40 research outputs found

    RegPredict: an integrated system for regulon inference in prokaryotes by comparative genomics approach

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    RegPredict web server is designed to provide comparative genomics tools for reconstruction and analysis of microbial regulons using comparative genomics approach. The server allows the user to rapidly generate reference sets of regulons and regulatory motif profiles in a group of prokaryotic genomes. The new concept of a cluster of co-regulated orthologous operons allows the user to distribute the analysis of large regulons and to perform the comparative analysis of multiple clusters independently. Two major workflows currently implemented in RegPredict are: (i) regulon reconstruction for a known regulatory motif and (ii) ab initio inference of a novel regulon using several scenarios for the generation of starting gene sets. RegPredict provides a comprehensive collection of manually curated positional weight matrices of regulatory motifs. It is based on genomic sequences, ortholog and operon predictions from the MicrobesOnline. An interactive web interface of RegPredict integrates and presents diverse genomic and functional information about the candidate regulon members from several web resources. RegPredict is freely accessible at http://regpredict.lbl.gov

    MAP4 Mechanism that Stabilizes Mitochondrial Permeability Transition in Hypoxia: Microtubule Enhancement and DYNLT1 Interaction with VDAC1

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    Mitochondrial membrane permeability has received considerable attention recently because of its key role in apoptosis and necrosis induced by physiological events such as hypoxia. The manner in which mitochondria interact with other molecules to regulate mitochondrial permeability and cell destiny remains elusive. Previously we verified that hypoxia-induced phosphorylation of microtubule-associated protein 4 (MAP4) could lead to microtubules (MTs) disruption. In this study, we established the hypoxic (1% O2) cell models of rat cardiomyocytes, H9c2 and HeLa cells to further test MAP4 function. We demonstrated that increase in the pool of MAP4 could promote the stabilization of MT networks by increasing the synthesis and polymerization of tubulin in hypoxia. Results showed MAP4 overexpression could enhance cell viability and ATP content under hypoxic conditions. Subsequently we employed a yeast two-hybrid system to tag a protein interacting with mitochondria, dynein light chain Tctex-type 1 (DYNLT1), by hVDAC1 bait. We confirmed that DYNLT1 had protein-protein interactions with voltage-dependent anion channel 1 (VDAC1) using co-immunoprecipitation; and immunofluorescence technique showed that DYNLT1 was closely associated with MTs and VDAC1. Furthermore, DYNLT1 interactions with MAP4 were explored using a knockdown technique. We thus propose two possible mechanisms triggered by MAP4: (1) stabilization of MT networks, (2) DYNLT1 modulation, which is connected with VDAC1, and inhibition of hypoxia-induced mitochondrial permeabilization

    ГСнСтичСская модСль Π±ΠΎΠ»Π΅Π·Π½ΠΈ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π½Π΅ΠΉΡ€ΠΎΠ½Π° Ρƒ ΠΌΡ‹ΡˆΠ΅ΠΉ Π»ΠΈΠ½ΠΈΠΈ B6SjL-tg: Π½ΠΎΠ²Ρ‹Π΅ Π΄Π°Π½Π½Ρ‹Π΅ ΠΎ Π΄ΠΈΠ½Π°ΠΌΠΈΠΊΠ΅ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Ρ… Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΠΉ ΠΈ иммуногистохимичСских проявлСний Π½Π΅ΠΉΡ€ΠΎΠ΄Π΅Π³Π΅Π½Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠ³ΠΎ процСсса

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    Introduction. Over the past several decades, the study of mutations associated with motor neuron disease has led to the development of a number of transgenic animal models of motor neuron disease. One of the causes of the familial form of this disorder is mutations in the gene encoding Cu/Zn superoxide dismutase 1. The B6SJL-Tg (SOD1*G93A) mouse strain expresses a mutant form of human superoxide dismutase 1. Aim of study. To assess motor functions, dynamics of survival, and morphological changes in the spinal cord of transgenic B6SJL-Tg (SOD1*G93A) mice. Material and methods. In total, 31 animals have been studied. Starting from the age of 22 weeks, once every two weeks, the β€œopen field” and β€œbeam walking” motor tests were performed. The morphological changes in the spinal cord were evaluated at intermediate (26–35 weeks) and late stages (40–45 weeks). Neuronal proteins NeuN and PGP9.5, gliofibrillar protein, cyclonucleotide phosphatase (a marker of oligodendroglia) and a marker protein of microglia IBA1 were detected by immunohistochemistry; antibodies MTC02 to the outer membrane protein were used to detect mitochondria. Results. Motor problems appeared at the age of 24–26 weeks and steadily progressed; one could see consistent paresis of the hindlimbs, then the forelimbs, which was accompanied by general hypotrophy of the animals. There was a greater variability in the timing of symptom onset and life expectancy in males compared to females. The neurodegenerative process with damage to motor neurons was accompanied by the activation of micro- and astroglia. A sharp decrease in immunoreactivity to the mitochondrial marker MTC02 was found. Conclusion. The obtained results demonstrate new details of the development of a complex of motor and pathomorphological changes characteristic of motor neuron disease in B6SJL-Tg (SOD1*G93A) mice. Clarification of the fine dynamics of the neurodegenerative process in these animals is of great importance for monitoring the course of the disease during preclinical trials of new drugs and methods of gene therapy.Π’Π²Π΅Π΄Π΅Π½ΠΈΠ΅. Π—Π° послСдниС нСсколько дСсятилСтий ΠΈΠ·ΡƒΡ‡Π΅Π½ΠΈΠ΅ ΠΌΡƒΡ‚Π°Ρ†ΠΈΠΉ, связанных с болСзнью Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π½Π΅ΠΉΡ€ΠΎΠ½Π°, ΠΏΡ€ΠΈΠ²Π΅Π»ΠΎ ΠΊ Ρ€Π°Π·Ρ€Π°Π±ΠΎΡ‚ΠΊΠ΅ ряда трансгСнных ΠΌΠΎΠ΄Π΅Π»Π΅ΠΉ этого заболСвания Π½Π° ΠΆΠΈΠ²ΠΎΡ‚Π½Ρ‹Ρ…. Одной ΠΈΠ· извСстных ΠΏΡ€ΠΈΡ‡ΠΈΠ½ сСмСйной Ρ„ΠΎΡ€ΠΌΡ‹ Π±ΠΎΠ»Π΅Π·Π½ΠΈ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π½Π΅ΠΉΡ€ΠΎΠ½Π° ΡΠ²Π»ΡΡŽΡ‚ΡΡ ΠΌΡƒΡ‚Π°Ρ†ΠΈΠΈ Π² Π³Π΅Π½Π΅, ΠΊΠΎΠ΄ΠΈΡ€ΡƒΡŽΡ‰Π΅ΠΌ Cu / Zn-супСроксиддисмутазу 1 (SOD1). Линия ΠΌΡ‹ΡˆΠ΅ΠΉ B6SJL-Tg (SOD1*G93A) экспрСссируСт ΠΌΡƒΡ‚Π°Π½Ρ‚Π½ΡƒΡŽ Ρ„ΠΎΡ€ΠΌΡƒ Π΄Π°Π½Π½ΠΎΠ³ΠΎ Π³Π΅Π½Π° ΠΈ ΠΌΠΎΠΆΠ΅Ρ‚ Ρ€Π°ΡΡΠΌΠ°Ρ‚Ρ€ΠΈΠ²Π°Ρ‚ΡŒΡΡ ΠΊΠ°ΠΊ анимальная модСль Π±ΠΎΠ»Π΅Π·Π½ΠΈ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π½Π΅ΠΉΡ€ΠΎΠ½Π°. ЦСль исслСдования – ΠΎΡ†Π΅Π½ΠΈΡ‚ΡŒ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Π΅ Ρ„ΡƒΠ½ΠΊΡ†ΠΈΠΈ, Π΄ΠΈΠ½Π°ΠΌΠΈΠΊΡƒ выТиваСмости ΠΈ морфологичСскиС измСнСния Π² спинном ΠΌΠΎΠ·Π³Π΅ трансгСнных ΠΌΡ‹ΡˆΠ΅ΠΉ B6SJL-Tg (SOD1*G93A). ΠœΠ°Ρ‚Π΅Ρ€ΠΈΠ°Π»Ρ‹ ΠΈ ΠΌΠ΅Ρ‚ΠΎΠ΄Ρ‹. Π’ исслСдованиС Π±Ρ‹Π»ΠΎ взято 31 ΠΆΠΈΠ²ΠΎΡ‚Π½ΠΎΠ΅ с ΡƒΠΊΠ°Π·Π°Π½Π½ΠΎΠΉ ΠΌΡƒΡ‚Π°Ρ†ΠΈΠ΅ΠΉ, ΠΊΠΎΡ‚ΠΎΡ€Ρ‹ΠΌ начиная с возраста 22 Π½Π΅Π΄, Ρ€Π°Π· Π² 2 Π½Π΅Π΄ ΠΏΡ€ΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Π΅ тСсты Β«ΠΎΡ‚ΠΊΡ€Ρ‹Ρ‚ΠΎΠ΅ ΠΏΠΎΠ»Π΅Β» ΠΈ Β«ΡΡƒΠΆΠ°ΡŽΡ‰Π°ΡΡΡ Π΄ΠΎΡ€ΠΎΠΆΠΊΠ°Β». ΠœΠΎΡ€Ρ„ΠΎΠ»ΠΎΠ³ΠΈΡ‡Π΅ΡΠΊΠΈΠ΅ измСнСния Π² спинном ΠΌΠΎΠ·Π³Π΅ ΠΎΡ†Π΅Π½ΠΈΠ²Π°Π»ΠΈ Π½Π° ΠΏΡ€ΠΎΠΌΠ΅ΠΆΡƒΡ‚ΠΎΡ‡Π½Ρ‹Ρ… (26–35 Π½Π΅Π΄) ΠΈ ΠΏΠΎΠ·Π΄Π½ΠΈΡ… стадиях (40–45 Π½Π΅Π΄). Π˜ΠΌΠΌΡƒΠ½ΠΎΠ³ΠΈΡΡ‚ΠΎΡ…ΠΈΠΌΠΈΡ‡Π΅ΡΠΊΠΈ выявляли Π½Π΅ΠΉΡ€ΠΎΠ½Π°Π»ΡŒΠ½Ρ‹Π΅ Π±Π΅Π»ΠΊΠΈ NeuN ΠΈ PGP9.5, глиофибриллярный Π±Π΅Π»ΠΎΠΊ, циклонуклСотидфосфатазу (ΠΌΠ°Ρ€ΠΊΠ΅Ρ€ ΠΎΠ»ΠΈΠ³ΠΎΠ΄Π΅Π½Π΄Ρ€ΠΎΠ³Π»ΠΈΠΈ) ΠΈ ΠΌΠ°Ρ€ΠΊΠ΅Ρ€Π½Ρ‹ΠΉ Π±Π΅Π»ΠΎΠΊ ΠΌΠΈΠΊΡ€ΠΎΠ³Π»ΠΈΠΈ IBA1, для выявлСния ΠΌΠΈΡ‚ΠΎΡ…ΠΎΠ½Π΄Ρ€ΠΈΠΉ использовали Π°Π½Ρ‚ΠΈΡ‚Π΅Π»Π° MTC02 ΠΊ Π±Π΅Π»ΠΊΡƒ Π½Π°Ρ€ΡƒΠΆΠ½ΠΎΠΉ ΠΌΠ΅ΠΌΠ±Ρ€Π°Π½Ρ‹. Π Π΅Π·ΡƒΠ»ΡŒΡ‚Π°Ρ‚Ρ‹. Π”Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Π΅ Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΡ появлялись Π² возрастС 24–26 Π½Π΅Π΄ ΠΈ Π½Π΅ΡƒΠΊΠ»ΠΎΠ½Π½ΠΎ прогрСссировали, наблюдался восходящий ΠΏΠ°Ρ€Π΅Π· Π·Π°Π΄Π½ΠΈΡ…, Π·Π°Ρ‚Π΅ΠΌ ΠΏΠ΅Ρ€Π΅Π΄Π½ΠΈΡ… конСчностСй, Ρ‡Ρ‚ΠΎ ΡΠΎΠΏΡ€ΠΎΠ²ΠΎΠΆΠ΄Π°Π»ΠΎΡΡŒ ΠΎΠ±Ρ‰Π΅ΠΉ Π³ΠΈΠΏΠΎΡ‚Ρ€ΠΎΡ„ΠΈΠ΅ΠΉ ΠΆΠΈΠ²ΠΎΡ‚Π½Ρ‹Ρ…. ΠžΡ‚ΠΌΠ΅Ρ‡Π΅Π½Π° бóльшая Π²Π°Ρ€ΠΈΠ°Π±Π΅Π»ΡŒΠ½ΠΎΡΡ‚ΡŒ Π² сроках появлСния симптомов ΠΈ ΠΏΡ€ΠΎΠ΄ΠΎΠ»ΠΆΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎΡΡ‚ΠΈ ΠΆΠΈΠ·Π½ΠΈ самцов ΠΏΠΎ ΡΡ€Π°Π²Π½Π΅Π½ΠΈΡŽ с самками. НСйродСгСнСративный процСсс с ΠΏΠΎΡ€Π°ΠΆΠ΅Π½ΠΈΠ΅ΠΌ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Ρ… Π½Π΅ΠΉΡ€ΠΎΠ½ΠΎΠ² сопровоТдался Π°ΠΊΡ‚ΠΈΠ²Π°Ρ†ΠΈΠ΅ΠΉ ΠΌΠΈΠΊΡ€ΠΎ- ΠΈ астроглии. ΠžΠ±Π½Π°Ρ€ΡƒΠΆΠ΅Π½ΠΎ Ρ€Π΅Π·ΠΊΠΎΠ΅ сниТСниС иммунорСактивности ΠΊ ΠΌΠΈΡ‚ΠΎΡ…ΠΎΠ½Π΄Ρ€ΠΈΠ°Π»ΡŒΠ½ΠΎΠΌΡƒ ΠΌΠ°Ρ€ΠΊΠ΅Ρ€Ρƒ MTC02. Π—Π°ΠΊΠ»ΡŽΡ‡Π΅Π½ΠΈΠ΅. ΠŸΠΎΠ»ΡƒΡ‡Π΅Π½Π½Ρ‹Π΅ Ρ€Π΅Π·ΡƒΠ»ΡŒΡ‚Π°Ρ‚Ρ‹ Π΄Π΅ΠΌΠΎΠ½ΡΡ‚Ρ€ΠΈΡ€ΡƒΡŽΡ‚ особСнности развития Ρƒ ΠΌΡ‹ΡˆΠ΅ΠΉ B6SJL-Tg (SOD1*G93A) комплСкса Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½Ρ‹Ρ… ΠΈ патоморфологичСских ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠΉ, Ρ…Π°Ρ€Π°ΠΊΡ‚Π΅Ρ€Π½Ρ‹Ρ… для Π±ΠΎΠ»Π΅Π·Π½ΠΈ Π΄Π²ΠΈΠ³Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π½Π΅ΠΉΡ€ΠΎΠ½Π°. Π£Ρ‚ΠΎΡ‡Π½Π΅Π½ΠΈΠ΅ Ρ‚ΠΎΠ½ΠΊΠΎΠΉ Π΄ΠΈΠ½Π°ΠΌΠΈΠΊΠΈ Π½Π΅ΠΉΡ€ΠΎΠ΄Π΅Π³Π΅Π½Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠ³ΠΎ процСсса Ρƒ ΠΌΠΎΠ΄Π΅Π»ΡŒΠ½Ρ‹Ρ… ΠΆΠΈΠ²ΠΎΡ‚Π½Ρ‹Ρ… ΠΈΠΌΠ΅Π΅Ρ‚ Π·Π½Π°Ρ‡Π΅Π½ΠΈΠ΅ для ΠΌΠΎΠ½ΠΈΡ‚ΠΎΡ€ΠΈΠ½Π³Π° тСчСния Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΏΡ€ΠΈ ΠΏΡ€ΠΎΠ²Π΅Π΄Π΅Π½ΠΈΠΈ доклиничСских испытаний Π½ΠΎΠ²Ρ‹Ρ… лСкарствСнных ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² ΠΈ ΠΌΠ΅Ρ‚ΠΎΠ΄ΠΎΠ² Π³Π΅Π½Π½ΠΎΠΉ Ρ‚Π΅Ρ€Π°ΠΏΠΈΠΈ

    Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

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