951 resultados para Mahila Kahanikarom Ki Kahani
Resumo:
The guanine nucleotide exchange factor C3G, along with the CrkII adaptor protein, mediates GTP activation of the small GTPase proteins Rap1 and R-Ras, facilitating their activation of downstream signaling pathways, which had been found to be important in the pathogenesis of glomerulonephritis. We found that expression of C3G protein was upregulated in glomerular epithelial cells in an experimental model of accelerated anti-GBM antibody-induced glomerulonephritis expression. To determine the consequence of its increased expression, we transfected C3G (using adenoviral constructs) into cultured glomerular epithelial cells and measured the activated forms (i.e., GTP-bound) forms of Rap1 and R-Ras. Activation of Rap1 was not affected by C3G; however, the basal level of GTP-bound R-Ras was decreased. Further, C3G over-expression enhanced the activation of R-Ras in response to endothelin. Overexpression of C3G also led to a significant reduction in glomerular epithelial cell spreading and decreased the cells' E-cadherin expression and augmented their migration. We found that C3G was overexpressed in accelerated anti-GBM antibody-induced glomerulonephritis and suggest that this modulates glomerular epithelial cell morphology and behavior.
Resumo:
Pseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial bio?lm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in bio?lm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal bio?lms, and to eradicate bio?lm completely when used in combination with conventional antibiotics.
Resumo:
In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor, ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S1´ and S2´ binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P1´ and aliphatic residues in P2´. From this library, six compounds were identified which exhibited sub- to low micromolar Ki values. The most potent inactivator, SH-CO2-Y-V-NH2 was capable of preventing ZapA-mediated hydrolysis of heat denatured IgA, indicating these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection.
Resumo:
To date, 9 FMRF amide-related peptides (FaRPs) have been identified in Caenorhabditis elegans. Eight of these peptides are encoded on the flp-1 gene. However, AF2 (KHEYLRF amide) which was not co-encoded was the most abundant FaRP identified in ethanolic extracts. Further radioimmunometrical screening of acidified ethanol extracts of C. elegans has revealed the presence of other novel FaRPs, which are not encoded on the flp-l gene. One of these peptides has been isolated by sequential rpHPLC and subjected to Edman degradation analysis and gas-phase sequencing and the unequivocal primary structure of the decapeptide Ala-Pro-Glu-Ala-Ser-Pro-Phe-Ile-Arg-Phe-NH2 was determined following a single gas-phase sequencing run. The molecular mass of the peptide was found to be 1133.7 Ha, determined using a time-of-flight mass spectrometer. Synthetic replicates of this peptide were found to induce a profound relaxation of both dorsal and ventral somatic muscle-strip preparations of Ascaris suum with a threshold for activity of 10 nM. The inhibitory response was not dependent on the presence of nerve cords, indicating a post-synaptic site-of-action. The relaxation was Ca++- and Cl--independent but was abolished in high-KI medium and could be distinguished from those of other inhibitory nematode FaRPs, including PF1 (SDPNFLRFamide)and PF1 (KPNFIRF amide). (C) 1997 Academic Press.
Resumo:
The chemical complexity of the defensive skin secretion of the red-eyed leaf frog, (Agalychnis callidryas), has not been elucidated in detail. During a systematic study of the skin secretion peptidomes of phyllomedusine frogs, we discovered a novel Kazal-type protein with potent trypsin inhibitory activity (Ki = 1.9 nM) that displays the highest degree of structural similarity with Kazal proteins from bony fishes. The protein was located in reverse-phase HPLC fractions following a screen of such for trypsin inhibition and subsequent partial Edman degradation of the peak active fraction derived the sequence: ATKPR-QYIVL-PRILRPV-GT. The molecular mass of the major component in this fraction was established by MALDI-TOF MS as 5893.09 Da. This partial sequence (assuming blank cycles to be Cys residues) was used to design a degenerate primer pool that was employed successfully in RACE-PCR to clone homologous precursor-encoding cDNA that encoded a mature Kazal protein of 52 amino acid residues with a computed molecular mass of 5892.82 Da. The protein was named A. callidryas Kazal trypsin inhibitor (ACKTI). BLAST analysis revealed that ACKTI contained a canonical Kazal motif (C-x(7)-C-x(6)-Y-x(3)-C-x(2,3)-C). This novel amphibian skin Kazal trypsin inhibitor adds to the spectrum of trypsin inhibitors of Kunitz- and Bowman Birk-type reported from this amphibian source.
Resumo:
An approach for evaluation of binding selectivity was suggested and exemplified using glycine/NMDA and AMPA receptors. For analyzing the pairwise selectivity, we propose to use the difference between biological activities (expressed as -log Ki) of ligands with respect to different receptor subtypes as a dependent variable for building comparative molecular field analysis (CoMFA) models. The resulting fields (which will be referred to as the "selectivity fields") indicate the ways of increasing selectivity of binding, inhibition, etc. As an example, CoMFA of a set of pyrazolo[1,5-c]quinazolines and triazolo[1,5-c]quinazolines was used for considering the binding selectivity with respect to glycine/NMDA and AMPA receptors. In addition, the mapping of these fields onto the molecular models of the corresponding receptors makes it possible to reveal the reasons for experimentally observed selectivity as well as to suggest additional ways of increasing selectivity.
Resumo:
One novel Kunitz BPTI-like peptide designated as BBPTI-1, with chymotrypsin inhibitory activity was identified from the venom of Burmese Daboia russelii siamensis. It was purified by three steps of chromatography including gel filtration, cation exchange and reversed phase. A partial N-terminal sequence of BBPTI-1, HDRPKFCYLPADPGECLAHMRSF was obtained by automated Edman degradation and a Ki value of 4.77. nM determined. Cloning of BBPTI-1 including the open reading frame and 3' untranslated region was achieved from cDNA libraries derived from lyophilized venom using a 3' RACE strategy. In addition a cDNA sequence, designated as BBPTI-5, was also obtained. Alignment of cDNA sequences showed that BBPTI-5 exhibited an identical sequence to BBPTI-1 cDNA except for an eight nucleotide deletion in the open reading frame. Gene variations that represented deletions in the BBPTI-5 cDNA resulted in a novel protease inhibitor analog. Amino acid sequence alignment revealed that deduced peptides derived from cloning of their respective precursor cDNAs from libraries showed high similarity and homology with other Kunitz BPTI proteinase inhibitors. BBPTI-1 and BBPTI-5 consist of 60 and 66 amino acid residues respectively, including six conserved cysteine residues. As these peptides have been reported to have influence on the processes of coagulation, fibrinolysis and inflammation, their potential application in biomedical contexts warrants further investigation. © 2013 Elsevier Inc.
Resumo:
Park Jae-Sang’s (otherwise known as PSY) bewilderingly successful pop contagion ‘Gangnam Style’ needs no introduction. As of January 2013, it has become the most watched video in YouTube’s history and has garnered over 1.23 billion hits since. ‘Gangnam Style’ has also become a rapid global pop phenomenon with multiple parodic reproductions, imitations and adaptations; Rapper PSY himself has become an international name and styled as the ‘anti-hero’ of the glamour-driven K-pop scene. His fame has transcended the social sphere and permeated the political stratosphere with politicians such as Barrack Obama and David Cameron being among the many whom PSY has exchanged pleasantries with. Apart from breaking ground and creating social and media history in many ways, ‘Gangnam Style’ has even been purported by UN Secretary-General Ban Ki Moon to be a “force for world peace” – cultural barriers are demolished as the world dances. Underlying this sentiment is the video’s almost universal appeal that assumes a supracultural yet equally paradoxical translatability: Korea’s neoteric ‘K-Wave’ phenomenon is at once local yet global, and where the latter is predicated on the former quality. The paper’s concern is thus two-fold. It will consider the dromological aspects of this musical contagion as it exemplifies and performs quite literally Paul Virilio’s thesis that the modern condition is driven by speed yet arrested to a dictatorship of movement. While many theories have been put forward for this astounding pop peculiarity, this paper would also examine the intercultural currents that advocate such a global (pop) cultural response. Through an analysis of sonic qualities – digital techno-beat rhythms, synth-based musicality, cyclical lyrics, horse-galloping movements – and acoustic receptions, it will consider the simultaneous and dichotomous currents of glocalisation and globalisation as it relates to the ways in which sonic ‘hyper-links’ establish new concepts of global-cultural identities even as these seem to be interrogated in the borderless worlds of hyper-mediatised realities and cultural technologies.
Resumo:
Alcohol-induced liver injury is the most common liver disease in which fatty acid metabolism is altered. It is thought that altered NAD+/NADH redox potential by alcohol in the liver causes fatty liver by inhibiting fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. β-Lapachone (βL), a naturally occurring quinone, has been shown to stimulate fatty acid oxidation in an obese mouse model by activating adenosine monophosphate-activated protein kinase (AMPK). In this report, we clearly show that βL reduced alcohol-induced hepatic steatosis and induced fatty acid oxidizing capacity in ethanol-fed rats. βL treatment markedly decreased hepatic lipids while serum levels of lipids and lipoproteins were increased in rats fed ethanol-containing liquid diets with βL administration. Furthermore, inhibition of lipolysis, enhancement of lipid mobilization to mitochondria and upregulation of mitochondrial β-oxidation activity in the soleus muscle were observed in ethanol/βL-treated animals compared to the ethanol-fed rats. In addition, the activity of alcohol dehydrogenase, but not aldehyde dehydrogenase, was significantly increased in rats fed βL diets. βL-mediated modulation of NAD+/NADH ratio led to the activation of AMPK signaling in these animals. Conclusion: Our results suggest that improvement of fatty liver by βL administration is mediated by the upregulation of apoB100 synthesis and lipid mobilization from the liver as well as the direct involvement of βL on NAD+/NADH ratio changes, resulting in the activation of AMPK signaling and PPARα-mediated β-oxidation. Therefore, βL-mediated alteration of NAD+/NADH redox potential may be of potential therapeutic benefit in the clinical setting.
Resumo:
In this paper, we investigate the potential improvement in signal reliability for indoor off-body communications when using spatial diversity at the base station. In particular, we utilize two hypothetical indoor base stations operating at 5.8 GHz each featuring four antennas which are spaced at either half- or one-wavelength apart. Three on-body locations are considered along with four types of user movement. The cross-correlation between the received signal envelopes observed at each base station antenna element was calculated and found to be always less than 0.5. Selection, maximal ratio, and equal gain combining of the received signal has shown that the greatest improvement is obtained when the user is mobile, with a maximum diversity gain of 11.34 dB achievable when using a four branch receiver. To model the fading envelope obtained at the output of the virtual combiners, we use diversity specific, theoretical probability density functions for multi-branch receivers operating in Nakagami-m fading channels. It is shown that these equations provide an excellent fit to the measured channel data.
Resumo:
In this paper we investigate the received signal characteristics of on-body communications channels at 2.45 GHz. The hypothetical body area network configuration considered a transmitter node situated on the person’s left waist and receiving nodes positioned on the head, knee and wrist of the person’s right side. The on-body channel measurements were performed in both anechoic and reverberant environments while the person was moving. It was found that the recently proposed shadowed κ‒μ fading model provided an excellent fit to the measured data.
Resumo:
In this paper, an analysis of spatial diversity and small-scale fading characteristics for body-to-bodycommunications is presented. The measurements were made at 2.45 GHz in an urban environment with uncontrolled pedestrian and vehicular traffic. The virtual array of four distributed receive antennas where situated on the centralchest, central waist, left waist and left wrist of the user’s body. Combining of the received signal measured at each ofthe antennas in the virtual array has shown that an average diversity gain of up to 11.8 dB can be achieved when usingfour distributed antennas and a maximal ratio combining scheme. To model the small-scale fading characteristics obtained at the output of the virtual combiners, we use diversity specific, theoretical probability density functions for multi-branch receivers operating in Nakagami-m fading channels. It is shown that these equations provide an excellent fit to the measured channel data.
Resumo:
In this paper we investigate the first and second order characteristics of the received signal at the output ofhypothetical selection, equal gain and maximal ratio combiners which utilize spatially separated antennas at the basestation. Considering a range of human body movements, we model the model the small-scale fading characteristics ofthe signal using diversity specific analytical equations which take into account the number of available signal branchesat the receiver. It is shown that these equations provide an excellent fit to the measured channel data. Furthermore, formany hypothetical diversity receiver configurations, the Nakagami-m parameter was found to be close to 1.
Resumo:
In this paper we compare a number of the classical models used to characterize fading in body area networks (BANs) with the recently proposed shadowed ț–ȝ fading model. In particular, we focus on BAN channels which are considered to be susceptible to shadowing by the human body. The measurements considered in this study were conducted at 2.45 GHz for hypothetical BAN channels operating in both anechoic and highly reverberant environments while the person was moving. Compared to the Rice, Nakagami and lognormal fading models, it was found that the recently proposed shadowed țμ fading model provided an enhanced fit to the measured data.