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951.
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Background
Insulin-degrading enzyme (IDE) is an allosteric Zn+2 metalloprotease involved in the degradation of many peptides including amyloid-β, and insulin that play key roles in Alzheimer''s disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates.Methodology/Principal Findings
In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-β, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only.Conclusion/Significance
This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible. 相似文献954.
Luo G Lin L Ibrahim AS Baquir B Pantapalangkoor P Bonomo RA Doi Y Adams MD Russo TA Spellberg B 《PloS one》2012,7(1):e29446
Extreme-drug-resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem-resistant isolates, and was ≥89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections. 相似文献
955.
This study investigated the proposition of relaxation offered by performing the Muslim prayers by measuring the alpha brain
activity in the frontal (F3–F4), central (C3–C4), parietal (P3–P4), and occipital (O1–O2) electrode placements using the International
10–20 System. Nine Muslim subjects were asked to perform the four required cycles of movements of Dhuha prayer, and the EEG were subsequently recorded with open eyes under three conditions, namely, resting, performing four cycles
of prayer while reciting the specific verses and supplications, and performing four cycles of acted salat condition (prayer movements without any recitations). Analysis of variance (ANOVA) tests revealed that there were no significant
difference in the mean alpha relative power (RPα) between the alpha amplitude in the Dhuha prayer and the acted conditions in all eight electrode positions. However, the mean RPα showed higher alpha amplitude during the prostration position of the Dhuha prayer and acted condition at the parietal and occipital regions in comparison to the resting condition. Findings were similar
to other studies documenting increased alpha amplitude in parietal and occipital regions during meditation and mental concentration.
The incidence of increased alpha amplitude suggested parasympathetic activation, thus indicating a state of relaxation. Subsequent
studies are needed to delineate the role of mental concentration, and eye focus, on alpha wave amplitude while performing
worshipping acts. 相似文献
956.
Joseph B. Williams Mohammed Shobrak Thomas M. Wilms Ibrahim A. Arif Haseeb A. Khan 《Saudi Journal of Biological Sciences》2012,19(2):121-130
Global warming is occurring at an alarming rate and predictions are that air temperature (Ta) will continue to increase during this century. Increases in Ta as a result of unabated production of greenhouse gases in our atmosphere pose a threat to the distribution and abundance of wildlife populations worldwide. Although all the animals worldwide will likely be affected by global warming, diurnal animals in the deserts will be particularly threatened in the future because Tas are already high, and animals have limited access to water. It is expected that Saudi Arabia will experience a 3–5 °C in Ta over the next century. For predicting the consequences of global warming for animals, it is important to understand how individual species will respond to higher air temperatures. We think that populations will not have sufficient time to make evolutionary adjustments to higher Ta, and therefore they will be forced to alter their distribution patterns, or make phenotypic adjustments in their ability to cope with high Ta. This report examines how increases in Ta might affect body temperature (Tb) in the animals of arid regions. We chose three taxonomic groups, mammals, birds, and reptiles (Arabian oryx, Arabian spiny-tailed lizard, vultures, and hoopoe larks) from Saudi Arabia, an area in which Ta often reaches 45 °C during midday in summer. When Ta exceeds Tb, animals must resort to behavioral and physiological methods to control their Tb; failure to do so results in death. The observations of this study show that in many cases Tb is already close to the upper lethal limit of around 47° C in these species and therefore allowing their Tb to increase as Ta increases are not an option. We conclude that global warming will have a detrimental impact on a wide range of desert animals, but in reality we know little about the ability of most animals to cope with change in Ta. The data presented should serve as base-line information on Tb of animals in the Kingdom for future scientists in Saudi Arabia as they explore the impact of global warming on animal species. 相似文献
957.
Huda A. Eltahir Ameera A. M. Adam Zeinab A. Yahia Noon F. Ali Dalia M. Mursi Ashraaf M. Higazi Nahid A. Eid Ahmed M. Elhassan Hiba S. Mohammed Muntaser E. Ibrahim 《Molecular biology reports》2012,39(12):10833-10836
The aim of this report is to determine frequencies and associations of p53 codon 72 arg/pro polymorphism with different types of cancer in Sudan. p53 codon72 arg/pro polymorphism distribution and allele frequencies in 264 samples of different types of cancers were investigated using PCR. The results were compared to 235 normal controls. The results indicated significant differences in frequency and genotype association between different types of cancers. Breast carcinoma patients most prominently showed excess of homozygous arg genotype as compared to controls with an Odd ratio (OR) of 19.44, 95?%CI: 6.6–78.3, P?<?0.0001. Less prominently cervical cancer showed genotype effect of 2.4 OR, 95?%CI: 1.12–5.33, P?=?0.015, while esophageal cancer had an OR of 0.57, 95?%CI: 0.23–1.42, P?=?0.1. In Burkitt’s lymphoma, however, in contrast the homozygous arg accounted for only 6.9?%, (OR 0.18, 95?%CI: 0.02–0.89, P?=?0.018). We concluded that p53 arg/pro polymorphism has different pattern of frequency in different types of cancer among Sudanese patients, indicating perhaps different etiology and biology of these tumours. 相似文献
958.
959.
Malte Spielmann Francesco Brancati Peter M. Krawitz Peter?N. Robinson Daniel M. Ibrahim Martin Franke Jochen Hecht Silke Lohan Katarina Dathe Anna?Maria Nardone Paola Ferrari Antonio Landi Lars Wittler Bernd Timmermann Danny Chan Ulrich Mennen Eva Klopocki Stefan Mundlos 《American journal of human genetics》2012,91(4):629-635
The study of homeotic-transformation mutants in model organisms such as Drosophila revolutionized the field of developmental biology, but how these mutants relate to human developmental defects remains to be elucidated. Here, we show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, shows features of a homeotic limb transformation in which the arms have acquired morphological characteristics of a leg. Using high-resolution array comparative genomic hybridization and paired-end whole-genome sequencing, we identified two deletions and a translocation 5′ of PITX1. The structural changes are likely to remove active PITX1 forelimb suppressor and/or insulator elements and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. We generated transgenic mice in which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype. 相似文献
960.
Parga JA Sauther ML Cuozzo FP Jacky IA Lawler RR 《American journal of physical anthropology》2012,147(1):21-29
In light of historical and recent anthropogenic influences on Malagasy primate populations, in this study ring-tailed lemur (Lemur catta) samples from two sites in southwestern Madagascar, Beza Mahafaly Special Reserve (BMSR) and Tsimanampetsotsa National Park (TNP), were evaluated for the genetic signature of a population bottleneck. A total of 45 individuals (20 from BMSR and 25 from TNP) were genotyped at seven microsatellite loci. Three methods were used to evaluate these populations for evidence of a historical bottleneck: M-ratio, mode-shift, and heterozygosity excess tests. Three mutation models were used for heterozygosity excess tests: the stepwise mutation model (SMM), two-phase model (TPM), and infinite allele model (IAM). M-ratio estimations indicated a potential bottleneck in both populations under some conditions. Although mode-shift tests did not strongly indicate a population bottleneck in the recent historical past when samples from all individuals were included, a female-only analysis indicated a potential bottleneck in TNP. Heterozygosity excess was indicated under two of the three mutation models (IAM and TPM), with TNP showing stronger evidence of heterozygosity excess than BMSR. Taken together, these results suggest that a bottleneck may have occurred among L. catta in southwestern Madagascar in the recent past. Given knowledge of how current major stochastic climatic events and human-induced change can negatively impact extant lemur populations, it is reasonable that comparable events in the historical past could have caused a population bottleneck. This evaluation additionally functions to highlight the continuing environmental and anthropogenic challenges faced by lemurs in southwestern Madagascar. 相似文献