Sequence preferences of DNA binding proteins are a primary mechanism by which cells interpret the genome. Despite the central importance of these proteins in physiology, development, and evolution, ...comprehensive DNA binding specificities have been determined experimentally for only a few proteins. Here, we used microarrays containing all 10-base pair sequences to examine the binding specificities of 104 distinct mouse DNA binding proteins representing 22 structural classes. Our results reveal a complex landscape of binding, with virtually every protein analyzed possessing unique preferences. Roughly half of the proteins each recognized multiple distinctly different sequence motifs, challenging our molecular understanding of how proteins interact with their DNA binding sites. This complexity in DNA recognition may be important in gene regulation and in the evolution of transcriptional regulatory networks.
With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of ...all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.
This study investigated causal antecedents' symmetric and asymmetric effects on satellite fans' intention to revisit the home ground of their favorite sports teams through the lens of appraisal ...theory of emotion and complexity theory. Results showed that team identification affected revisit intention through sport nostalgia and customer equity. The fuzzy set qualitative comparative analysis (fsQCA) suggested five different configurations that can explain the formation of satellite fans' revisit intention. In particular, "value equity" and "nostalgia as personal identity" were essential for explaining satellite fans' revisit intention. This study contributes to a better understanding of satellite fans' behaviors.
Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a ...nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC.
A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS).
Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio HR, 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials.
Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
MicroRNAs (miRNAs) are noncoding RNAs that suppress translation of specific mRNAs. The miRNA machinery interacts with fragile X mental retardation protein (FMRP), which functions as translational ...repressor. We show that miR-125b and miR-132, as well as several other miRNAs, are associated with FMRP in mouse brain. miR-125b and miR-132 had largely opposing effects on dendritic spine morphology and synaptic physiology in hippocampal neurons. FMRP knockdown ameliorates the effect of miRNA overexpression on spine morphology. We identified NMDA receptor subunit NR2A as a target of miR-125b and show that NR2A mRNA is specifically associated with FMRP in brain. In hippocampal neurons, NR2A expression is negatively regulated through its 3′ UTR by FMRP, miR-125b, and Argonaute 1. Regulation of NR2A 3′UTR by FMRP depends in part on miR-125b. Because NMDA receptor subunit composition profoundly affects synaptic plasticity, these observations have implications for the pathophysiology of fragile X syndrome, in which plasticity is altered.
► A large set of microRNAs are biochemically associated with FMRP in mouse brain ► miR-125b promotes thinner spines and weaker synapses; miR-132 induces opposite changes ► The NMDA receptor subunit NR2A is regulated by FMRP and miR-125b through its 3′ UTR ► These effects involve a functional interaction between these miRNAs and FMRP
Summary Background Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in two placebo-controlled phase 3 trials, and is approved for patients with metastatic ...castration-resistant prostate cancer. The objective of the TERRAIN study was to compare the efficacy and safety of enzalutamide with bicalutamide in patients with metastatic castration-resistant prostate cancer. Methods TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic, community, and private health-care provision sites across North America and Europe. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day, both taken orally, in addition to ADT, until disease progression. Patients were stratified by a permutated block method (block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at the discretion of the patient and study investigator. This trial is registered with ClinicalTrials.gov , number NCT01288911. Findings Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and 191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 20·0 months (IQR 15·0–25·6) in the enzalutamide group and 16·7 months (10·2–21·9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15·7 months 95% CI 11·5–19·4) compared with patients in the bicalutamide group (5·8 months 4·8–8·1; hazard ratio 0·44 95% CI 0·34–0·57; p<0·0001). Of the most common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue (51 28% of 183 patients in the enzalutamide group vs 38 20% of 189 in the bicalutamide group), back pain (35 19% vs 34 18%), and hot flush (27 15% vs 21 11%); those occurring more frequently with bicalutamide were nausea (26 14% vs 33 17%), constipation (23 13% vs 25 13%), and arthralgia (18 10% vs 30 16%). The most common grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension (13 7% vs eight 4%), hydronephrosis (three 2% vs seven 4%), back pain (five 3% vs three 2%), pathological fracture (five 3% vs two 1%), dyspnoea (four 2% vs one 1%), bone pain (one 1% vs four 2%), congestive cardiac failure (four 2% vs two 1%), myocardial infarction (five 3% vs none), and anaemia (four 2% vs none). Serious adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly related to treatment (due to systemic inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group. Interpretation The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. Funding Astellas Pharma, Inc and Medivation, Inc.
The relationship between mindfulness and well-being and ill-being has been demonstrated to a great extent. In sports, the fulfillment of individuals’ basic psychological needs depends mostly on ...support from others, such as that from a coach in a sports team context. However, a possible way for individuals to fulfill their basic psychological needs is by enhancing mindfulness rather than depending on others. Therefore, building on SDT and mindfulness, this study examines the mediating effect of basic psychological needs on mindfulness to predict subjective vitality and athlete burnout in professional golfers. The participants were 120 golfers (47% females), with a mean age and golf experience of 22.28 and 9.48 years, respectively. The association between mindfulness and subjective vitality was partially mediated by the need for autonomy and relatedness. By contrast, the association between mindfulness and burnout was partially mediated by the need for competence and relatedness, thus supporting our mediation analysis. Overall, the study highlights mindfulness as a potential mechanism to ensure the fulfillment of basic psychological needs in golf training, which could enhance golfers’ subjective vitality and reduce the occurrence of burnout.
To examine unintentional drowning mortality by age and body of water across 60 countries, to provide a starting point for further in-depth investigations within individual countries.
The latest ...available three years of mortality data for each country were extracted from WHO Health Statistics and Information Services (updated at 13 November 2013). We calculated mortality rate of unintentional drowning by age group for each country. For countries using International Classification of Disease 10 (ICD-10) detailed 3 or 4 Character List, we further examined the body of water involved.
A huge variation in age-standardised mortality rate (deaths per 100 000 population) was noted, from 0.12 in Turkey to 9.19 in Guyana. Of the ten countries with the highest age-standardised mortality rate, six (Belarus, Lithuania, Latvia, Russia, Ukraine and Moldova) were in Eastern Europe and two (Kazakhstan and Kyrgyzstan) were in Central Asia. Some countries (Japan, Finland and Greece) had a relatively low rank in mortality rate among children aged 0-4 years, but had a high rank in mortality rate among older adults. On the contrary, South Africa and Colombia had a relatively high rank among children aged 0-4 years, but had a relatively low rank in mortality rate among older adults. With regard to body of water involved, the proportion involving a bathtub was extremely high in Japan (65%) followed by Canada (11%) and the USA (11%). Of the 13 634 drowning deaths involving bathtubs in Japan between 2009 and 2011, 12 038 (88%) were older adults aged 65 years or above. The percentage involving a swimming pool was high in the USA (18%), Australia (13%), and New Zealand (7%). The proportion involving natural water was high in Finland (93%), Panama (87%), and Lithuania (85%).
After considering the completeness of reporting and quality of classifying drowning deaths across countries, we conclude that drowning is a high-priority public health problem in Eastern Europe, Central Asia, Japan (older adults involving bathtubs), and the USA (involving swimming pools).
This study examines the relationships among perceived price, quality, and value and their impact on the intent to participate in marathon events. An online questionnaire survey was administered to ...individuals who had participated in a marathon within the past ten years. Participants were selected using purposive sampling. A total of 609 valid responses were collected. The results showed that both perceptions of price and quality of marathon events are significant predictors of intention to participate in marathon events. Moreover, participants’ perceived value mediated the impacts of perceived price and quality on behavioral intention. The findings offer key implications, including ways to promote active participation in marathon events. In addition, the findings emphasize the need to account for and fully understand perceived price and quality when designing marketing strategies aimed at attracting marathon participants.
Background/objectiveThe literature has discussed the potential for nurturing, integrating, and optimizing physical literacy to thereby enhance quality of life. Progression could be made through the ...disposition of acquiring movements and engaging in physical activity, but data supporting such an argument remains limited. This cross-sectional study attempted to empirically investigate these two variables by assessing the levels of motivation and satisfaction among university students in Taiwan. The hypothesis posited a positive correlation between physical literacy and quality of life, with the mediating effects of motivation and satisfaction taken into consideration.MethodsBy applying the time segregation method, participants were asked to complete a set of questionnaires at the beginning and the end of the first semester during the 2021 - 2022 academic year. The initial phase involved gathering demographic information and assessing the perceived physical literacy score. The scores for motivation, satisfaction, and quality of life were measured in the subsequent phase. SmartPLS version 3.3 was used to conduct data analysis. After ratifying the model's goodness-of-fit, partial least squares structural equation modeling was used to test the hypotheses in the research model.ResultsA total of 388 students (male n = 320, female n = 68; mean age: 18.5 years) participated in this study. Moderate explanatory power was found in the relationships of perceived physical literacy to physical education satisfaction (βPPLI → PES = 0.137, t = 6.439, R2 = 0.642) and motivation (βPPLIA → SIMS = 0.511, t = 32.701, R2 = 0.607). Results then indicated that motivation is the mediator of the relationship between physical literacy and physical education satisfaction (βPPLI → SIMS → PES = 0.373, t = 4.015). Furthermore, this satisfaction mediated the relationship between physical literacy and quality of life (βPPLI → PES → QoLS = 0.070, t = 4.47).ConclusionThis study connected theoretical knowledge regarding physical literacy with practice, suggesting that ongoing physical education may nurture the habit of lifelong participation in physical activity, thus further improving quality of life.
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