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31.
Rakesh Kumar Lili Wang Leonard I. Wiebe Edward E. Knaus 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):265-286
Abstract A new class of 5-halo (or methoxy)-6-alkoxy (azido or hydroxy)-5,6-dihydro-2′,3′-didehydro-3′-deoxythymidines (4–17) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodmgs of 2′,3′-didehydro-3′-deoxythymidine (D4T) were designed to have properties which would enhance their duration of action, lipophilicity and cephalic delivery to the central nervous system. The 5,6-dihydro derivatives of D4T (4–15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, OEt, N3, OH) to the 5,6-olefinic bond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are more lipophilic (P = 0.70 – 4.0 range) than D4T (P = 0.12) and are stable to E. coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy-5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse liver soluble enzyme fraction, was extensive (50–95%). The most potent anti-HIV-1 agents, 5-iodo-6-methoxy (10, 11), 5-bromo-6-azido (14, 15) and 5-methoxy-6-hydroxy (16, 17) derivatives of D4T, exhibited anti-HIV activities comparable to D4T. 相似文献
32.
Cong Cao Mengia S. Rioult-Pedotti Paolo Migani Crystal J. Yu Rakesh Tiwari Keykavous Parang Mark R. Spaller Dennis J. Goebel John Marshall 《PLoS biology》2013,11(2)
Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) TrkB receptor signaling, which is known to be essential for both the induction and maintenance of LTP. We report that TrkB signaling in the AS mouse is defective, and show that reduction of Arc expression to control levels rescues the signaling deficits. Moreover, the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and elevated levels of Arc were found to impede PSD-95/TrkB association. In Ube3A deficient mice, the BDNF-induced recruitment of PSD-95, as well as PLCγ and Grb2-associated binder 1 (Gab1) with TrkB receptors was attenuated, resulting in reduced activation of PLCγ-α-calcium/calmodulin-dependent protein kinase II (CaMKII) and PI3K-Akt, but leaving the extracellular signal-regulated kinase (Erk) pathway intact. A bridged cyclic peptide (CN2097), shown by nuclear magnetic resonance (NMR) studies to uniquely bind the PDZ1 domain of PSD-95 with high affinity, decreased the interaction of Arc with PSD-95 to restore BDNF-induced TrkB/PSD-95 complex formation, signaling, and facilitate the induction of LTP in AS mice. We propose that the failure of TrkB receptor signaling at synapses in AS is directly linked to elevated levels of Arc associated with PSD-95 and PSD-95 PDZ-ligands may represent a promising approach to reverse cognitive dysfunction. 相似文献
33.
Chandana Basu Mallick Florin Mircea Iliescu M?rt M?ls Sarah Hill Rakesh Tamang Gyaneshwer Chaubey Rie Goto Simon Y. W. Ho Irene Gallego Romero Federica Crivellaro Georgi Hudjashov Niraj Rai Mait Metspalu C. G. Nicholas Mascie-Taylor Ramasamy Pitchappan Lalji Singh Marta Mirazon-Lahr Kumarasamy Thangaraj Richard Villems Toomas Kivisild 《PLoS genetics》2013,9(11)
Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India. 相似文献
34.
Stephen L. Hicks Rakesh Sharma Amad N. Khan Claire M. Berna Andrea Waldecker Kevin Talbot Chris Kennard Martin R. Turner 《PloS one》2013,8(12)
The neurodegenerative disorder amyotrophic lateral sclerosis may render patients unable to speak or write, so that objective assessment of cognitive impairment, which is commonly of a dysexecutive nature, is challenging. There is therefore a need to develop other methods of assessment that utilize other relatively unaffected motor systems. In this proof-of-principle study a novel eye-tracking version of the trail-making test was compared with performance on the standard written version in a group of healthy volunteers. There was good correlation for speed between both versions of Part B (R2=0.73), suggesting that this is a viable method to objectively assess cognitive impairment in disorders where patients are unable to speak or write. 相似文献
35.
Sajad H. Ahanger Arumugam Srinivasan Dasari Vasanthi Yogesh S. Shouche Rakesh K. Mishra 《Nucleic acids research》2013,41(2):804-816
The conservation of hox genes as well as their genomic organization across the phyla suggests that this system of anterior–posterior axis formation arose early during evolution and has come under strong selection pressure. Studies in the split Hox cluster of Drosophila have shown that proper expression of hox genes is dependent on chromatin domain boundaries that prevent inappropriate interactions among different types of cis-regulatory elements. To investigate whether boundary function and their role in regulation of hox genes is conserved in insects with intact Hox clusters, we used an algorithm to locate potential boundary elements in the Hox complex of mosquito, Anopheles gambiae. Several potential boundary elements were identified that could be tested for their functional conservation. Comparative analysis revealed that like Drosophila, the bithorax region in A. gambiae contains an extensive array of boundaries and enhancers organized into domains. We analysed a subset of candidate boundary elements and show that they function as enhancer blockers in Drosophila. The functional conservation of boundary elements from mosquito in fly suggests that regulation of hox genes involving chromatin domain boundaries is an evolutionary conserved mechanism and points to an important role of such elements in key developmentally regulated loci. 相似文献
36.
Mayank Singh Clayton R. Hunt Raj K. Pandita Rakesh Kumar Chin-Rang Yang Nobuo Horikoshi Robert Bachoo Sara Serag Michael D. Story Jerry W. Shay Simon N. Powell Arun Gupta Jessie Jeffery Shruti Pandita Benjamin P. C. Chen Dorothee Deckbar Markus L?brich Qin Yang Kum Kum Khanna Howard J. Worman Tej K. Pandita 《Molecular and cellular biology》2013,33(16):3390
37.
38.
Dr. Atanu Kumar Pati Arti Parganiha Anjana Kar Rakesh Soni Sushmita Roy Vivek Choudhary 《Chronobiology international》2013,30(6):1179-1197
The aim of the present study was to evaluate the characteristics of the circadian rest‐activity rhythm of cancer patients. Thirty‐one in‐patients, consisting of 19 males and 12 females, were randomly selected from the Regional Cancer Center, Pandit Jawaharlal Nehru Medical College, Raipur, India. The rest‐activity rhythm was studied non‐invasively by wrist actigraphy, and compared with 35 age‐matched apparently healthy subjects (22 males and 13 females). All subjects wore an Actiwatch (AW64, Mini Mitter Co. Inc., USA) for at least 4–7 consecutive days. Fifteen‐second epoch length was selected for gathering actigraphy data. In addition, several sleep parameters, such as time in bed, assumed sleep, actual sleep time, actual wake time, sleep efficiency, sleep latency, sleep bouts, wake bouts, and fragmentation index, were also recorded. Data were analyzed using several statistical techniques, such as cosinor rhythmometry, spectral analysis, ANOVA, Duncan's multiple‐range test, and t‐test. Dichotomy index (I<O) and autocorrelation coefficient (r24) were also computed. The results validated a statistically significant circadian rhythm in rest‐activity with a prominent period of 24 h for most cancer patients and control subjects. Results of this study further revealed that cancer patients do experience a drastic alteration in the circadian rest‐activity rhythm parameters. Both the dichotomy index and r24 declined in the group of cancer patients. The occurrence of the peak (acrophase, Ø) of the rest‐activity rhythm was earlier (p<0.001) in cancer patients than age‐ and gender‐matched control subjects. Results of sleep parameters revealed that cancer patients spent longer time in bed, had longer assumed and actual sleep durations, and a greater number of sleep and wake bouts compared to control subjects. Further, nap frequency, total nap duration, average nap, and total nap duration per 1 h awake span were statistically significantly higher in cancer patients than control subjects. In conclusion, the results of the present study document the disruption of the circadian rhythm in rest‐activity of cancer in‐patients, with a dampening of amplitude, lowering of mean level of activity, and phase advancement. These alterations of the circadian rhythm characteristics could be attributed to disease, irrespective of variability due to gender, sites of cancer, and timings of therapies. These results might help in designing patient‐specific chronotherapeutic protocols. 相似文献
39.
Yelena Katsenovich Denny Carvajal Rakesh Guduru Leonel Lagos Chen-Zhong Li 《Geomicrobiology journal》2013,30(2):120-130
Production of nuclear fuel has resulted in hazardous waste streams that have contaminated the soil and groundwater. Arthrobacter strains, G975, G968, and G954 were used in the prescreening tests to evaluate their tolerance to UO2 2+ and investigate bacteria-U(VI) interactions under oxidizing pH-neutral conditions. Experiments have shown G975 is the fastest growing and the most uranium tolerant strain that removed about 90% of uranium from growth media. Atomic Force Microscopy images exhibited an irregular surface structure, which perhaps provided a larger surface area for uranium precipitation. The data indicate that aerobic heterotrophic bacteria may offer a solution to sequestering uranium in oxic conditions, which prevail in the vadose zone. 相似文献
40.
Stephen GS Vreden Jeetendra K Jitan Rakesh D Bansie Malti R Adhin 《Memórias do Instituto Oswaldo Cruz》2013,108(8):968-973
The emerging resistance to artemisinin derivatives that has been reported in
South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first
line therapy for uncomplicated Plasmodium falciparum infections in
Suriname. This drug assessment was performed according to the recommendations of the
World Health Organization in 2011. The decreasing number of malaria cases in
Suriname, which are currently limited to migrating populations and gold miners,
precludes any conclusions on artemether efficacy because adequate numbers of patients
with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3
parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the
emergence of resistance to artemether. The prevalence of day 3 parasitaemia was
assessed in a study in 2011 and was compared to that in a study in 2005/2006. The
same protocol was used in both studies and artemether-lumefantrine was the study
drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3
compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable
patients in the 2011 study who were followed up until day 28 had negative slides and
similar findings were obtained in all 38 evaluable patients in the 2005/2006 study.
The significantly increased incidence of parasite persistence on day 3 may be an
indication of emerging resistance to artemether. 相似文献