Gemcitabine alters the proteasome composition and immunopeptidome of tumour cells

The antigenic makeup of tumour cells can have a profound effect on the progression of cancer and success of immunotherapies. Therefore, one strategy to improve the efficacy of cancer treatments is to augment the antigens displayed by tumours. The present study explores how the recognition of tumour cells may be altered by non-cytotoxic concentrations of gemcitabine (GEM). Testing a panel of chemotherapeutics in human cancer cell lines in vitro, it was found that GEM increased surface expression of HLA-A,B,C and that underlying this were specific increases in β-2-microglobulin and immunoproteasome subunit proteins. Furthermore, the peptide antigen repertoire displayed on HLA class I was altered, revealing a number of novel antigens, many of which that were derived from proteins involved in the DNA-damage response. Changes in the nature of the peptide antigens eluted from HLA-A,B,C after GEM treatment consisted of amino acid anchor-residue modifications and changes in peptide length which rendered peptides likely to favour alternative HLA-alleles and increased their predicted immunogenicity. Signalling through the MAPK/ERK and NFκB/RelB pathways was associated with these changes. These data may explain observations made in previous in vivo studies, advise as to which antigens should be used in future vaccination protocols and reinforce the idea that chemotherapy and immunotherapy could be used in combination

Structural plasticity of the social brain: Differential change after socio-affective and cognitive mental training

Although neuroscientific research has revealed experience-dependent brain changes across the life span in sensory, motor, and cognitive domains, plasticity relating to social capacities remains largely unknown. To investigate whether the targeted mental training of different cognitive and social skills can induce specific changes in brain morphology, we collected longitudinal magnetic resonance imaging (MRI) data throughout a 9-month mental training intervention from a large sample of adults between 20 and 55 years of age. By means of various daily mental exercises and weekly instructed group sessions, training protocols specifically addressed three functional domains: (i) mindfulness-based attention and interoception, (ii) socio-affective skills (compassion, dealing with difficult emotions, and prosocial motivation), and (iii) socio-cognitive skills (cognitive perspective-taking on self and others and metacognition). MRI-based cortical thickness analyses, contrasting the different training modules against each other, indicated spatially diverging changes in cortical morphology. Training of present-moment focused attention mostly led to increases in cortical thickness in prefrontal regions, socio-affective training induced plasticity in frontoinsular regions, and socio-cognitive training included change in inferior frontal and lateral temporal cortices. Module-specific structural brain changes correlated with training-induced behavioral improvements in the same individuals in domain-specific measures of attention, compassion, and cognitive perspective-taking, respectively, and overlapped with task-relevant functional networks. Our longitudinal findings indicate structural plasticity in well-known socio-affective and socio-cognitive brain networks in healthy adults based on targeted short daily mental practices. These findings could promote the development of evidence-based mental training interventions in clinical, educational, and corporate settings aimed at cultivating social intelligence, prosocial motivation, and cooperation

Aşçı kadın

Aziz'in Türk Sesi'nde tefrika edilen Aşçı Kadın adlı romanıTefrika yarım kalmıştır. Arşivdeki eksikler nedeniyle tefrikanın tamamlanıp tamamlanmadığı bilinmemektedir

Анализ причин обводненности добывающих скважин на нефтяных месторождениях

В процессе исследования рассмотрены причины преждевременного обводнения скважин, алгоритм подбора скважин-кандидатов для проведения водоизоляционных работ (ВИР), методы диагностики водопритоков, факторы, влияющие на эффективность ВИР и мероприятия по снижению обводненности скважинной продукции. Рассмотрен опыт применения технологии выравнивания профиля приемистости на месторождении АО "Газпромнефть-ННГ".During the research, the causes of premature well flooding, the algorithm for selecting candidate wells for water shutoff, methods for diagnosing water inflow, factors affecting the effectiveness of water shutoff and measures to reduce the water content of well products are considered. The experience of applying the technology of conformance control at the field of JSC Gazpromneft-NNG is considered

Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations

Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action

Эколого-технологические основы формирования визуальной среды города (на примере многофункционального здания г. Томска)

Процессы урбанизации, которые особо ускорились в ХХ веке, вызывают большой интерес у представителей различных наук и у самих горожан, поскольку бурный рост городского населения превращается в глобальную проблему и сильно меняет городскую среду. В ходе роста и развития городов концептуально иной становится окружающая человека среда с новым пониманием ценностей жизни, красоты и гармонии. Как показывает действительность и многочисленные исследования - естественная связь человека с природой значительно ослабевает именно в городах. Это в значительной мере оказывает влияние на психоэмоциональное и физическое состояние горожан. Изучая визуальную среду современного города, мы можем существенным образом обогатить эстетическую составляющую и несколько смягчить негативные последствия урбанизации.The rapid growth of the urban population presents a global challenge and ultimately augments the urban environment. While cities growth and develop, the environment with new understandings of values, beauty and harmony becomes conceptually different. In most cities, the natural connection of individuals with nature has significantly weakened. Their everyday environment is an artificial urban environment. In cities a special lifestyle different from the style of life in the countryside is formed, affecting to a large extent the physical and especially the mental health of the citizens. Through exploring the visual environment of the modern city, we can significantly enrich the aesthetic component and mitigate the negative effects of anthropogenic impact, creating a favorable habitat

M\"ossbauer, nuclear inelastic scattering and density functional studies on the second metastable state of Na2[Fe(CN)5NO]⋅\cdot2H2O

The structure of the light-induced metastable state SII of Na2[Fe(CN)5NO]$\cdot$2H2O 14 was investigated by transmission M\"ossbauer spectroscopy (TMS) in the temperature range 15 between 85 and 135 K, nuclear inelastic scattering (NIS) at 98 K using synchrotron 16 radiation and density functional theory (DFT) calculations. The DFT and TMS results 17 strongly support the view that the NO group in SII takes a side-on molecular orientation 18 and, further, is dynamically displaced from one eclipsed, via a staggered, to a second 19 eclipsed orientation. The population conditions for generating SII are optimal for 20 measurements by TMS, yet they are modest for accumulating NIS spectra. Optimization 21 of population conditions for NIS measurements is discussed and new NIS experiments on 22 SII are proposed

Анализ конкурентоспособности предприятия на рынке телекоммуникационных услуг

В результате исследования дана характеристика рынка телекоммуникационных услуг, определены методики оценки конкурентоспособности услуг и товаров предприятия, выявлены факторы, определяющие конкурентоспособность товаров и услуг, представлены особенности конкуренции на рынке телекоммуникационных услуг, дана характеристика деятельности компании ПАО "Ростелеком", проведен анализ конкурентоспособности ПАО "Ростелеком" и предоставляемых услуг, выполнена разработка мероприятий по повышению конкурентоспособности предприятия.As a result of the research, the characteristics of the telecommunications services market are given, the methods for assessing the competitiveness of services and goods of the enterprise are defined, the factors determining the competitiveness of goods and services are identified, the features of competition in the telecommunications market are presented, the performance of the company PJSC "Rostelecom" is given, the competitiveness analysis of PJSC "Rostelecom" "And the services provided, the development of measures to increase the competitiveness of the enterpris

Microbial Enrichment of a Novel Growing Substrate and its Effect on Plant Growth

The quality of torrefied grass fibers (TGF) as a new potting soil ingredient was tested in a greenhouse experiment. TGF was colonized with previously selected microorganisms. Four colonization treatments were compared: (1) no inoculants, (2) the fungus Coniochaeta ligniaria F/TGF15 alone, (3) the fungus followed by inoculation with two selected bacteria, and (4) the fungus with seven selected bacteria. Cultivation-based and DNA-based methods, i.e., PCR-DGGE and BOX-PCR, were applied to assess the bacterial and fungal communities established in the TGF. Although colonization was not performed under sterile conditions, all inoculated strains were recovered from TGF up to 26 days incubation. Stable fungal and bacterial populations of 108 and 109 CFU/g TGF, respectively, were reached. As a side effect of the torrefaction process that aimed at the chemical stabilization of grass fibers, potentially phytotoxic compounds were generated. These phytotoxic compounds were cold-extracted from the fibers and analyzed by gas chromatography mass spectrometry. Four of 15 target compounds that had previously been found in the extract of TGF were encountered, namely phenol, 2-methoxyphenol, benzopyran-2-one, and tetrahydro-5,6,7,7a-benzofuranone. The concentration of these compounds decreased significantly during incubation. The colonized TGF was mixed with peat (P) in a range of 100%:0%, 50%:50%, 20%:80%, and 0%:100% TGF/P (w/w), respectively, to assess suitability for plant growth. Germination of tomato seeds was assessed three times, i.e., with inoculated TGF that had been incubated for 12, 21, and 26 days. In these tests, 90–100% of the seeds germinated in 50%:50% and 20%:80% TGF/P, whereas on average only 50% of the seeds germinated in pure TGF. Germination was not improved by the microbial inoculants. However, plant fresh weight as well as leaf area of 28-day-old tomato plants were significantly increased in all treatments where C. ligniaria F/TGF15 was inoculated compared to the control treatment without microbial inoculants. Colonization with C. ligniaria also protected the substrate from uncontrolled colonization by other fungi. The excellent colonization of TGF by the selected plant-health promoting bacteria in combination with the fungus C. ligniaria offers the possibility to create disease suppressive substrate, meanwhile replacing 20% to 50% of peat in potting soil by TGF

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling