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Summary Twelve cases of lissencephaly are reported. A high resolution chromosome study was performed on each in order to detect small chromosomal anomalies, undetectable with routine techniques. Only one case was shown to have an unbalanced karyotype with a microdeletion of the short arm of chromosome 17(del 17p). This child also had symptoms of the Miller-Dieker syndrome, consisting of lissencephaly, characteristic facies, pre- and post-natal growth retardation and other birth defects. As proposed by Dobyns, it seems justifiable to classify lissencephalies into four different groups, according to other clinical manifestations and results of chromosome studies. 相似文献
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《Bioorganic & medicinal chemistry》2016,24(7):1504-1512
Human serum albumin (HSA) and bovine β-lactoglobulin (β-Lg) are both introduced as blood and oral carrier scaffolds with high affinity for a wide range of pharmaceutical compounds. Prodigiosin, a natural three pyrrolic compound produced by Serratia marcescens, exhibits many pharmaceutical properties associated with health benefits. In the present study, the interaction of prodigiosin with HSA and β-Lg was investigated using fluorescence spectroscopy, circular dichroism (CD) and computational docking. Prodigiosin interacts with the Sudlow’s site I of HSA and the calyx of β-Lg with association constant of 4.41 × 104 and 1.99 × 104 M−1 to form 1:1 and 2:3 complexes at 300 K, respectively. The results indicated that binding of prodigiosin to HSA and β-Lg caused strong fluorescence quenching of both proteins through static quenching mechanism. Electrostatic and hydrophobic interactions are the major forces in the stability of PG–HSA complex with enthalpy- and entropy-driving mode, although the formation of prodigiosin–β-Lg complex is entropy-driven hydrophobic associations. CD spectra showed slight conformational changes in both proteins due to the binding of prodigiosin. Moreover, the ligand displacement assay, pH-dependent interaction and protein–ligand docking study confirmed that the prodigiosin binds to residues located in the subdomain IIA and IIIA of HSA and central calyx of β-Lg. 相似文献
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The aim of this work was to study the influence of β-cyclodextrin (β-CD) on the biopharmaceutic properties of diclofenac (DCF).
To this purpose the physicochemical characterization of diclofenac-β-cyclodextrin binary systems was performed both in solution
and solid state. Solid phase characterization was performed using differential scanning calorimetry (DSC), powder x-ray diffractometry
(XRD), and Fourier transform infrared spectroscopy (FTIR). Phase solubility analyses, and in vitro permeation experiments
through a synthetic membrane were performed in solution. Moreover, DCF/β-CD interactions were studied in DMSO by1H nuclear magnetic resonance (NMR) spectroscopy. The effects of different preparation methods and drug-to-β-CD molar ratios
were also evaluated. Phase solubility studies revealed 1∶1 M complexation of DCF when the freeze-drying method was used for
the preparation of the binary system. The true inclusion for the freeze-dried binary system was confirmed by1H NMR spectroscopy, DSC, powder XRD, and IR studies. The dissolution study revealed that the drug dissolution rate was improved
by the presence of CDs and the highest and promptest release was obtained with the freeze-dried binary system. Diffusion experiments
through a silicone membrane showed that DCF diffusion was higher from the saturated drug solution (control) than the freeze-dried
inclusion complexes, prepared using different DCF-β-CD molar ratios. However, the presence of the inclusion complex was able
to stabilize the system giving rise to a more regular diffusion profile.
Published: October 22, 2005 相似文献
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Arthur HM Bamforth SD 《Birth defects research. Part A, Clinical and molecular teratology》2011,91(6):423-434
Transforming growth factor β (TGFβ) regulates one of the major signaling pathways that control tissue morphogenesis. In vitro experiments using heart explants indicated the importance of this signaling pathway for the generation of cushion mesenchymal cells, which ultimately contribute to the valves and septa of the mature heart. Recent advances in mouse genetics have enabled in vivo investigation into the roles of individual ligands, receptors, and coreceptors of this pathway, including investigation of the tissue specificity of these roles in heart development. This work has revealed that (1) cushion mesenchyme can form in the absence of TGFβ signaling, although mesenchymal cell numbers may be misregulated; (2) TGFβ signaling is essential for correct remodeling of the cushions, particularly those of the outflow tract; (3) TGFβ signaling also has a role in ensuring accurate remodeling of the pharyngeal arch arteries to form the mature aortic arch; and (4) mesenchymal cells derived from the epicardium require TGFβ signaling to promote their differentiation to vascular smooth muscle cells to support the coronary arteries. In addition, a mouse genetics approach has also been used to investigate the disease pathogenesis of Loeys-Dietz syndrome, a familial autosomal dominant human disorder characterized by a dilated aortic root, and associated with mutations in the two TGFβ signaling receptor genes, TGFBR1 and TGFBR2. Further important insights are likely as this exciting work progresses. 相似文献
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Silva Vde A Cargnelutti MT Giesel GM Palmieri LC Monteiro RQ Verli H Lima LM 《PloS one》2011,6(9):e24735
Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors. 相似文献
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Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to evaluate their toxicological properties and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure–activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent. 相似文献
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The bacterial outer membrane protein OmpA is composed of an N-terminal 171-residue beta-barrel domain (OmpA(171)) that spans the bilayer and a periplasmic, C-terminal domain of unknown structure. OmpA has been suggested to primarily serve a structural role, as no continuous pore through the center of the barrel can be discerned in the crystal structure of OmpA(171). However, several groups have recorded ionic conductances for bilayer-reconstituted OmpA(171). To resolve this apparent paradox we have used molecular dynamics (MD) simulations on OmpA(171) to explore the conformational dynamics of the protein, in particular the possibility of transient formation of a central pore. A total of 19 ns of MD simulations of OmpA(171) have been run, and the results were analyzed in terms of 1) comparative behavior of OmpA(171) in different bilayer and bilayer-mimetic environments, 2) solvation states of OmpA(171), and 3) pore characteristics in different MD simulations. Significant mobility was observed for residues and water molecules within the beta-barrel. A simulation in which putative gate region side chains of the barrel interior were held in a non-native conformation led to an open pore, with a predicted conductance similar to experimental measurements. The OmpA(171) pore has been shown to be somewhat more dynamic than suggested by the crystal structure. A gating mechanism is proposed to explain its documented channel properties, involving a flickering isomerization of Arg138, forming alternate salt bridges with Glu52 (closed state) and Glu128 (open state). 相似文献
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Haofan Wang Youngjoo Byun Cyril Barinka Mrudula Pullambhatla Hyo-eun C. Bhang James J. Fox Jacek Lubkowski Ronnie C. Mease Martin G. Pomper 《Bioorganic & medicinal chemistry letters》2010,20(1):392-397
We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure–activity relationship studies of the P1′ site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with Ki values below 20 nM. Among them, compound 32d (Ki = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1′ pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d. 相似文献
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Abhi Das 《Journal of biomolecular structure & dynamics》2016,34(4):800-813
The interaction of the plant alkaloid aristololactam-β-D-glucoside (ADG) and the anticancer agent daunomycin (DAN) with human hemoglobin was studied by different spectroscopic and calorimetric methods. The binding affinity values of ADG and DAN, estimated from spectroscopic experiments, were 3.79 × 104 and 6.68 × 104 M?1, respectively. From circular dichroism, 3D fluorescence, and FTIR studies it was observed that, DAN induced stronger conformational changes than ADG in the protein. From synchronous fluorescence spectroscopy results, a pronounced shift in the maximum emission wavelength of tyrosine residues was observed in both cases suggesting that the drugs changed the polarity around tyrosine residues with marginal change around the tryptophan residues. The thermodynamics of the binding interaction analyzed using microcalorimetry presented single binding events that were exothermic in nature in both cases. The binding was driven by large positive standard molar entropy changes with small favorable enthalpy contributions. Negative heat capacity changes in both cases are correlated to the involvement of significant hydrophobic forces in the complexation process. The affinity of DAN to Hb was higher than that of ADG. 相似文献
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The binding of two sugar containing antibiotics viz. aristololactam-β-D-glucoside and daunomycin with single and double stranded poly(A) was investigated by spectroscopic and calorimetric studies. The binding affinity of daunomycin to ss poly(A) was of the order of 106 M− 1 and that to ds poly(A) was of the order of 105 M− 1. Aristololactam-β-D-glucoside showed a relatively weaker binding with an affinity of the order of 104 M− 1 with both the conformations of poly(A). Fluorescence studies showed maximum quenching for daunomycin-ss poly(A) complexes. The binding constants calculated from fluorescence spectroscopy were in good agreement with that obtained from UV spectroscopy. Moderate perturbation of circular dichroic spectra of both the conformations of poly(A) in presence of these molecules with concomitant formation of prominent extrinsic CD bands in the 300-450 nm region further revealed the association. Isothermal titration calorimetry results showed an overall entropy driven binding in all the four systems though the entropy change was maximum in daunomycin-ss poly(A) binding. The binding affinity was also maximum for daunomycin-ss poly(A) and varied as daunomycin-ds poly(A)>aristololactam-β-D-glucoside-ds poly(A)>aristololactam-β-D-glucoside-ss poly(A). A 1:1 binding stoichiometry was observed in all the cases, as confirmed by Job plot analysis, indicating the interaction to consist of a single binding mode. Ferrocyanide quenching studies showed good stacking interaction in all cases but was best for daunomycin-ss poly(A) interaction. No self-structure formation was observed in poly(A) with both daunomycin and aristololactam-β-D-glucoside suggesting the hindrance of the sugar moiety for such structural organization. 相似文献
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《Inorganica chimica acta》1988,151(1):49-54
Bindings of fluoroaniline to cytochrome P-450scc (P-450scc) and metmyoglobin (metMb) were studied in terms of optical absorption at various temperatures and pH values. The following results were obtained. (i) P-450scc formed a low-spin complex on addition of fluoroaniline, while metMb remained in the high- spin state. (ii) The affinities of fluoroaniline compounds to P-450scc are more marked than those to metMb. (iii) The affinity of para-fluoroaniline to P-450scc is more marked than that of ortho- and meta- fluoroaniline. (iv) The temperature dependences of Kb values of fluoroaniline were more prominent for P-450scc than those for metMb, suggesting that the heme environment of P-450scc is more labile to temperature compared to that of metMb. (v) Enthalpy-entropy compensation effects were observed with fluoroaniline bindings to P-450scc and metMb. The correlation coefficients (r) of 0.986 and 0.998 and isokinetic temperatures (β) of 420 K and 571 K were calculated for P-450scc and metMb, respectively. (vi) Increasing pH value enhances the affinity of fluoroaniline to both P-450scc and metMb, which is in contrast to the binding of cholesterol to P-450scc. 相似文献
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《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2020,1865(11):158635
Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate that β-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linking these nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively.This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro. 相似文献
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Scalp hair and fingernail samples of 42 medical radiographers and 42 nonradiographers (control) with matching age groups and
food habits were collected for this study. Trace metal estimation by atomic absorption spectrometry (AAS) has indicated a
significant increase (P < 0.001) in Zn, Cu, and Cd contents in the radiographers’ hair and nails. Scanning electron microscopy
(SEM) reveled structural changes in the hair and nails of radiographers. Significant alterations in the Zn and Cd contents
along with extensive structural damage in the hair and nails probably indicate that low-dose Χ-radiation imposes stress on
these radiation workers. 相似文献
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The apolipoprotein E family consists of three major protein isoforms: apolipoprotein E4 (ApoE4), ApoE3, and ApoE2. The isoforms, which contain 299 residues, differ only by single-amino acid changes, but of the three, only ApoE4 is a risk factor for Alzheimer’s disease. At micromolar concentrations, lipid-free ApoE exists predominantly as tetramers. In more dilute solutions, lower-molecular mass species predominate. Using fluorescence correlation spectroscopy (FCS), intermolecular fluorescence resonance energy transfer (FRET), and sedimentation methods, we found that the association?dissociation reaction of ApoE can be modeled with a monomer?dimer?tetramer process. Equilibrium constants have been determined from the sedimentation data, while the individual rate constants for association and dissociation were determined by measurement of the kinetics of dissociation of ApoE and are in agreement with the equilibrium constants. Dissociation kinetics as measured by intermolecular FRET show two phases reflecting the dissociation of tetramer to dimer and of dimer to monomer, with dissociation from tetramer to dimer being more rapid than the dissociation from dimer to monomer. The rate constants differ for the different ApoE isoforms, showing that the association?dissociation process is isoform specific. Strikingly, the association rate constants are almost 2 orders of magnitude slower than expected for a diffusion-controlled process. Dissociation kinetics were also monitored by tryptophan fluorescence in the presence of acrylamide and the data found to be consistent with the monomer?dimer?tetramer model. The approach combining multiple methods establishes the reaction scheme of ApoE self-association. 相似文献
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Dominic D. W. S. Wong Victor J. Chan Amanda A. McCormack Sarah B. Batt 《Applied microbiology and biotechnology》2010,86(5):1463-1471
A novel xyloglucan-specific endo-β-1,4-glucanase gene (xeg5A) was isolated, cloned, and expressed in Esherichia coli. The enzyme XEG5A consisted of a C-terminal catalytic domain and N-terminal sequence of ~90 amino acid residues with unknown
function. The catalytic domain assumed an (α/β)8-fold typical of glycoside hydrolase (GH) family 5, with the two catalytic residues Glu240 and Glu362 located on opposite
sides of the surface groove of the molecule. The recombinant enzyme showed high specificity towards tamarind xyloglucan and
decreasing activity towards xyloglucan oligosaccharide (HDP-XGO), carboxymethyl cellulose, and lichenan. Tamarind xyloglucan
was hydrolyzed to three major fragments, XXXG, XXLG/XLXG, and XLLG. The hydrolysis followed the Michaelis–Menten kinetics,
yielding K
m and V
max of 3.61 ± 0.23 mg/ml and 0.30 ± 0.01 mg/ml/min, respectively. However, the hydrolysis of HDP-XGO showed a decrease in the
rate at high concentrations suggesting appearance of excess substrate inhibition. The addition of XXXG resulted in linear
noncompetitive inhibition on the hydrolysis of tamarind xyloglucan giving a K
i of 1.46 ± 0.13 mM. The enzyme was devoid of transglycosylase activities. 相似文献
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Babita Aneja Mohammad Irfan Md. Imtaiyaz Hassan Amresh Prakash Umesh Yadava Constantin G. Daniliuc 《Journal of enzyme inhibition and medicinal chemistry》2016,31(5):834-852
Novel monocyclic β-lactam derivatives bearing aryl, phenyl and heterocyclic rings were synthesized as possible antibacterial agents. Cyclization of imines (3h, 3t) with phenylacetic acid in the presence of phosphoryl chloride and triethyl amine did not afford the expected β-lactams. Instead, highly substituted 1,3-oxazin-4-ones (4h, 4t) were isolated as the only product and confirmed by single crystal X-ray analysis of 4t. The results of antibacterial activity showed that compound 4l exhibited considerable antibacterial activity with MIC and MBC values of 62.5?µg/mL against Klebsiella pneumoniae. Cytotoxicity assay on Chinese Hamster Ovary (CHO) cell line revealed non-cytotoxic behavior of compounds 4d, 4h, 4k and 4l up to 200?μg/mL conc. Molecular docking was performed for compound 4l with penicillin binding protein-5 to identify the nature of interactions. The results of both in silico and in vitro evaluation provide the basis for compound 4l to be carried as a potential lead molecule in the drug discovery pipeline against bacterial infections. 相似文献