Ancient agriculture in Southeast Arabia: A three thousand year record of runoff farming from central Oman (Rustaq)

Runoff farming is a key hydro-agricultural strategy that has proven efficient in arid areas. Research in Arabia on the function, development, maintenance, durability and abandonment of this technology is scarce. A multiproxy investigation (cartography, sedimentology, pedology, geochemistry, paleo-ecology and chronology) was conducted on a recently abandoned terraced area in Rustaq, Northern Oman. The aim was to characterize the formation, function and management of this runoff system and the driving factors behind its success. Cycles of cultivation were identified during the Iron Age II/III periods (specifically 750–450 BCE), the Early Pre-Islamic Period (PIR) (specifically 350–200 BCE), the Early and Middle Islamic periods (specifically 8–10th C CE, 13th-14th C CE) and the late Islamic period (specifically 17th C CE and later). This expansion and perenniality was possible thanks to: 1- available water (local to micro-regional orogenic precipitation despite a regional aridification during these periods); 2- suitable soils (weathered geological outcrops, probable aeolian /dust particles); 3- a system of production combining crops and husbandry; 4- a progressive increase in agricultural specialization (crops grown and techniques) in parallel with a diversification in hydraulic technology. These results are to some degree in accordance with known phases of settlement intensification and economic growth, but also reveal the persistence of small-scale rural livelihoods during periods of harsh conditions for which archaeological traces are very scarce

Підходи до підвищення пероральної біодоступності активних фармацевтичних інгредієнтів другого класу за біофармацевтичною класифікаційною системою

Aim. To compare existing approaches used for enhancing oral bioavailability (BA) of class II active pharmaceutical ingredients (API) and categorize them in the order of most promising.Materials and methods. The material of the article was literary data about approaches used for enhancing oral bioavailability of class II active pharmaceutical ingredients with a high permeability and poor solubility. Methods of information search, methods of comparison and generalization, systematic methods were used to carry out the researchtasks.Results and discussion. During last 20 years, the share of class II API in accordance with the biopharmaceutical classification system (i.e. with low solubility and high permeability) is continuously increasing at the world market and different stages of pharmaceutical product development. The approaches to improving oral BA of class II API which can be used to develop generic and modified generic drugs have been discussed in this article. These approaches were considered from the point of view of the principle of increasing the oral BA. It is concluded that promising approaches to increase oral BA should meet the following requirements: rapid achievement of oversaturated API concentration and its subsequent maintenance, keeping the whole API dose dissolved during transit through the intestines. Increased solubility and specific surface area are used as the main levers in all these approaches to improve oral bioavailability. At the same time, the ability to form supersaturated solutions and the retention of high concentrations during transit through the intestine differs depending on the approach.Conclusions. The most promising approaches to increase oral bioavailability, contributing to the formation of supersaturated solutions and maintaining high concentrations during transit are included: solid amorphous dispersions of API; digestible formulations that form micelles/emulsions in the intestine; and digestible inclusion complexes with cyclodextrins.Цель работы заключается в сравнении существующих подходов к повышению пероральной биодоступности активных фармацевтических ингредиентов II класса по биофармацевтической классификационной системе и определения среди них наиболее перспективных.Материалы и методы. Материалом статьи служили данные литературы относительно подходов к повышению пероральной биодоступности активных фармацевтических ингредиентов II класса, которые имеют высокую проницаемость и неудовлетворительную растворимость. Для исследования использованы методы информационного поиска, систематизации, сравнения и обобщения.Результаты и их обсуждение. В течение последних 20 лет на мировом рынке и на различных этапах разработки лекарственных средств наблюдается постоянное увеличение доли активных фармацевтических ингредиентов ІІ класса согласно биофармацевтической классификационной системе, т. е. с низкой растворимостью и высокой проницаемостью. Рассмотрены подходы к повышению пероральной биодоступности активных фармацевтических ингредиентов ІІ класса, которые могут быть использованы для разработки генерических и модифицированных генерических лекарственных средств. Данные подходы рассмотрены с точки зрения принципа повышения пероральной биодоступности. Было сделано заключение, что перспективные подходы к повышению пероральной биодоступности должны соответствовать следующим требованиям: быстрое достижение высокой (перенасыщенной) концентрации и последующее удержание высокой концентрации, которое позволяет растворить активные фармацевтические ингредиенты в течение транзита через кишечник. Повышение растворимости и удельной поверхностной площади используются как основные рычаги во всех упомянутых подходах к повышению пероральной биодоступности. В то же время способность к образованию перенасыщенных растворов и удержание высокой концентрации в течение транзита через кишечник отличаютсяв зависимости от подхода.Выводы. К наиболее перспективным подходам к повышению пероральной биодоступности, способствующим образованию перенасыщенных растворов и поддержанию высокой концентрации в течение транзита, были отнесены: твердые аморфные дисперсии активных фармацевтических ингредиентов рецептуры, которыеобразуют в кишечнике мицеллы/эмульсии или содержат комплексы включения с циклодекстринами и поддаются перевариванию.Мета роботи полягає у порівнянні існуючих підходів до підвищення пероральної біодоступності активних фармацевтичних інгредієнтів ІІ класу за біофармацевтичною класифікаційною системою та визначення серед них найбільш перспективних.Матеріали та методи. Матеріалом статті слугували дані наукових досліджень стосовно підходів до підвищення пероральної біодоступності активних фармацевтичних інгредієнтів ІІ класу, що мають високу проникність та незадовільну розчинність. Для дослідження використані методи інформаційного пошуку, систематизації, порівняння та узагальнення.Результати та їх обговорення. Впродовж останніх 20 років на світовому ринку та різних етапах розробки лікарських засобів спостерігається постійне збільшення частки активних фармацевтичних інгредієнтів ІІ класу за біофармацевтичною класифікаційною системою, тобто з низькою розчинністю та високою проникністю. Розглянуті підходи до підвищення пероральної біодоступності активних фармацевтичних інгредієнтів ІІ класу, які можуть бути використані для розробки генеричних та модифікованих генеричних лікарських засобів. Наведені підходи розглянуті з точки зору принципу підвищення пероральної біодоступності. Зроблено висновок, що перспективні підходи до підвищення пероральної біодоступності повинні відповідати таким вимогам: швидкому досягненню високої (перенасиченої) концентрації і подальшому утриманню високої концентрації, що дозволяє розчинити активні фармацевтичні інгредієнти впродовж транзиту через кишківник. Підвищення розчинності і питомої поверхневої площі використовуються як основні важелі у всіх згаданих підходах до підвищення пероральної біодоступності. У той же час здатність до утворення перенасичених розчинів і утримання високої концентрації впродовж транзиту через кишківник відрізняється в залежності від підходу.Висновки. До найбільш перспективних підходів до підвищення пероральної біодоступності, що сприяють утворенню перенасичених розчинів і підтримці високої концентрації впродовж транзиту, були віднесені: тверді аморфні дисперсії активних фармацевтичних інгредієнтів, рецептури, які утворюють в кишківнику міцели/емульсії або містять комплекси включення з циклодекстринами і піддаються перетравлюванню

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

A geo-archaeological approach to the study of hydro-agricultural systems in arid areas of Western Syria

Over the last 30 years, geoarchaeological surveys undertaken in the Near East have offered a powerful way of studying, inter alia, water supply systems at a microregional to regional scale. However, efforts to synthesize the results of surveys at a sub-continental scale in order to understand local differences and similarities, and compare local strategies through time, require specific tools. In this paper, we develop a methodology designed to characterize and facilitate comparison of strategies employed across the arid areas of Western Syria. This requires microregional field studies undertaken at the level of specific landscapes to be integrated within a wider GIS framework, based upon thematic layers (soils, rainfalls, hydrology) at a uniform spatial scale of assessment (in this case the pixel of a Landsat image), and a common description of the agronomic potential in those areas in which specific hydraulic installations were employed. In contrast to the usual practice of modelling, which depends upon the downscaling of environmental data (land cover, rainfall maps) generated at a continental scale, we stress here the need to generalize upwards, from observations made at the microregional level, by using common descriptors and qualitative indicators. The GIS analysis of these data provides a weighted average model derived from field evidence for the different technical choices made (i.e. the decision to utilize specific water management devices) in relation to the various agronomic landscapes

L'utilisation de systèmes d'Information Géographique appliquée à l'archéologie

National audienc

A CASE OF THE LEFT ATRIUM APPENDAGE OCCLUSION, SUGGESTIONS ON THE CLINICAL FIELD DEVELOPMENT

Aim. To evaluate the possibility of hybrid procedure that includes single-moment cryoballoon isolation of pulmonary veins (PV) ostia and implantation of occluder into the left atrium appendage (LAA) in patients of high thromboembolic and hemorrhagic risk and prominent symptoms in atrial fibrillation (AF) paroxysms.Material and methods. From 2012 to 2016 y., 72 procedures performed, of LAA occluder implantation for patients with high thromboembolic and hemorrhagic risk (mean age 68±7,4 y. o., 48 females, 24 males, mean rate by CHA2DS2VASc 4,82±1,48 points), of those 3 underwent single-moment cryoballoon isolation of the PV ostia without electrical isolation of LAA. The parameters of the intervention were assessed, and prevalence of intra-operation complications in AF patients that included single-moment catheter cryoballoon isolation of PV ostia and implantation of LAA occluding device, in comparison with isolated LAA occluder implantation.Results. Occluding device implantation was successful in 100% cases. Periprocedural efficacy of PV ostia isolation was 100%. In both groups, intraoperational complications were absent. Mean heparin time and dosage of contrast in the hybrid intervention group were higher: 94,3±6,8 min vs 59,7±19,95 min (p<0,05), 196,8±20,82 mL vs 124,6±30,24 mL (p<0,05), respectively.Conclusion. Performing of the hybrid intervention that includes single-moment catheter isolation of PV ostia and implantation of the occluding device into LAA increases mean procedure duration and contrast load in comparison to isolated LAA occluder implantation, with no operational risk increase

The dynamics of mangrove ecosystems, changes in sea level and strategies of Neolithic settlements along the coast of Oman (6000-3000 cal. BC)

This paper focus on the Holocene palaeogeography of the Ja'alan coast from the 6th to the 4th millennium cal. BC, integrating the dynamics of mangroves, lagoons, khors-estuaries and deltas, with sea-level change and the evidence from Neolithic shell middens. The distribution and maturation of mangrove ecosystems along the Arabian coasts has varied considerably, affected by physical forces such as sea-level changes, climate, tidal amplitude and duration as well as the quantity of fresh water inflow associated with the monsoon systems along the Arabian coast. Palaeo-mangroves and lagoons, today replaced by large sabkhas, appear to be correlated to mid-Holocene fossil deltas and estuaries that currently function episodically, depending on the rhythm of winter rains. All these parameters have determined and impacted the location of settlement networks and the economic strategies of the first Arabian farmers along the eastern Arabian coast. The mid-Holocene sea-level highstand stability (5th millennium BC) can be considered to be an optimum period for mangrove development and can be correlated with Neolithic sites around the mangroves. The decline of mangroves since 3000/2500 cal. BC and further degradation is mainly attributed to the prevailing arid climate that reduced summer monsoon effects in the tropical area by favouring the extension of sabkhas. We discuss these aspects based on new archaeological surveys, excavations and geoarchaeological studies.Peer Reviewe