Miracle-dz/UniFAR-FTUs huggingface dataset:
(-)-7′-Isothiocyanato-11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM841), a High-Affinity Electrophilic Ligand, Interacts Covalently with a Cysteine in Helix Six and Activates the CB1 Cannabinoid Receptor

The CB1 cannabinoid receptor has been shown to play important physiological roles in the central nervous system, as well as peripherally, and is a target for development of therapeutic medications. To gain insight on the ligand binding site(s) and structural features of activation, we designed and synthesized (-)-7′-isothiocyanato-11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM841), a classical cannabinoid affinity label that incorporates an isothiocyanate substituent as an electrophilic reactive group capable of interacting irreversibly with a suitably located and properly oriented nucleophilic amino acid residue at or near the binding site. To obtain evidence for the site of covalent attachment of AM841, C6.47, identified in part by interactive ligand docking, was mutated to serine, alanine, and leucine to reduce or eliminate the nucleophilic character. Wild-type (WT) and mutant CB1 receptors were evaluated for their abilities to recognize a series of cannabinergic ligands. Each bound comparably to WT, excluding C6.47L, which displayed a reduced affinity for 3H-labeled (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP55940), AM841, 11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM4056), and (-)-7′-bromo-11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM4043) and an improvement in affinity for (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC). The affinity of 3H-labeled [2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](naphthyl)methanone (WIN55212-2) was unchanged across all mutants. It is noteworthy that AM841 was shown to bind irreversibly to WT CB1 but exhibited no covalent attachment with the mutants and behaved as an agonist suggesting irreversible attachment to C6.47 maintains CB1 in its active state. The evidence presented identifies C6.47 as the site of covalent bond formation with AM841 and combined with the binding data fully supports the molecular modeling. These studies present the first report of tandem applications of affinity labeling, site-directed mutagenesis, and interactive ligand docking for CB1.
Heme oxygenase inhibitor zinc protoporphyrin IX causes an activation of nitric oxide synthase in the rabbit internal anal sphincter.

The studies were performed in the rabbit internal anal sphincter (IAS) smooth muscle strips to examine the influence of the heme oxygenase inhibitor, [zinc protporphyrin (ZnPP IX)], on basal tone. ZnPP IX produced a concentration-dependent fall in the basal tone and was the focus of our investigation. To examine the mechanism of the fall in IAS tone by ZnPP IX, the effect of different concentrations of ZnPP IX on basal IAS tone and the release of nitric oxide were examined before and after the neurotoxin tetrodotoxin and various nitric oxide synthase (NOS) inhibitors. The inhibitory effect of ZnPP IX was blocked by the NOS inhibitors L-NG-nitroarginine, NG-monomethyl-L- arginine and L-N5-(1-iminoethyl)ornithine and the neurotoxin TTX. The fall in IAS tension by ZnPP IX was accompanied by a release of NO. ZnPP IX(1 x 10(-3)M) caused a fall in IAS tension of 43.7% which was reduced to 16.5% in the presence of L-NG-nitroarginine (1 x 10(-4)M). Furthermore, the fall in IAS tone in the presence of ZnPP IX was restored both by the NOS inhibitors and tetrodotoxin. The basal release of nitric oxide in these experiments was 0.50 +/- 0.07 nmol and in the presence of ZnPP IX (1 x 10(-3)M), it increased to 1.72 +/- 0.28 nmol (more than a 3-fold increase). Thus the fall in the basal IAS tone by ZnPP IX was associated with a release of NO from the myenteric neurons as these effects were significantly blocked by the NOS inhibitors and tetrodotoxin. We conclude that in the rabbit IAS, ZnPP IX causes a fall in the basal IAS tension by the activation of NOS in myenteric neurons. We speculate that in the resting state, the heme oxygenase pathway exerts important counter-regulatory effects on the NOS pathway and when blocked (e.g., by ZnPP IX), the underlying NOS pathway is unmasked leading to a massive and prolonged release of NO. The exact significance of this mechanism remains to be determined.
Performance Lag Address Programme (PLAP): The View of Teachers in Inclusive Primary and Secondary Schools

DOI: 10.15580/GJER.2018. 6.080218110 The policy on Education For All (EFA) has been the hallmark of access to education with equal opportunities, equal provision of services and allocation of resources towards basic education in Zimbabwe. To this effect, The Director’s Circular number 26 of 2008 on guidelines on remedial work at primary and secondary school levels alludes to Performance Lag Address Programme (PLAP). This study was prompted by the unevenness of the training of teachers by non specialist professionals and the ineffective use of non-standardised assessment tools for screening learners. This creates professional doldrums of what exactly teachers should do. The aim was to capacitate accountability approaches towards PLAP. The research was qualitative and a case design was applied. A sample of 80 participants comprising education officers, schools administrators and teachers was purposively drawn from Masvingo District namely, offices, primary and secondary schools respectively. Semi-structured interviews, an open ended questionnaire and document analysis were used to generate data. It emerged from the study that most PLAP trainers are not in tandem with the mechanics of Individualised Educational Programmes (IEP) and most of teachers are confused with PLAP demands and voluntarily opted not to engage in the programme. It is recommended that PLAP trainers should be specialist professionals with qualifications in special needs education should not hurriedly and haphazardly train teachers. Training centres should also be established and should equip teachers with requisite mechanics of handling diverse learners. Submitted: 02/08/2018 Accepted: 31/08/2018 Published: 06/09/2018
Heterotachy and Functional Shift in Protein Evolution

Study of structure/function relationships constitutes an important field of research, especially for modification of protein function and drug design. However, the fact that rational design (i.e. the modification of amino acid sequences by means of directed mutagenesis, based on knowledge of the three‐dimensional structure) appears to be much less efficient than irrational design (i.e. random mutagenesis followed by in vitro selection) clearly indicates that we understand little about the relationships between primary sequence, three‐dimensional structure and function. The use of evolutionary approaches and concepts will bring insights to this difficult question. The increasing availability of multigene family sequences that has resulted from genome projects has inspired the creation of novel in silico evolutionary methods to predict details of protein function in duplicated (paralogous) proteins. The underlying principle of all such approaches is to compare the evolutionary properties of homologous sequence positions in paralogs. It has been proposed that the positions that show switches in substitution rate over time‐‐i.e., 'heterotachous sites'‐‐are good indicators of functional divergence. However, it appears that heterotachy is a much more general process, since most variable sites of homologous proteins with no evidence of functional shift are heterotachous. Similarly, it appears that switches in substitution rate are as frequent when paralogous sequences are compared as when orthologous sequences are compared. Heterotachy, instead of being indicative of functional shift, may more generally reflect a less specific process related to the many intra‐ and inter‐molecular interactions compatible with a range of more or less equally viable protein conformations. These interactions will lead to different constraints on the nature of the primary sequences, consistently with theories suggesting the non‐independence of substitutions in proteins. However, a specific type of amino acid variation might constitute a good indicator of functional divergence: substitutions occurring at positions that are generally slowly evolving. Such substitutions at constrained sites are indeed much more frequent soon after gene duplication. The identification and analysis of these sites by complementing structural information with evolutionary data may represent a promising direction to future studies dealing with the functional characterization of an ever increasing number of multi‐gene families identified by complete genome analysis. IUBMB Life, 55: 257‐265, 2003
Identification of Interindividual and Intraindividual Movement Patterns in Handball Players of Varying Expertise Levels

The authors examined the movement patterns of 5 left-handed handball players (ranging from beginner to national level) who threw a handball to different sections of a goal as if a goalkeeper were present. The authors used time-continuous, 3-dimensional kinematic data to assess interindividual movement patterns and considered participants' intraindividual differences relative to different targets. Cluster analysis yielded the highest assignment rates for level of expertise; a mean of 92% of trials was correctly assessed. The authors observed an interaction with expertise for the intraindividual movement patterns. Variability in the novice throwers was increased, whereas (a) advanced throwers experienced a period of stability, and (b) the expert thrower's variability was increased. The results indicate that random variability characterizes novice motor performance, whereas active functional variability may exemplify expert motor performance.
Health Care Student Knowledge and Willingness to Work in Infectious Disease Outbreaks

Abstract Objective Health care workers are critical first responders. Understanding which factors motivate their willingness to work (WTW) during infectious disease outbreaks may guide improvements in preparedness. The perspective of health care students, the future workforce, remains largely unexplored. This study compared factors influencing WTW among medical, nursing, and pharmacy students. Methods A printed survey was administered to 631 medical, nursing, and pharmacy students. The questionnaire elicited information regarding prior disaster training, disease-related knowledge, and WTW in the setting of infectious diseases with contact or respiratory transmission. Results Analyses of the 579 respondents (92% response rate) demonstrated that students were less fearful for their health and more willing to work during outbreaks with contact transmission than during those with respiratory transmission. Medical students were the most fearful for their health, but they demonstrated the greatest WTW, followed by nursing students, and then pharmacy students. Medical students were also the most knowledgeable about infectious diseases. Prior disaster training was associated with greater WTW. Conclusions Extent of disease-related knowledge and prior disaster training appear to influence WTW. Our findings, taken in the context of a remarkable underemphasis on disaster preparedness in health care curricula, call for a broader incorporation of disaster training to improve the WTW of health care students, and, ultimately, health care workers. (Disaster Med Public Health Preparedness. 2017;11:694–700)
Comparative Chemical Analysis of Mentha piperita and M. spicata and a Fast Assessment of Commercial Peppermint Teas

The hydrodistilled essential oils and volatile compounds (by static headspaces technique) of Mentha piperita L. and M. spicata L. were characterized by GC-MS. Headspace analysis of Mentha piperita revealed the existence of menthone (25.4%), 1,8-cineole (17.7%) and menthol (12.1%) as the main components, while the essential oil contained high amounts of menthol (46.8%) and menthone (25.6%). By contrast, headspace analysis of M spicata showed a high content of limonene (37.0%) together with carvone (13.0%), β-pinene (10.4%) and α-pinene (9.8%), while the essential oil was reach in carvone (51.7%), dihydrocarveol (11.5%) and cis-dihydrocarvone (9.1%). Eleven samples of peppermint tea available on the Romanian market were analysed by headspace GC-MS. The volatile profile of the tea samples was compared with that of Mentha piperita L. and certain differences were emphasized and discussed.
Can Education Unlock Scale? The Demand Impact of Educational Games on a Large-Scale Unsubsidised Index Insurance Programme in Ethiopia

Abstract There is increasing concern that voluntary index insurance may fail to produce sustainable impacts at scale. Despite this concern, most research is focused on experimental or highly subsidised projects – little is known about farmer demand for market priced, commercially focused index insurance. We estimate the impact of attending a randomly administered education game for index insurance on the likelihood of purchase in the context of an unsubsidised, non-loan-linked commercial insurance programme in Ethiopia. This programme has already scaled to the tens of thousands via labour-based liquidity programmes and cash only sales. We find that the likelihood of purchasing unsubsidised insurance in commercial sales rose by an average of 10 per cent across villages, and that the average amount of insurance purchased increased by 33 per cent. These results demonstrate a possibility for financial education to increase demand, particularly among the subset of farmers who are not eligible for liquidity programmes.
Effect of a practice-based strategy on test ordering performance of primary care physicians: a randomized trial.

CONTEXT Numbers of diagnostic tests ordered by primary care physicians are growing and many of these tests seem to be unnecessary according to established, evidence-based guidelines. An innovative strategy that focused on clinical problems and associated tests was developed. OBJECTIVE To determine the effects of a multifaceted strategy aimed at improving the performance of primary care physicians' test ordering. DESIGN Multicenter, randomized controlled trial with a balanced, incomplete block design and randomization at group level. Thirteen groups of primary care physicians underwent the strategy for 3 clinical problems (arm A; cardiovascular topics, upper and lower abdominal complaints), while 13 other groups underwent the strategy for 3 other clinical problems (arm B; chronic obstructive pulmonary disease and asthma, general complaints, degenerative joint complaints). Each arm acted as a control for the other. SETTING Primary care physician groups in 5 regions in the Netherlands with diagnostic centers recruited from May to September 1998. STUDY PARTICIPANTS Twenty-six primary care physician groups, including 174 primary care physicians. INTERVENTION During the 6 months of intervention, physicians discussed 3 consecutive, personal feedback reports in 3 small group meetings, related them to 3 evidence-based clinical guidelines, and made plans for change. MAIN OUTCOME MEASURE According to existing national, evidence-based guidelines, a decrease in the total numbers of tests ordered per clinical problem, and of some defined inappropriate tests, is considered a quality improvement. RESULTS For clinical problems allocated to arm A, the mean total number of requested tests per 6 months per physician was reduced from baseline to follow-up by 12% among physicians in the arm A intervention, but was unchanged in the arm B control, with a mean reduction of 67 more tests per physician per 6 months in arm A than in arm B (P =.01). For clinical problems allocated to arm B, the mean total number of requested tests per 6 months per physician was reduced from baseline to follow-up by 8% among physicians in the arm B intervention, and by 3% in the arm A control, with a mean reduction of 28 more tests per physician per 6 months in arm B than in arm A (P =.22). Physicians in arm A had a significant reduction in mean total number of inappropriate tests ordered for problems allocated to arm A, whereas the reduction in inappropriate test ordered physicians in arm B for problems allocated to arm B was not statistically significant. CONCLUSION In this study, a practice-based, multifaceted strategy using guidelines, feedback, and social interaction resulted in modest improvements in test ordering by primary care physicians.
In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.

1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/- 0.12 nmol min-1 mg-1 protein; mean +/- s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of sulphonamides, imidazoles and aminoquinoline compounds. The most potent inhibition was evident with the 1-substituted imidazole antimycotic drugs ketoconazole, clotrimazole and miconazole and the sulphonamide sulphaphenazole (IC50 values of 16.5, 2.5, 0.85 and 0.5 microM respectively). A number of compounds showed little or no inhibition of tolbutamide hydroxylase as judged by an IC50 of greater than or equal to 500 microM. 3. The Km value for tolbutamide hydroxylase was 125 microM and Vmax, 0.44 nmol min-1 mg-1 protein. All the substituted imidazoles examined in kinetic studies 1v vs 1s, Line-weaver-Burk plots) produced either non-competitive or mixed inhibition. The sulphonamides exhibited competitive inhibition, the Ki for sulphaphenazole being 0.22 microM. Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4. Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.
TIME BUDGET PRESSURE SEBAGAI PEMODERASI PENGARUH DUE PROFESSIONAL CARE DAN PENGALAMAN AUDIT PADA KUALITAS AUDIT

This study aims to examine the effect of due professional care and audit experience on audit quality with time budget pressure as a moderation variable. This study was conducted at Public Accounting Firm in Bali in 2016. The number of samples taken 62 auditors who are willing to participate in this research. The sample in this research is determined by purposive sampling method. Data analysis technique used is analysis of Multiple Linear Regression and Moderated Regression Analysis. This research successfully demonstrated due professional care and audit experience had a positive effect on audit quality. This study also shows the time budget pressure to strengthen the due professional care relationship on audit quality with moderation test results showing a positive effect. The result of moderation testing between audit experience and time budget pressure shows a negative influence which means time budget pressure weakens the relationship between audit experience on audit quality.
Bifunctional compounds eliciting anti‐inflammatory and anti‐cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning

Certain organophosphorus (OP) nerve agents (e.g. soman) induce neuroinflammatory processes during acute poisoning. An increased level of typical inflammation markers was also observed in poisoning by alkylating agents such as sulfur mustard (HD). The therapeutic potential of new bifunctional compounds was investigated, eliciting activity of non‐steroidal anti‐inflammatory drug (NSAID) and anti‐cholinesterase (anti‐ChE) activity, as an antidotal treatment for both soman and HD poisoning in mice. Three bifunctional compounds were used that include the ChE inhibitor pyridostigmine (PYR) coupled to either ibuprofen (IBU) or diclofenac (DICLO) through an eight (octyl) or ten (decyl) hydrocarbon chain spacer: IBU‐PO, IBU‐PD and DICLO‐PD. These compounds are 15–25 fold less toxic than PYR in mice and exert peripheral and central anti‐inflammatory and anti‐ChE activity in vivo. IBU‐PO (4 mg kg−1, i.p.), IBU‐PD (4 mg kg−1, i.p.) and PYR (0.13 mg kg−1, i.p.) reduced to control levels the brain edema in soman‐poisoned mice (1.1 LD50, s.c.). Pre‐treatment with IBU‐PO, IBU‐PD and DICLO‐PD 4–5 h before soman challenge (2.2–2.3 LD50, s.c.) combined with antidotal treatment (atropine, 11 mg kg−1, 2‐PAM‐Cl, 25 mg kg−1, i.m.) afforded a longer 24 h survival rate (SR) than with PYR pre‐treatment. DICLO‐PD exhibited the largest protection efficacy (SR = 70% vs 17% with PYR). These results indicate a longer duration of action of bifunctional compounds compared with PYR. DICLO‐PD (5% in propyleneglycol) reduced significantly the HD‐induced edema in mouse ear‐skin (51% increase in biopsy weight compared with 100% without treatment). Quantitative evaluation of ear‐skin sections showed that only following DICLO‐PD treatment was there a marked decrease in edema. DICLO‐PD also elicited a significant decrease in HD‐induced vesication as displayed by the reduced sub‐epidermal blister level. The data indicate possible use of NSAID‐ChEI bifunctional compounds for the medical treatment of both nerve and alkylating chemical agents. Copyright © 2005 John Wiley & Sons, Ltd.
Pedestrian detection using a mixture mask model

Pedestrian detection is one of the fundamental tasks of an intelligent transportation system. Differences in illumination, posture and point of view make pedestrian detection confront with great challenges. In this paper, we focus on the main defect in the existing methods: the interference of the non-person area. Firstly, we use mapping vectors to map the original feature matrix to the different mask spaces, then using a part-based structure, we implicitly formulate the model into a multiple-instance problem, and finally use a MIL-SVM to solve the problem. Based on the model, we design a system which can find pedestrians from pictures. We give detailed description on the model and the system in this paper. The experimental results on public data sets show that our method decreases the miss rate greatly.
Post-earthquake housing reconstruction in the Sikkim Himalaya: approaches, challenges, and lessons learnt

ABSTRACT The Himalayan state of Sikkim, India was hit by an earthquake in 2011 that caused widespread devastation. This article reports on the housing reconstruction project in the state, focusing on three questions: what are the key planning decisions, what are the main implementation challenges, and what are the lessons learnt? The findings indicate that key planning decisions need to be taken on implementation mechanisms, financing strategies, beneficiary identification, housing design, and procurement. The main implementation challenges are enabling homeowner involvement, slow progress, timely procurement, and stalled house construction. The article also identifies useful lessons for other agencies involved in reconstruction.