Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration.

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche

Fungal enzyme sets for plant polysaccharide degradation

Enzymatic degradation of plant polysaccharides has many industrial applications, such as within the paper, food, and feed industry and for sustainable production of fuels and chemicals. Cellulose, hemicelluloses, and pectins are the main components of plant cell wall polysaccharides. These polysaccharides are often tightly packed, contain many different sugar residues, and are branched with a diversity of structures. To enable efficient degradation of these polysaccharides, fungi produce an extensive set of carbohydrate-active enzymes. The variety of the enzyme set differs between fungi and often corresponds to the requirements of its habitat. Carbohydrate-active enzymes can be organized in different families based on the amino acid sequence of the structurally related catalytic modules. Fungal enzymes involved in plant polysaccharide degradation are assigned to at least 35 glycoside hydrolase families, three carbohydrate esterase families and six polysaccharide lyase families. This mini-review will discuss the enzymes needed for complete degradation of plant polysaccharides and will give an overview of the latest developments concerning fungal carbohydrate-active enzymes and their corresponding families

Fluid challenges in intensive care: the FENICE study A global inception cohort study

Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57-61 %). In 43 % (CI 41-45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34-37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20-24 %). No safety variable for the FC was used in 72 % (CI 70-74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account

PbTiO₃(001) Capped with ZnO(112̅0): An ab Initio Study of Effect of Substrate Polarization on Interface Composition and CO₂ Dissociation

Catalytic conversion of CO₂ into useful chemicals is an attractive alternative to expensive physical carbon sequestration methods. However, this approach is challenging because current chemical conversion methods employ high temperatures or pressures, thereby increasing cost and potentially leading to net carbon positive processes. In this paper, we examine the interface properties of ZnO(112̅0)/PbTiO₃ and its surface interaction with CO₂, CO and O. We show that the stoichiometry of the stable interface is dependent on the substrate polarization and can be controlled by changing the growth conditions. Using a model reaction, we demonstrate that a dynamically tuned catalysis scheme could enable significantly lower-energy approaches for CO₂ conversion

FIRST RUSSIAN TYPE 2 DIABETES MELLITUS SIMULATION MODEL WITH DISCREET EVENTS MODELING. HEALTH-ECONOMIC ANALYSIS

Goal: to develop the model of of type 2 diabetes mellitus outcomes validated in Russian clinical conditions and to perform pharmacoeconomic evaluation of glucose lowering therapies. Materials and methods: Existing type 2 DM models were evaluated. Risk equations for type 2 DM complications were compiled. Demographic, biochemical etc. patient parameters were used as input parameters. Glucose lowering drug’s effectiveness were incorporated into the model as its ability to modify input parameters (HbA1c, lipids, etc.). Cost-effectiveness analysis was performed. Results: The developed model allows to assess the risk of type 2 DM complications in 5 years in patient with predefined risk factors. Among comparing strategies of type 2 DM therapies liraglutide (Victoza®) was considered as the cost-effective strategy with ICER/QALY – 470 120.40 RUR, which is 51% of the willingness-to-pay threshold in Russia. With the lowest complication treatment costs inside the total direct costs, liraglutide monotherapy demonstrated the most long-term sustainable glycemic control and HbA1c goal parameters

ПЕРВЫЙ В РОССИИ ОПЫТ ПОСТРОЕНИЯ СИМУЛЯЦИОННОЙ МОДЕЛИ ИСХОДОВ САХАРНОГО ДИАБЕТА 2-ГО ТИПА С ДИСКРЕТНЫМ МОДЕЛИРОВАНИЕМ СОБЫТИЙ. КЛИНИКО-ЭКОНОМИЧЕСКАЯ ЭКСПЕРТИЗА

Goal: to develop the model of of type 2 diabetes mellitus outcomes validated in Russian clinical conditions and to perform pharmacoeconomic evaluation of glucose lowering therapies. Materials and methods: Existing type 2 DM models were evaluated. Risk equations for type 2 DM complications were compiled. Demographic, biochemical etc. patient parameters were used as input parameters. Glucose lowering drug’s effectiveness were incorporated into the model as its ability to modify input parameters (HbA1c, lipids, etc.). Cost-effectiveness analysis was performed. Results: The developed model allows to assess the risk of type 2 DM complications in 5 years in patient with predefined risk factors. Among comparing strategies of type 2 DM therapies liraglutide (Victoza®) was considered as the cost-effective strategy with ICER/QALY – 470 120.40 RUR, which is 51% of the willingness-to-pay threshold in Russia. With the lowest complication treatment costs inside the total direct costs, liraglutide monotherapy demonstrated the most long-term sustainable glycemic control and HbA1c goal parameters.Цель работы – создать модель исходов сахарного диабета 2-го типа, валидированную для применения в условиях здравоохранения Российской Федерации (РФ). На основании модели провести клинико-экономическую экспертизу стратегий терапии пероральными сахароснижающими средствами. Материалы и методы: Были проанализированы существующие модели СД2, на основании которых путем компилирования рассчитаны уравнения рисков развития осложнений диабета, в которых входными параметрами служили демографические, биохимические и др. характеристики пациента. Эффективность терапии сахароснижающими средствами учитывалась, как их влияние на изменение биохимических параметров (HbA1c, липидограммы, артериального давления). Проведен анализ «затраты-эффективность» путемсимуляции исходов модельного пациента. Результаты: Разработанная модель позволяла прогнозировать исходы сахарного диабета через 5 лет у пациента с набором значений факторов риска. Среди сравниваемых стратегий терапии наиболее целесообразной, с экономических позиций, была терапия аналогом человеческого ГПП-1, лираглутидом (Виктоза®), ICER/QALY которой составлял 470 120,40 руб., что меньше расчетного значения порога готовности общества платить в РФ на 51%. При самой низкой доле затрат на лечение осложнений СД2 в структуре суммарных прямых затрат лираглутид позволял в течение максимально длительного времени обеспечивать контроль гликемии и достигать целевых значений HbA1c в режиме монотерапии