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61.
Ilana Chefetz Edward Grimley Kun Yang Linda Hong Ekaterina V. Vinogradova Radu Suciu Ilya Kovalenko David Karnak Cynthia A. Morgan Mikhail Chtcherbinine Cameron Buchman Brandt Huddle Scott Barraza Meredith Morgan Kara A. Bernstein Euisik Yoon David B. Lombard Andrea Bild Ronald J. Buckanovich 《Cell reports》2019,26(11):3061-3075.e6
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Lyukmanova EN Shenkarev ZO Schulga AA Ermolyuk YS Mordvintsev DY Utkin YN Shoulepko MA Hogg RC Bertrand D Dolgikh DA Tsetlin VI Kirpichnikov MP 《The Journal of biological chemistry》2007,282(34):24784-24791
Different snake venom neurotoxins block distinct subtypes of nicotinic acetylcholine receptors (nAChR). Short-chain alpha-neurotoxins preferentially inhibit muscle-type nAChRs, whereas long-chain alpha-neurotoxins block both muscle-type and alpha7 homooligomeric neuronal nAChRs. An additional disulfide in the central loop of alpha- and kappa-neurotoxins is essential for their action on the alpha7 and alpha3beta2 nAChRs, respectively. Design of novel toxins may help to better understand their subtype specificity. To address this problem, two chimeric toxins were produced by bacterial expression, a short-chain neurotoxin II Naja oxiana with the grafted disulfide-containing loop from long-chain neurotoxin I from N. oxiana, while a second chimera contained an additional A29K mutation, the most pronounced difference in the central loop tip between long-chain alpha-neurotoxins and kappa-neurotoxins. The correct folding and structural stability for both chimeras were shown by (1)H and (1)H-(15)N NMR spectroscopy. Electrophysiology experiments on the nAChRs expressed in Xenopus oocytes revealed that the first chimera and neurotoxin I blockalpha7 nAChRs with similar potency (IC(50) 6.1 and 34 nM, respectively). Therefore, the disulfide-confined loop endows neurotoxin II with full activity of long-chain alpha-neurotoxin and the C-terminal tail in neurotoxin I is not essential for binding. The A29K mutation of the chimera considerably diminished the affinity for alpha7 nAChR (IC(50) 126 nM) but did not convey activity at alpha3beta2 nAChRs. Docking of both chimeras toalpha7 andalpha3beta2 nAChRs was possible, but complexes with the latter were not stable at molecular dynamics simulations. Apparently, some other residues and dimeric organization of kappa-neurotoxins underlie their selectivity for alpha3beta2 nAChRs. 相似文献
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Rabinovich ML Vasil'chenko LG Karapetyan KN Shumakovich GP Yershevich OP Ludwig R Haltrich D Hadar Y Kozlov YP Yaropolov AI 《Biotechnology journal》2007,2(5):546-558
Amorphous cellulose was used as a specific carrier for the deposition of self-assembled multienzyme complexes capable of catalyzing coupled reactions. Naturally glycosylated fungal cellobiohydrolases (CBHs) of glycosyl hydrolase families 6 and 7 were specifically deposited onto the cellulose surface through their family I cellulose-binding modules (CBM). Naturally glycosylated fungal laccase was then deposited onto the preformed glycoprotein layer pretreated by ConA, through the interaction of mannosyl moieties of fungal glycoproteins with the multivalent lectin. The formation of a cellulase-ConA-laccase composite was proven by direct and indirect determination of activity of immobilized laccase. In the absence of cellulases and ConA, no laccase deposition onto the cellulose surface was observed. Finally, basidiomycetous cellobiose dehydrogenase (CDH) was deposited onto the cellulose surface through the specific interaction of its FAD domain with cellulose. The obtained paste was applied onto the surface of a Clark-type oxygen electrode and covered with a dialysis membrane. In the presence of traces of catechol or dopamine as mediators, the obtained immobilized multienzyme composite was capable of the coupled oxidation of cellulose by dissolved oxygen, thus providing the basis for a sensitive assay of the mediator. Swollen amorphous cellulose plays three different roles in the obtained biosensor as: (i) a gelforming matrix that captures the analyte and its oxidized intermediate, (ii) a specific carrier for protein self-assembly, and (iii) a source of excess substrate for a pseudo-reagent-less assay with signal amplification. The detection limit of such a tri-enzyme biosensor is 50-100 nM dopamine. 相似文献
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Shestakov MP 《Journal of physiological anthropology》2007,26(3):419-423
The paper is devoted to a neurobionic simulation model for controlling balance in a biomechanical pendulum. The model is realized by a complex of fuzzy regulators and an artificial neural network. Fuzzy regulators are used for simulating the physiological characteristics of the motor system and the functions of the sensory systems. The second level of control is the central integrator. It is realized as an artificial neural network (ANN), which simulates a real process of analysis and synthesis of afferent signals, formation of the model of action, etc.Equilibrium control in a multijoint biomechanical object is a specific example of a self-developing multilevel system of movement control. In the course of elaboration of the model and further examination of its behavior we have received model results which revealed correspondence with the results demonstrated by real subjects in stabilographic tests performed after long-term space flights. We concluded that the model permits us to simulate the peculiarities of human movement control and can be used for creating individual plans of recovery and rehabilitation of patients after long-term motionless or learning movement control in unknown environments. 相似文献
68.
One of the major goals of comparative genomics is to understand the evolutionary history of each nucleotide in the human genome sequence, and the degree to which it is under selective pressure. Ascertainment of selective constraint at nucleotide resolution is particularly important for predicting the functional significance of human genetic variation and for analyzing the sequence substructure of cis-regulatory sequences and other functional elements. Current methods for analysis of sequence conservation are focused on delineation of conserved regions comprising tens or even hundreds of consecutive nucleotides. We therefore developed a novel computational approach designed specifically for scoring evolutionary conservation at individual base-pair resolution. Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score. We computed SCONE scores in a continuous fashion across 1% of the human genome for which high-quality sequence information from up to 23 genomes are available. We show that SCONE scores are clearly correlated with the allele frequency of human polymorphisms in both coding and noncoding regions. We find that the majority of noncoding conserved nucleotides lie outside of longer conserved elements predicted by other conservation analyses, and are experiencing ongoing selection in modern humans as evident from the allele frequency spectrum of human polymorphism. We also applied SCONE to analyze the distribution of conserved nucleotides within functional regions. These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved “chunks.” Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences. A small subset of these fragmented positions may be identified with high confidence. 相似文献
69.
Anvar Soleimani Amirhossein Bahreyni Mostafa K. Roshan Arash Soltani Mikhail Ryzhikov Mojtaba Shafiee Mohammad Soukhtanloo Mahmoud R. Jaafari Baratali Mashkani Seyed M. Hassanian 《Journal of cellular physiology》2019,234(3):2329-2336
The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease. 相似文献
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Mehran Pashirzad Mojtaba Shafiee Majid Khazaei Hamid Fiuji Mikhail Ryzhikov Saman Soleimanpour AmirReza Hesari Amir Avan Seyed Mahdi Hassanian 《Journal of cellular physiology》2019,234(2):1237-1247
Prostate cancer is a major cause of cancer-related death in males. Wnt/β-catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. 相似文献