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121.
Yongqi Deng Zhiwei Yang Gerald W. Shipps Sie-Mun Lo Robert West Joyce Hwa Shuqin Zheng Constance Farley Jean Lachowicz Margaret van Heek Alan S. Bass Dinesh P. Sinha Craig R. Mahon Mark E. Cartwright 《Bioorganic & medicinal chemistry letters》2013,23(3):791-796
Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. 相似文献
122.
Gunjan Arora Andaleeb Sajid Mary Diana Arulanandh Richa Misra Anshika Singhal Santosh Kumar Lalit K. Singh Abid R. Mattoo Rishi Raj Souvik Maiti Sharmila Basu-Modak Yogendra Singh 《Biometals》2013,26(5):715-730
Bacillus anthracis Ser/Thr protein kinase PrkC (BasPrkC) is important for virulence of the bacterium within the host. Homologs of PrkC and its cognate phosphatase PrpC (BasPrpC) are the most conserved mediators of signaling events in diverse bacteria. BasPrkC homolog in Bacillus subtilis regulates critical processes like spore germination and BasPrpC modulates the activity of BasPrkC by dephosphorylation. So far, biochemical and genetic studies have provided important insights into the roles of BasPrkC and BasPrpC; however, regulation of their activities is not known. We studied the regulation of BasPrkC/BasPrpC pair and observed that Zn2+ metal ions can alter their activities. Zn2+ promotes BasPrkC kinase activity while inhibits the BasPrpC phosphatase activity. Concentration of Zn2+ in growing B. anthracis cells was found to vary with growth phase. Zn2+ was found to be lowest in log phase cells while it was highest in spores. This variation in Zn2+ concentration is significant for understanding the antagonistic activities of BasPrkC/BasPrpC pair. Our results also show that BasPrkC activity is modulated by temperature changes and kinase inhibitors. Additionally, we identified Elongation Factor Tu (BasEf-Tu) as a substrate of BasPrkC/BasPrpC pair and assessed the impact of their regulation on BasEf-Tu phosphorylation. Based on these results, we propose Zn2+ as an important regulator of BasPrkC/BasPrpC mediated phosphorylation cascades. Thus, this study reveals additional means by which BasPrkC can be activated leading to autophosphorylation and substrate phosphorylation. 相似文献
123.
124.
Myles Horton Jayesh Modi Shiel K. Patel Andrew M. Demchuk Mayank Goyal Michael D. Hill Shelagh B. Coutts 《PloS one》2013,8(6)
Background
TIA and minor stroke have a high risk of recurrent stroke. Abnormalities on CT/CTA and MRI predict recurrent events in TIA and minor stroke. However there are many other imaging abnormalities that could potentially predict outcome that have not been assessed in this population. Also the definition of recurrent events used includes deterioration due to stroke progression or recurrent stroke and whether imaging is either of these is not known.Aims
To improve upon the clinical, CT/CTA and MRI parameters that predict recurrent events after TIA and minor stroke by assessing further imaging parameters. Secondary aim was to explore predictors of stroke progression versus recurrent stroke.Methods
510 consecutive TIA and minor stroke patients had CT/CTA and most had MRI. Primary outcome was recurrent events (stroke progression or recurrent stroke) within 90 days. Further imaging parameters were assessed for prediction of recurrent events (combined outcome of stroke progression and recurrent stroke). We also explored predictors of symptom progression versus recurrence individually.Results
36 recurrent events (36/510, 7.1% (95% CI: 5.0–9.6)) including 19 progression and 17 recurrent strokes. On CT/CTA: white matter disease, prior stroke, aortic arch focal plaque≥4 mm, or intraluminal thrombus did not predict recurrent events (progression or recurrent stroke). On MRI: white matter disease, prior stroke, and microbleeds did not predict recurrent events. Parameters predicting the individual outcome of symptom progression included: ongoing symptoms at initial assessment, symptom fluctuation, intracranial occlusion, intracranial occlusion or stenosis, and the CT/CTA metric. No parameter was strongly predictive of a distinct recurrent stroke.Conclusions
There was no imaging parameter that could improve upon our original CT/CTA or MRI metrics to predict the combined outcome of stroke progression or a recurrent stroke after TIA and minor stroke. We are better at using imaging to predict stroke progression rather than recurrent stroke. 相似文献125.
Lu Yang Paul O’Neill Kareen Martin Juan C. Maass Vassil Vassilev Raj Ladher Andrew K. Groves 《PloS one》2013,8(1)
The inner ear develops from a patch of thickened cranial ectoderm adjacent to the hindbrain called the otic placode. Studies in a number of vertebrate species suggest that the initial steps in induction of the otic placode are regulated by members of the Fibroblast Growth Factor (FGF) family, and that inhibition of FGF signaling can prevent otic placode formation. To better understand the genetic pathways activated by FGF signaling during otic placode induction, we performed microarray experiments to estimate the proportion of chicken otic placode genes that can be up-regulated by the FGF pathway in a simple culture model of otic placode induction. Surprisingly, we find that FGF is only sufficient to induce about 15% of chick otic placode-specific genes in our experimental system. However, pharmacological blockade of the FGF pathway in cultured chick embryos showed that although FGF signaling was not sufficient to induce the majority of otic placode-specific genes, it was still necessary for their expression in vivo. These inhibitor experiments further suggest that the early steps in otic placode induction regulated by FGF signaling occur through the MAP kinase pathway. Although our work suggests that FGF signaling is necessary for otic placode induction, it demonstrates that other unidentified signaling pathways are required to co-operate with FGF signaling to induce the full otic placode program. 相似文献
126.
127.
Low‐Overpotential Electrocatalytic Water Splitting with Noble‐Metal‐Free Nanoparticles Supported in a sp3 N‐Rich Flexible COF
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Dinesh Mullangi Vishal Dhavale Sorout Shalini Shyamapada Nandi Sean Collins Tom Woo Sreekumar Kurungot Ramanathan Vaidhyanathan 《Liver Transplantation》2016,6(13)
Covalent organic frameworks (COFs) are crystalline organic polymers with tunable structures. Here, a COF is prepared using building units with highly flexible tetrahedral sp3 nitrogens. This flexibility gives rise to structural changes which generate mesopores capable of confining very small (<2 nm sized) non‐noble‐metal‐based nanoparticles (NPs). This nanocomposite shows exceptional activity toward the oxygen‐evolution reaction from alkaline water with an overpotential of 258 mV at a current density of 10 mA cm?2. The overpotential observed in the COF‐nanoparticle system is the best in class, and is close to the current record of ≈200 mV for any noble‐metal‐free electrocatalytic water splitting system—the Fe–Co–Ni metal‐oxide‐film system. Also, it possesses outstanding kinetics (Tafel slope of 38.9 mV dec?1) for the reaction. The COF is able to stabilize such small‐sized NP in the absence of any capping agent because of the COF–Ni(OH)2 interactions arising from the N‐rich backbone of the COF. Density‐functional‐theory modeling of the interaction between the hexagonal Ni(OH)2 nanosheets and the COF shows that in the most favorable configuration the Ni(OH)2 nanosheets are sandwiched between the sp3 nitrogens of the adjacent COF layers and this can be crucial to maximizing their synergistic interactions. 相似文献
128.
Ravi Prakash Suneedh Manthri Shaikh Tayyaba Anna Joy Sunil Saksena Raj Devender Singh Ashok Agarwal 《PloS one》2016,11(3)
Background
Violence against sex workers can heighten their vulnerability to HIV and other sexually transmitted infections (STIs). Evidence suggests the risk of acquiring STI/HIV infections among female sex workers (FSWs) who have experienced violence to be almost three-times higher than FSWs, who have not experienced violence. Moreover, an experience of physical and sexual violence makes it difficult for them to negotiate safer sex with their partners and often act as a barrier to utilization of prevention services.Methods
This study utilizes data from 2785 FSWs aged 18 years and above who participated in a cross-sectional behavioural study conducted during 2013–14 in Thane district, Maharashtra. A probability-based two-stage cluster sampling method was used for data collection. This study assesses the effect of physical violence on self-reported STI symptoms (any STI and multiple STIs) and treatment seeking for the last STI symptom using propensity score matching method.Results
About 18% of sampled FSWs reported physical violence at the time of the survey. The likelihood of experiencing such violence was significantly higher among FSWs who solicited clients at public places, engaged in other economic activities apart from sex work, had savings, and reported high client volume per week. FSWs experiencing violence were also inconsistent condom users while engaging in sex with regular partners and clients. The average adjusted effect of violence clearly depicted an increase in the risk of any STI (11%, p<0.05) and multiple STIs (8%, p<0.10) and reduction in treatment seeking (10%, p<0.05).Conclusions
This study demonstrates a significant effect of physical violence on reporting of any STI symptom and treatment seeking. Findings call for the immediate inclusion of strategies aimed to address violence related challenges in HIV prevention program currently being provided at Thane district. Such strategies would further help in enhancing the access to tailored STI prevention and care services among FSWs in the district. 相似文献129.
Paresh Vamanrao Dave Amar Niranjan Shah Pankaj B. Nimavat Bhavesh B. Modi Kirit R. Pujara Pradip Patel Keshabhai Mehariya Kiran Vaman Rade Soma Shekar Kuldeep S. Sachdeva John E. Oeltmann Ajay M. V. Kumar 《PloS one》2016,11(2)
Background
The World Health Organization recommends direct observation of treatment (DOT) to support patients with tuberculosis (TB) and to ensure treatment completion. As per national programme guidelines in India, a DOT provider can be anyone who is acceptable and accessible to the patient and accountable to the health system, except a family member. This poses challenges among children with TB who may be more comfortable receiving medicines from their parents or family members than from unfamiliar DOT providers. We conducted a non-inferiority trial to assess the effect of family DOT on treatment success rates among children with newly diagnosed TB registered for treatment during June–September 2012.Methods
We randomly assigned all districts (n = 30) in Gujarat to the intervention (n = 15) or usual-practice group (n = 15). Adult family members in the intervention districts were given the choice to become their child’s DOT provider. DOT was provided by a non-family member in the usual-practice districts. Using routinely collected clinic-based TB treatment cards, we compared treatment success rates (cured and treatment completed) between the two groups and the non-inferiority limit was kept at 5%.Results
Of 624 children with newly diagnosed TB, 359 (58%) were from intervention districts and 265 (42%) were from usual-practice districts. The two groups were similar with respect to baseline characteristics including age, sex, type of TB, and initial body weight. The treatment success rates were 344 (95.8%) and 247 (93.2%) (p = 0.11) among the intervention and usual-practice groups respectively.Conclusion
DOT provided by a family member is not inferior to DOT provided by a non-family member among new TB cases in children and can attain international targets for treatment success.Trial Registration
Clinical Trials Registry–India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2015/09/006229 相似文献130.
Dinesh Mondal Murari Lal Das Vijay Kumar M. Mamun Huda Pradeep Das Debashis Ghosh Jyoti Priyanka Greg Matlashewski Axel Kroeger Alexander Upfill-Brown Rajib Chowdhury 《PLoS neglected tropical diseases》2016,10(8)
BackgroundWe investigated the efficacy, safety and cost of lime wash of household walls plus treatment of sand fly breeding places with bleach (i.e. environmental management or EM), insecticide impregnated durable wall lining (DWL), and bed net impregnation with slow release insecticide (ITN) for sand fly control in the Indian sub-continent.MethodsThis multi-country cluster randomized controlled trial had 24 clusters in each three sites with eight clusters per high, medium or low sand fly density stratum. Every cluster included 45–50 households. Five households from each cluster were randomly selected for entomological measurements including sand fly density and mortality at one, three, nine and twelve months post intervention. Household interviews were conducted for socioeconomic information and intervention acceptability assessment. Cost for each intervention was calculated. There was a control group without intervention.FindingsSand fly mortality [mean and 95%CI] ranged from 84% (81%-87%) at one month to 74% (71%-78%) at 12 months for DWL, 75% (71%-79%) at one month to 49% (43%-55%) at twelve months for ITN, and 44% (34%-53%) at one month to 22% (14%-29%) at twelve months for EM. Adjusted intervention effect on sand fly density measured by incidence rate ratio ranged from 0.28 (0.23–0.34) at one month to 0.62 (0.51–0.75) at 12 months for DWL; 0.72 (0.62–0.85) at one month to 1.02 (0.86–1.22) at 12 months for ITN; and 0.89 (0.76–1.03) at one months to 1.49 (1.26–1.74) at 12 months for EM. Household acceptance of EM was 74% compared to 94% for both DWL and ITN. Operational cost per household in USD was about 5, 8, and 2 for EM, DWL and ITN, respectively. Minimal adverse reactions were reported for EM and ITN while 36% of households with DWL reported transient itching.InterpretationDWL is the most effective, durable and acceptable control method followed by ITN. The Visceral Leishmaniasis (VL) Elimination Program in the Indian sub-continent should consider DWL and ITN for sand fly control in addition to IRS. 相似文献