Hybrid Modeling of Cell Signaling and Transcriptional Reprogramming and Its Application in C. elegans Development

Modeling of signal driven transcriptional reprogramming is critical for understanding of organism development, human disease, and cell biology. Many current modeling techniques discount key features of the biological sub-systems when modeling multiscale, organism-level processes. We present a mechanistic hybrid model, GESSA, which integrates a novel pooled probabilistic Boolean network model of cell signaling and a stochastic simulation of transcription and translation responding to a diffusion model of extracellular signals. We apply the model to simulate the well studied cell fate decision process of the vulval precursor cells (VPCs) in C. elegans, using experimentally derived rate constants wherever possible and shared parameters to avoid overfitting. We demonstrate that GESSA recovers (1) the effects of varying scaffold protein concentration on signal strength, (2) amplification of signals in expression, (3) the relative external ligand concentration in a known geometry, and (4) feedback in biochemical networks. We demonstrate that setting model parameters based on wild-type and LIN-12 loss-of-function mutants in C. elegans leads to correct prediction of a wide variety of mutants including partial penetrance of phenotypes. Moreover, the model is relatively insensitive to parameters, retaining the wild-type phenotype for a wide range of cell signaling rate parameters

The Russian Arctic: innovative possibilities at the turn of the past and the future

Under the growth of the geopolitical tension a political, economic and symbolic meanings of the Russian presence in the Arctic region take on special significance. The theme of an innovation development of the Arctic and its symbolic sense for the citizens of our country are actual for the modern political discourse. The considerable scientific and technical reserve accumulated during the Soviet period and representation of the Arctic as a major symbolic resource for Russian people that helps to determine the sense of patriotism and the pride for the country can promote the growth of the authority of Russia in the region. The development of the Arctic is being conducted in two ways: expansion of the extraction of hydrocarbons and strengthening of a military and political presence. The Russian consolidation in the Arctic can potentially increase the state status in the international community. However, in order to pretend to the strong positions in the region it is absolutely necessary to answer to the arctic technological challenge by the innovative technologies and decisions

Антиоксидант з кори дуба як джерело поліфенолів у пивоварінні

The analysis of the current state of production and use of hop and hop product in brewing. The advantages and disadvantages of СО2 hop extract relative to other hop product were demonstrated. The investigations aimed to identify the phenolic compounds of plant antioxidants that promote protein coagulation and oxidation protection of bitter substances during boiling the wort with the CO2 hop extract were carried. As a result the technology of use of the CO2 hop extract together with oak bark antioxidant was proposed. The use of the CO2 hop extract in conjunction with oak bark antioxidant gives the opportunity to produce less oxidized beer with a long shelf life and save hops in an amount of 8–10%. In addition, the antioxidant not only stabilizes the quality of beer, but also increases its physiological value. The results of the research can be used as the basis for the development of new sorts of beer with increased physiological value.Приведен анализ современного состояния производства и применения хмеля и продуктов его переработки в пивоварении. Показаны преимущества и недостатки СО2-екстракта хмеля по сравнению с другими продуктами переработки хмеля. Проведенные исследования, направленные на выявление фенольных веществ растительных антиоксидантов, что способствуют коагуляции белков и защите от окисления горьких веществ при кипячении сусла с СО2-екстрактом хмелю. Предложена технология использования СО2-екстракту хмелю вместе с антиоксидантом из коры дуба, которая дает возможность получить менее окисленное пиво с длительным сроком хранения и экономить хмель в количестве 8-10 %. Кроме этого, антиоксидант не только стабилизирует качество пива, но и увеличивает его физиологичную ценность. Это может быть основой для создания нового сорта пива с повышенной физиологичной ценностью.Наведено аналіз сучасного стану виробництва й застосування хмелю та продуктів його переробки в пивоварстві. Показані переваги й недоліки СО2-екстракту хмелю в порівнянні з іншими продуктами переробки хмелю. Проведені дослідження, направлені на виявлення фенольних речовин рослинних антиоксидантів, що сприяють коагуляції білків і захисту від окиснення гірких речовин при кип'ятінні сусла із СО2-екстрактом хмелю. Запропоновано технологію використання СО2-екстракту хмелю разом з антиоксидантом з кори дуба, яка дає можливість одержати менш окиснене пиво із тривалим строком зберігання й економити хміль у кількості 8-10%. Крім цього, антиоксидант не тільки стабілізує якість пива, але й збільшує його фізіологічну цінність. Це може бути основою для створення нового сорту пива з підвищеною фізіологічною цінністю

Delayed Development of Aneurysmal Dilatations in Patients with Extracranial Carotid Artery Dissections

Peer reviewe

The Integrated Genomic Landscape of Thymic Epithelial Tumors

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin