Ultrafast dynamics of heme distortion in the O2-sensor of a thermophilic anaerobe bacterium

Heme-Nitric oxide and Oxygen binding protein domains (H-NOX) are found in signaling pathways of both prokaryotes and eukaryotes and share sequence homology with soluble guanylate cyclase, the mammalian NO receptor. In bacteria, H-NOX is associated with kinase or methyl accepting chemotaxis domains. In the O2-sensor of the strict anaerobe Caldanaerobacter tengcongensis (Ct H-NOX) the heme appears highly distorted after O2 binding, but the role of heme distortion in allosteric transitions was not yet evidenced. Here, we measure the dynamics of the heme distortion triggered by the dissociation of diatomics from Ct H-NOX using transient electronic absorption spectroscopy in the picosecond to millisecond time range. We obtained a spectroscopic signature of the heme flattening upon O2 dissociation. The heme distortion is immediately (<1 ps) released after O2 dissociation to produce a relaxed state. This heme conformational change occurs with different proportions depending on diatomics as follows: CO < NO < O2. Our time-resolved data demonstrate that the primary structural event of allostery is the heme distortion in the Ct H-NOX sensor, contrastingly with hemoglobin and the human NO receptor, in which the primary structural events are respectively the motion of the proximal histidine and the rupture of the iron-histidine bond.

The role of matrix metalloproteinases in the myocardial remodeling

The main structural event in the development of heart failure is the myocardial remodeling. The extracellular matrix, that was knows as, considered an inert framework of cardiomyocytes, plays an important role in cardiac remodeling. The enzyme system, primarily responsible for the degradation of the extracellular matrix, is a matrix metalloproteinases (MMP). This review examines the evidence for the participation of MMP in the myocardial remodeling and recent studies of MMP as prognostic markers. Regulation of induction and/or activation of MMP are potential therapeutic targets.

Aβ Beyond the AD Pathology: Exploring the Structural Response of Membranes Exposed to Nascent Aβ Peptide

The physiological and pathological roles of nascent amyloid beta (Aβ) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer’s Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aβ, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with Aβ in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the Aβ variant. Interestingly, Aβ monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility.

Effects and Mechanisms of Acupuncture Combined with Mesenchymal Stem Cell Transplantation on Neural Recovery after Spinal Cord Injury: Progress and Prospects

Spinal cord injury (SCI) is a structural event with devastating consequences worldwide. Due to the limited intrinsic regenerative capacity of the spinal cord in adults, the neural restoration after SCI is difficult. Acupuncture is effective for SCI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve neural protection by the inhibition of inflammation, oxidation, and apoptosis. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating multiple cellular signal transduction pathways, such as the Wnt, Notch, and Rho/Rho kinase (ROCK) pathways. Several studies have demonstrated that the efficacy of combining acupuncture with mesenchymal stem cells (MSCs) transplantation is superior to either procedure alone. The advantage of the combined treatment is dependent on the ability of acupuncture to enhance the survival of MSCs, promote their differentiation into neurons, and facilitate targeted migration of MSCs to the spinal cord. Additionally, the differentiation of MSCs into neurons overcomes the problem of the shortage of endogenous neural stem cells (NSCs) in the acupuncture-treated SCI patients. Therefore, the combination of acupuncture and MSCs transplantation could become a novel and effective strategy for the treatment of SCI. Such a possibility needs to be verified by basic and clinical research.

COMPLEX SIMULATION-STATISTICAL METHOD FOR SYNTHESIZING CONDITIONALLY REAL DATA ARRAYS BASED ON A STRUCTURAL-PARAMETRIC MODEL OF INTERACTION BETWEEN USERS OF INFORMATION AND TELECOMMUNICATION SERVICES

The article presents a solution to the problem of synthesizing training tasks and data arrays when organizing a computer training platform for conducting practical exercises to investigate information security incidents. Two main stages of the synthesis of the background and situa-tional components of the conditionally real data arrays based on the structural-parametric model of interaction between users of information and telecommunication services are pro-posed: the formation of static and dynamic components. 14КОМПЛЕС НЫЙИ. ТОАИЦ-МЛИМПЧ К ЕЛЙИДЗ-ВЕИЛЛИУ МЙОДО Р 1Ь35Х / 2020Вступление в силу Федерального закона «О безопасности критической информацион-ной инфраструктуры Российской Федера-ции» свидетельствует об актуальности и зна-чимости решения задачи по обнаружению, предупреждению и ликвидации последствий компьютерных атак и реагирования на ком-пьютерные инциденты. Условием качествен-ного решения данных задач является практи-ко-ориентированная профессиональная под-готовка соответствующих специалистов. Для организации и проведения практи-ческих занятий по расследованию инциден-тов информационной безопасности в сетях документальной электросвязи и сети Интер-нет как на потоках магистратуры по направ-лению «Информационная безопасность», так и на потоках специалитета «Информацион-ная безопасность телекоммуникационных систем» и «Информационно-аналитические системы безопасности» необходимо созда-ние учебного компьютерного полигона, осна-щенного современными образцами инфор-мационно-аналитических систем безопасно-сти (далее – ИАСБ), такими как IBM I21, МФИ СОФТ «Январь»2, Lampyre3, Gephi4 и др. ИАСБ – это аппаратно-программные ком-плексы для проведения поисково-аналитиче-ской работы, имеющие возможность нака-пливать и анализировать данные о взаимо-действии пользователей информационно-те-1 http://www.ibm.com/software/ products/ru/analysts-notebook2 http://www.mfisoft.ru/direction/sorm/sorm-3/3 http://www.lampyre.io4 http://www.gephi.orgлекоммуникационных сервисов (далее – ИТ-сервисов). Однако подключение учебных ИАСБ к действующему оборудованию опера-торов связи, являющемуся источником ин-формации о взаимодействии пользователей ИТ-сервисов, невозможно в соответствии со ст. 64 Федерального закона «О связи». Также отсутствует возможность применения насто-ящих массивов биллинговой информации в силу того, что такие массивы содержат персо-нальные данные пользователей, а доступ к ним ограничен законодательно. Обзор литературы позволяет сделать вы-вод об отсутствии готовых методов и алгорит-мов генерации массивов данных, отражающих взаимодействие пользователей ИТ-сервисов.Для решения данной проблемы при соз-дании учебного компьютерного полигона по расследованию инцидентов информацион-ной безопасности в учебно-научном центре «Информационная безопасность» ИРИТ-РтФ УрФУ им. первого Президента России Б.Н. Ельцина разработано программное обеспе-чение (далее – ПО). Данное ПО работает в со-ответствии с созданной структурно-параме-трической моделью взаимодействия пользо-вателей в ИТ-сервисах и позволяет синтези-ровать массивы условно-реальных данных. Файлы, содержащие сгенерированные мас-сивы, в дальнейшем загружаются в базу дан-ных ИАСБ для проведения практических за-нятий по решению поисково-аналитических задач. На текущем этапе разработки ПО спо-собно генерировать массивы условно-реаль-ных данных о взаимодействии пользователей социальных сетей и сетей мобильной связи.Static components are synthesized based on the method of forming the structure of social graphs using a composition of models for constructing complex networks with various struc-tural parameters: the Watts-Strogatz model is used for a mobile communication service, and the Barabashi-Albert model is used for a social network service. To preserve the relationship between users in various services, a method is proposed for determining the largest common part of social graphs, based on the mutual differentiation of vertices and the allocation of a partial isomorphism of the compared graphs. When generating vertex attributes, the method of searching for social groups (families) is used, based on the Bron-Kerbosch algorithm for find-ing a click of a given size in a graph.For the synthesis of dynamic components of data arrays that describe the performance of communication events, the mathematical apparatus of color Petri nets is used. An interaction event in information and telecommunication services is represented in the form of a Petri net label, which contains the necessary set of parameters, depending on the type of service. It is proposed to use the structural, event, social and temporal statistical characterist

Assessment of ESR1 and ERBB2 mutations in estrogen receptor positive (ER+) metastatic breast cancers (MBC).

1040 Background: Mutations (mut) in ESR1 have been reported in ER+ breast cancers (BC) as an acquired resistance mut to aromatase inhibitor (AI) therapy. Acquired ERBB2 mut have also been reported in MBC patients (pts) that cause activated ERBB2 signaling. The emergence of acquired secondary mut presents challenges in effective treatment approaches. Methods: Comprehensive genomic profiling was performed on 83 BC samples with 48 metastatic; 34 primary samples. Targeted next-generation sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA (germline) samples. Results: ESR1-mut were found in 23%(11/48) of ER+ MBC tissues with no mut detected in primary ER+ BCs. Mutations-D538G, Y537S and E380Q in the ligand binding domain of ER were the most common alterations, found in 54.5%, 18% and 18% of ESR1 mut samples, respectively. An ER+ HER2- liver biopsy obtained after 20 mos on AI + everolimus had ESR1-D538G and TSC2 structural event. Protein array showed high expression of androgen receptor (AR) and p-AR and activation of ERBB1/2/3, p-SRC and p-4EBP1 in this sample. Further, a functionally uncharacterized ESR1 mut was found in ER+, HER2+ and a triple negative MBC tissue (the primary BC had been ER+). Mut in PI3K pathway (PIK3CA, ARID1A, TSC1/2, PTEN) were present in 8/11 samples with ESR1 mut. Activating mut in ERBB2 were found in 3/83 samples; all 3 were in ER+ MBC samples with one case harboring mut in both ERBB2 and ESR1 (E380Q – uncertain degree of constitutive activity). Interestingly, a BC sample with ER+ HER2- liver met harbored both ERBB2 (V777L) and ERBB3 (E928G) mut; this pt responded well to trastuzumab/pertuzumab (HP) therapy. A pt with ER+ HER2-ERBB2- L755S mut met to gallbladder found after 7 mos on letrozole/palbociclib therapy responded well to HP and T-DM1 therapy. All 3 ERBB2-mut cancers had a CDH1 frameshift mut suggesting enrichment in pretreated lobular MBCs (Ross J. CCR, 2013). Conclusions: This study shows a 23% and 6% ESR1 and ERBB2 mut rate in MBC samples. No ESR1 and ERBB2 mut were present in primary BC samples. Our findings suggest that pts with lobular MBC should be monitored for acquired ERBB2 mut, and that ERBB2 mut may not arise in BCs which harbor known constitutively active ESR1 mut.