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81.
The synthesis of chain-modified analogues of the naturally-occurring glycosidase inhibitor, salacinol, and its selenium analogue, blintol is described. The modification consists of a frame shift of the sulfate moiety by one carbon atom in the zwitterionic structures as well as an extension of the acyclic chain to five carbons. The target molecules were synthesized by alkylation of 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio (or seleno)-D-arabinitol at the ring heteroatom by 2,3,5-tri-O-p-methoxybenzyl D- or L-xylitol-1,4-cyclic sulfate, followed by deprotection with trifluoroacetic acid. Two of the four compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values of 20+/-4 and 53+/-5 microM. 相似文献
82.
The pharmaceutical industry is committed to marketing safer drugs with fewer side effects, predictable pharmacokinetic properties and quantifiable drug-drug interactions. Drug metabolism is a major determinant of drug clearance and interindividual pharmacokinetic differences, and an indirect determinant of the clinical efficacy and toxicity of drugs. Progressive advances in the knowledge of metabolic routes and enzymes responsible for drug biotransformation have contributed to understanding the great metabolic variations existing in human beings. Phenotypic as well genotypic differences in the expression of the enzymes involved in drug metabolism are the main causes of this variability. However, only a minor part of phenotypic variability in man is attributable to gene polymorphisms, thus making the definition of a normal liver complex. At present, the use of human in vitro hepatic models at early preclinical stages means that the process of selecting drug candidates is becoming much more rational. Cultured human hepatocytes are considered to be the closest model to human liver. However, the fact that hepatocytes are located in a microenvironment that differs from that of the cell in the liver raises the question: to what extent does drug metabolism variability observed in vitro actually reflect that of the liver in vivo? By comparing the metabolism of a model compound both in vitro and in vivo in the same individual, a good correlation between the in vitro and in vivo relative abundance of oxidized metabolites and the hydrolysis of the compound was observed. Thus, it is reasonable to consider that the variability observed in human hepatocytes reflects the existing phenotypic heterogeneity of the P450 expression in human liver. 相似文献
83.
Li AP 《Chemico-biological interactions》2007,168(1):16-29
The recent developments in the isolation, culturing, and cryopreservation of human hepatocytes, and the application of the cells in drug development are reviewed. Recent advances include the improvement of cryopreservation procedures to allow cell attachment, thereby extending the use of the cells to assays that requires prolong culturing such as enzyme induction studies. Applications of human hepatocytes in drug development include the evaluation of metabolic stability, metabolite profiling and identification, drug-drug interaction potential, and hepatotoxic potential. The use of intact human hepatocytes, because of the complete, undisrupted metabolic pathways and cofactors, allows the development of data more relevant to humans in vivo than tissue fractions such as human liver microsomes. Incorporation of key in vivo factors with the intact hepatocytes in vitro may help predictive human in vivo drug properties. For instance, evaluation of drug metabolism and drug-drug interactions with intact human hepatocytes in 100% human serum may eliminate the need to determine in vivo intracellular concentrations for the extrapolation of in vitro data to in vivo. Co-culturing of hepatocytes and nonhepatic primary cells from other organs in the integrated discrete multiple organ co-culture (IdMOC) may allow the evaluation of multiple organ interactions in drug metabolism and drug toxicity. In conclusion, human hepatocytes represent a critical experimental model for drug development, allowing early evaluation of human drug properties to guide the design and selection of drug candidates with a high probability of clinical success. 相似文献
84.
85.
Comparison of the complete human genome sequence to one of its closest relatives, the chimpanzee genome, provides a unique opportunity for exploring recent evolutionary events affecting the microsatellites in these species. A simple assumption on microsatellite distribution is that the total length of perfect repeats is constant compared to that of imperfect ones regardless of the repeat sequence. In this paper, we show that this is valid for most of the chimpanzee genome but not for a number of human chromosomes. Our results suggest accelerated evolution of microsatellites in the human genome relative to the chimpanzee lineage. 相似文献
86.
A recombinant DING protein from Pseudomonas fluorescens has been previously shown to have a phosphate-binding site, and to be mitogenic for human cells. Here we report the three-dimensional structure of the protein, confirming a close similarity to the "Venus flytrap" structure seen in other human and bacterial phosphate-binding proteins. Site-directed mutagenesis confirms the role of a key residue involved in phosphate binding, and that the mitogenic activity is not dependent on this property. Deletion of one of the two hinged domains that constitute the Venus flytrap also eliminates phosphate binding whilst enhancing mitogenic activity. 相似文献
87.
A. Kolahi M. Hoviattalab T. Rezaeian M. Alizadeh M. Bostan H. Mokhtarzadeh 《Biomedical signal processing and control》2007,2(1):59-67
In this paper a complete design of a high speed optical motion analyzer system has been described. The main core of the image processing unit has been implemented by the differential algorithm procedure. Some intelligent and conservative procedures that facilitate the search algorithm have also been proposed and implemented for the processing of human motions. Moreover, an optimized modified direct linear transformation (MDLT) method has been used to reconstruct 3D markers positions which are used for deriving kinematic characteristics of the motion. Consequently, a set of complete tests using some simple mechanical devices were conducted to verify the system outputs. Considering the system verification for human motion analysis, we used the system for gait analysis and the results including joint angles showed good compatibility with other investigations. Furthermore, a sport application example of the system has been quantitatively presented and discussed for Iranian National Karate-kas. The low computational cost, the high precision in detecting and reconstructing marker position with 2.39 mm error, and the capability of capturing from any number of cameras to increase the domain of operation of the subject, has made the proposed method a reliable approach for real-time human motion analysis. No special environment limitation, portability, low cost hardware and built in units for simulations and kinematic analysis are the other significant specifications of this system. 相似文献
88.
Expression of sialyl Lewis x (sLe(x)) and sialyl Lewis a (sLe(a)) on cell-surface glycoproteins endows cells with the ability to adhere to E-, P-, and L-selectins present on endothelia, platelets, or leukocytes. Special arrangements of these glycotopes in cancers are thought to play a key role in metastasis. Previous studies have mostly described membrane-bound sLe(x) and sLe(a) activities. In this report, the major O-glycans of the secreted human ovarian cyst sialoglycoproteins from a Le(a+) nonsecretor individual (human ovarian cyst sample 350) were characterized by MS/MS analyses and immuno-/lectin-chemical assays. The results showed that HOC 350 carries a large number of epitopes for sLe(x), sLe(a), and Le(a) reactive antibodies. Advanced MS/MS sequencing coupled with mild periodate oxidation and exoglycosidase digestions further revealed that the O-glycans from HOC 350 are mostly of core 1 and 2 structures, extended and branched on the 3-arm with both type I and type II chains, complete with variable degrees of terminal sialylation and/or fucosylation to yield the sLe(x) or sLe(a) epitopes. Thus, the underlying core and peripheral backbone structures are similar to that of a previously proposed composite structural model for nonsialylated human ovarian cysts O-glycans, but with some notable distinguishing structural features in addition to sialylation. 相似文献
89.
The impact of a malaria elimination initiative on school outcomes: Evidence from Southern Mozambique
Despite the significant improvements achieved over the last ten years, primary education attainment in Mozambique is still low. Potential reasons acting from the demand perspective include ill health, among other factors. In Mozambique, ill health is still largely linked to malaria, which is a leading cause of outpatient contacts, hospital admissions and death, particularly among under-five and school-aged children. Despite this, in Mozambique and more generally, in malaria endemic countries, the identification and measurement of how improved malaria indicators may contribute to better school outcomes remains largely unknown. In particular, there is a low understanding of the extent to which better health translates immediately into school indicators, such as absenteeism and grades. In this study, we exploit the first year of a malaria elimination initiative implemented in Magude district (Southern Mozambique) that started in 2015, as a quasi-experiment to estimate the impact of malaria on selected primary school outcomes. While malaria was not eliminated, its incidence drastically dropped. We use as control a neighbouring district (Manhiça) with similar socio-economic and epidemiological characteristics. By employing a difference-in-differences (DiD) approach, we examine whether the positive health shock translated into improved school outcomes. Using information from school registers, we generated a dataset on school attendance and grades for 9,848 primary-school students from 9 schools (4 in the treated district and 5 in the control district). In our main specification, a repeated cross-section analysis, we find that the elimination initiative led to a 28% decrease in school absenteeism and a 2% increase in students’ grades. Our results are robust across different specifications, including a panel DiD individual fixed effects estimate on a sub-sample of students. These findings provide evidence on the negative impact of malaria on primary education attainment and suggest remarkable economic benefits consequent to its elimination. 相似文献
90.
We hypothesize that the impact of antibiotics is moderated by a population’s inherent (genetic) resistance to infectious disease. Using the introduction of sulfa drugs in 1937, we show that US states that are more genetically susceptible to infectious disease saw larger declines in their bacterial mortality rates following the introduction of sulfa drugs in 1937. This suggests area-level genetic endowments of disease resistance and the discovery of medical technologies have acted as substitutes in determining levels of health across the US. We also document immediate effects of sulfa drug exposure to the age of the workforce and cumulative effects on educational attainment for cohorts exposed to sulfa drugs in early life. 相似文献