A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

ANGEGHAKOT 1 (ARMENIA ) AND THE IDENTIFICATION OF THE MOUSTERIAN CULTURAL FACIES OF « YEREVAN POINTS » TYPE IN THE SOUTHERN CAUCASUS

International audienceIn 2003 a prehistoric site was discovered at an altitude of 1 800 m in the district of Angeghakot in the valley of the Vorotan (southeastern Armenia) by an Armenian-French multidisciplinary team. This site provides evidence for the presence of hunter-gatherers in the region during the Middle Palaeolithic. The lithic industry collected on the surface, mainly obsidian, has been identified as belonging to the Mousterian facies typical of the " Zagros-Taurus " , consisting of numerous Mousterian points, " Yerevan points " , microlithic tools, and the presence of the " truncating-facetting " technique. These recent data raise questions about the variability of facies in the Lesser Caucasus and allow us to draw a much larger distribution map of the sites where microlithic industries and resharpened points are present. Angeghakot 1, located on a cultural crossroads between Asia Minor, the Near East and Europe, raises questions related to the existence of a real Caucasian cultural system ; it represents a local economic variant in the exploitation of obsidian, strongly linked to the environmental constraints which existed in these mountain ranges at the end of the Pleistocene. Résumé : Au Caucase, dans la vallée du Vorotan (sud-est de l'Arménie), la découverte en 2003 par une équipe pluridisciplinaire arméno-française d'un gisement situé à 1 800 m d'altitude dans la commune d'Angeghakot, atteste la fréquentation de la région par des groupes de chasseurs-cueilleurs au Paléolithique moyen. L'industrie lithique, élaborée principalement sur l'obsidienne et récoltée en surface, a permis d'identifier le faciès moustérien typique du « Zagros-Taurus » composé de nombreuses pointes moustériennes, de poin-tes d'Erevan, d'outils microlithiques et la présence de la technique de « troncature-facettage ». Ces nouvelles données soulèvent des questions sur la variabilité des faciès du Petit Caucase. Elles permettent l'élaboration d'une carte de distribution plus vaste de ces sites qui se distinguent par leurs industries microlithiques et leurs pointes réaffûtées. Angeghakot 1, situé au carrefour des cultures d'Asie mineure, du Proche-Orient et de l'Europe, contribue également à poser la question de l'existence d'un système culturel caucasien, sous la forme d'une variante économique locale de l'exploitation de l'obsidienne, fortement liée aux contraintes environnementales présentes dans les chaînes de montagnes à la fin du Pléistocène

ANGEGHAKOT 1 (ARMENIA ) AND THE IDENTIFICATION OF THE MOUSTERIAN CULTURAL FACIES OF « YEREVAN POINTS » TYPE IN THE SOUTHERN CAUCASUS

International audienceIn 2003 a prehistoric site was discovered at an altitude of 1 800 m in the district of Angeghakot in the valley of the Vorotan (southeastern Armenia) by an Armenian-French multidisciplinary team. This site provides evidence for the presence of hunter-gatherers in the region during the Middle Palaeolithic. The lithic industry collected on the surface, mainly obsidian, has been identified as belonging to the Mousterian facies typical of the " Zagros-Taurus " , consisting of numerous Mousterian points, " Yerevan points " , microlithic tools, and the presence of the " truncating-facetting " technique. These recent data raise questions about the variability of facies in the Lesser Caucasus and allow us to draw a much larger distribution map of the sites where microlithic industries and resharpened points are present. Angeghakot 1, located on a cultural crossroads between Asia Minor, the Near East and Europe, raises questions related to the existence of a real Caucasian cultural system ; it represents a local economic variant in the exploitation of obsidian, strongly linked to the environmental constraints which existed in these mountain ranges at the end of the Pleistocene. Résumé : Au Caucase, dans la vallée du Vorotan (sud-est de l'Arménie), la découverte en 2003 par une équipe pluridisciplinaire arméno-française d'un gisement situé à 1 800 m d'altitude dans la commune d'Angeghakot, atteste la fréquentation de la région par des groupes de chasseurs-cueilleurs au Paléolithique moyen. L'industrie lithique, élaborée principalement sur l'obsidienne et récoltée en surface, a permis d'identifier le faciès moustérien typique du « Zagros-Taurus » composé de nombreuses pointes moustériennes, de poin-tes d'Erevan, d'outils microlithiques et la présence de la technique de « troncature-facettage ». Ces nouvelles données soulèvent des questions sur la variabilité des faciès du Petit Caucase. Elles permettent l'élaboration d'une carte de distribution plus vaste de ces sites qui se distinguent par leurs industries microlithiques et leurs pointes réaffûtées. Angeghakot 1, situé au carrefour des cultures d'Asie mineure, du Proche-Orient et de l'Europe, contribue également à poser la question de l'existence d'un système culturel caucasien, sous la forme d'une variante économique locale de l'exploitation de l'obsidienne, fortement liée aux contraintes environnementales présentes dans les chaînes de montagnes à la fin du Pléistocène

ANGEGHAKOT 1 (ARMENIA ) AND THE IDENTIFICATION OF THE MOUSTERIAN CULTURAL FACIES OF « YEREVAN POINTS » TYPE IN THE SOUTHERN CAUCASUS

International audienceIn 2003 a prehistoric site was discovered at an altitude of 1 800 m in the district of Angeghakot in the valley of the Vorotan (southeastern Armenia) by an Armenian-French multidisciplinary team. This site provides evidence for the presence of hunter-gatherers in the region during the Middle Palaeolithic. The lithic industry collected on the surface, mainly obsidian, has been identified as belonging to the Mousterian facies typical of the " Zagros-Taurus " , consisting of numerous Mousterian points, " Yerevan points " , microlithic tools, and the presence of the " truncating-facetting " technique. These recent data raise questions about the variability of facies in the Lesser Caucasus and allow us to draw a much larger distribution map of the sites where microlithic industries and resharpened points are present. Angeghakot 1, located on a cultural crossroads between Asia Minor, the Near East and Europe, raises questions related to the existence of a real Caucasian cultural system ; it represents a local economic variant in the exploitation of obsidian, strongly linked to the environmental constraints which existed in these mountain ranges at the end of the Pleistocene. Résumé : Au Caucase, dans la vallée du Vorotan (sud-est de l'Arménie), la découverte en 2003 par une équipe pluridisciplinaire arméno-française d'un gisement situé à 1 800 m d'altitude dans la commune d'Angeghakot, atteste la fréquentation de la région par des groupes de chasseurs-cueilleurs au Paléolithique moyen. L'industrie lithique, élaborée principalement sur l'obsidienne et récoltée en surface, a permis d'identifier le faciès moustérien typique du « Zagros-Taurus » composé de nombreuses pointes moustériennes, de poin-tes d'Erevan, d'outils microlithiques et la présence de la technique de « troncature-facettage ». Ces nouvelles données soulèvent des questions sur la variabilité des faciès du Petit Caucase. Elles permettent l'élaboration d'une carte de distribution plus vaste de ces sites qui se distinguent par leurs industries microlithiques et leurs pointes réaffûtées. Angeghakot 1, situé au carrefour des cultures d'Asie mineure, du Proche-Orient et de l'Europe, contribue également à poser la question de l'existence d'un système culturel caucasien, sous la forme d'une variante économique locale de l'exploitation de l'obsidienne, fortement liée aux contraintes environnementales présentes dans les chaînes de montagnes à la fin du Pléistocène

Figure 1: Direct Conversion Receiver DC OFFSET SUPPRESSION IN DOUBLE BALANCE DIRECT CONVERSION RECEIVERS

Abstract The double balance mixer scheme in-phase signal input and double-quadrature Local Oscillator (LO) is suggested for application on IQ direct conversion receivers. The influence of the gain and phase mismatches of splitters is investigated. It is shown that a similar scheme using square-law detectors is promising on optical applications

Early Pleistocene climate cycles in continental deposits of the Lesser Caucasus of Armenia inferred from palynology, magnetostratigraphy, and Ar-40/Ar-39 dating

Plio-Pleistocene diatomitic sequences in the Shamb paleo-lake (South Armenia, Lessee Caucasus) offer a rare opportunity to give new insights on the paleo-climate of Western Asia. We present an integrated palynological, Ar-40/Ar-39 geochronologic and magnetostratigraphic study for the most complete section in the sedimentary deposits of the Shamb paleo-lake. Ar-40/Ar-39 dating of two volcaniclastic layers provided ages of 1.24 +/- 0.03 and 1.16 +/- 0.02 Ma (2 sigma). Magnetostratigraphic data show that the entire Shamb section is of reversed polarity which, combined with Ar-40/Ar-39 dating, suggests that the entire section correlates with part of the Matuyama period (1.785-1.070 Ma). Pollen assemblages and macroremains diversity clearly show an alternation of glacial and interglacial phases. Age calibrations and accumulation rate extrapolation allow a direct correlation of climate changes with the global isotopic curve, and show that the Shamb section probably ranges from approximately 1.300 to 1.080 Ma (marine isotopic stages 40 to 31). The vegetation of the Lesser Caucasus developed in a mosaic pattern in a Pleistocene continental, mostly and climate. comparable to the present-day climate. The observed vegetation changes record a dominant climate response to the obliquity orbital parameter, but the influence of precession could not be established from the Shamb data. Pollen and macroflora both indicate that glacial periods were cold and dry and that interglacials were warm with local humidity. The Early Pleistocene climatic model for Western Asia is thus similar to the climatic model for the Mediterranean area

Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose

Abstract Background Excess dietary fructose intake associated with metabolic syndrome and insulin resistance and increased risk of developing type 2 diabetes. Previous animal studies have reported that diabetic animals have significantly impaired behavioural and cognitive functions, pathological synaptic function and impaired expression of glutamate receptors. Correction of the antioxidant status of laboratory rodents largely prevents the development of fructose-induced plurimetabolic changes in the nervous system. We suggest a novel concept of efficiency of Stevia leaves for treatment of central diabetic neuropathy. Methods By in vivo extracellular studies induced spike activity of hippocampal neurons during high frequency stimulation of entorhinal cortex, as well as neurons of basolateral amygdala to high-frequency stimulation of the hippocampus effects of Stevia rebaudiana Bertoni plant evaluated in synaptic activity in the brain of fructose-enriched diet rats. In the conditions of metabolic disorders caused by fructose, antioxidant activity of Stevia rebaudiana was assessed by measuring the NOX activity of the hippocampus, amygdala and spinal cord. Results In this study, the characteristic features of the metabolic effects of dietary fructose on synaptic plasticity in hippocampal neurons and basolateral amygdala and the state of the NADPH oxidase (NOX) oxidative system of these brain formations are revealed, as well as the prospects for development of multitarget and polyfunctional phytopreparations (with adaptogenic, antioxidant, antidiabetic, nootropic activity) from native raw material of Stevia rebaudiana. Stevia modulates degree of expressiveness of potentiation/depression (approaches but fails to achieve the norm) by shifting the percentage balance in favor of depressor type of responses during high-frequency stimulation, indicating its adaptogenic role in plasticity of neural networks. Under the action of fructose an increase (3–5 times) in specific quantity of total fraction of NOX isoforms isolated from the central nervous system tissue (amygdala, hippocampus, spinal cord) was revealed. Stevia exhibits an antistress, membrane-stabilizing role reducing the level of total fractions of NOX isoforms from central nervous system tissues and regulates NADPH-dependent O2 − −producing activity. Conclusion Generally, in condition of metabolic disorders caused by intensive consumption of dietary fructose Stevia leaves contributes to the control of neuronal synaptic plasticity possibly influencing the conjugated NOX-specific targets

Early Levallois technology and the Lower to Middle Paleolithic transition in the Southern Caucasus

Levallois technology is the name for the stone knapping technique used to create tools thousands of years ago. The technique appeared in the archeological record across Eurasia 200 to 300 thousand years ago (ka) and appeared earlier in Africa. Adler et al. challenge the hypothesis that the technique's appearance in Eurasia was the result of the expansion of hominins from Africa. Levallois obsidian artifacts in the southern Caucasus, dated at 335 to 325 ka, are the oldest in Eurasia. This suggests that Levallois technology may have evolved independently in different hominin populations. Stone technology cannot thus be used as a reliable indicator of Paleolithic human population change and expansion