and n-butanol successively using partition chromatography. Total phenolic contents and antioxidant potential were checked using standard protocols. Total phenolic contents of all extracts were determined, using Folin–Ciocalteu reagent, and ranged between 151 ± 2.1 and 396 ± 1.6 for stem bark, 137 ± 0.9 and 430 ± 2.2 for, and 39 ± 0.6 and 231 ± 1.7 for seeds. The antioxidant potential of extracts was evaluated; namely, DPPH, FRAP, and total antioxidant models. The ethyl acetate extract of stem-bark, leaves, and seeds showed the highest activity in DPPH (94.5 ± 2.1%, 96.30 ± 0.9%, and 92.30 ± 1.1%, IC50 15.9 ± 0.5 μg, 14.5 ± 0.8, and 102.7 ± 1.3, resp.), FRAP (7.7 ± 0.6, 7.5 ± 0.7 and 6.6 ± 0.7, resp.), and total antioxidant (0.95 ± 0.09, 1.19 ± 0.09, and 0.686 ± 0.08, resp.). Strong correlations were observed between total phenols versus total antioxidant activity, DPPH, and FRAP with R2 values ranging from 0.8185 to 0.9951 (stem-bark), 0.6728 to 0.8648 (leaves), and 0.8658 to 0.9910 (seed) which indicated that phenolic contents are the major constituents responsible for antioxidant activity.