Introgression of Brown Norway \u3cem\u3eCYP4A\u3c/em\u3e Genes onto the Dahl Salt-Sensitive Background Restores Vascular Function in SS-5\u3csup\u3eBN\u3c/sup\u3e Consomic Rats

The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NGnitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction

Fluoropolymer compositions, optical devices, and methods for fabricating optical devices

Optical waveguides interconnect optical information processing devices, or connect such devices with other optical communication links such as glass optical fibers. Fluoropolymers consisting of alternating perfluorocyclobutane and aryl ether linkages possess suitable properties for optical waveguides and other devices due to tunability in optical properties of the copolymers. Perfluorocyclobutane (PFCB) copolymer may be employed in solutions that exhibit a high solids content. Such solutions show useful physical properties for optical waveguide devices since the solutions are capable of achieving single step film thicknesses, when applied to a substrate, of greater than about 0.6 microns, and sometimes may achieve a thickness of 10 microns or more

An exploratory study of government ministerial libraries in Maseru, Lesotho.

Thesis (M.I.S.)-University of KwaZulu-Natal, Pietermaritzburg, 2004.The present study explores the status of government ministerial libraries in Maseru, Lesotho, with the purpose of discovering the factors which affect the growth and development of these libraries. To provide a wider context within which to view this study literature dealing with government libraries was examined. Nineteen government ministerial libraries were chosen as a population for the study. However, only fourteen ministerial libraries were eventually surveyed. Twenty library workers were interviewed using a structured questionnaire as the data collection instrument. The collected information was analysed manually. The study established that there are very few laws and regulations that govern the existence of libraries in Lesotho. The responses showed that even though there are government ministerial policies they do not accommodate libraries. The majority of these libraries do not get support from government for library material and therefore they depend only on donations which are not adequate, most of the time, for the needs of the users. The responses also revealed that the majority of government libraries do not function in the way that fully-fledged libraries do. The library workers revealed that the educational standards of library workers in Lesotho are not satisfactory at all. Among the staff of government libraries that were interviewed only five had a university degree, two had a university diploma and two had university certificates. It was found that some of the library services had not performed well becasue of one-man libraries and a lack of qualified staff The responses from the interviews established that government ministerial libraries in Lesotho are static; they do not grow and develop largely out of a lack of recognition, a lack of interest and a lack of upport from the government. Recommendations are based on the findings of the study with the hope that they will provide a basis for properly equipped and adequately staffed library services in all ministries in future

Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides.

Mannose-6-phosphate (M6P) is an essential precursor for mannosyl glycoconjugates, including lipid-linked oligosaccharides (LLO; glucose(3)mannose(9)GlcNAc(2)-P-P-dolichol) used for protein N-glycosylation. In permeabilized mammalian cells, M6P also causes specific LLO cleavage. However, the context and purpose of this paradoxical reaction are unknown. In this study, we used intact mouse embryonic fibroblasts to show that endoplasmic reticulum (ER) stress elevates M6P concentrations, leading to cleavage of the LLO pyrophosphate linkage with recovery of its lipid and lumenal glycan components. We demonstrate that this M6P originates from glycogen, with glycogenolysis activated by the kinase domain of the stress sensor IRE1-α. The apparent futility of M6P causing destruction of its LLO product was resolved by experiments with another stress sensor, PKR-like ER kinase (PERK), which attenuates translation. PERK's reduction of N-glycoprotein synthesis (which consumes LLOs) stabilized steady-state LLO levels despite continuous LLO destruction. However, infection with herpes simplex virus 1, an N-glycoprotein-bearing pathogen that impairs PERK signaling, not only caused LLO destruction but depleted LLO levels as well. In conclusion, the common metabolite M6P is also part of a novel mammalian stress-signaling pathway, responding to viral stress by depleting host LLOs required for N-glycosylation of virus-associated polypeptides. Apparently conserved throughout evolution, LLO destruction may be a response to a variety of environmental stresses.This work is supported by NIH grants DK-042394, HL-052173, and HL-057346 to R.J.K.; by NIH grants AI-073898 and GM-056927 to I.M.; by NIH grant R-37-DK047119 and a Principal Research Fellowship from the Wellcome Trust to D.R.; by NIH grant GM-031278 and support from the Robert Welch Foundation to J.R.F.; and by NIH grant GM-038545 and Robert Welch Foundation grant I-1168 to M.A.L

Development of Epoxyeicosatrienoic Acid Analogs with in Vivo Anti-Hypertensive Actions

Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase. Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12-ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was −0.3 ± 2 for treated and 12 ± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12-ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases

India's rainfed sorghum improvement: Three decades of genetic gain assessment for yield, grain quality, grain mold and shoot fly resistance

Sorghum is a climate-resilient cereal and staple food crop for more than 200 million people in arid and semi-arid countries of Asia and Africa. Despite the economic importance, the productivity of sorghum in India is constrained by biotic and abiotic stresses such as incidences of shoot fly, grain mold and drought. Indian sorghum breeding focused on dual-purpose (grain and fodder), short-duration varieties with multiple resistance/tolerance to pests and diseases and improved nutritional quality (high protein, iron and zinc and low fat). In this context, it is important to ascertain the genetic progress made over 30 years by assessing the efficiency of past achievements in genetic yield potential and to facilitate future genetic improvement. The current study determined the genetic gain in 24 sorghum varieties developed by the national and state level research systems during 1990-2020. The 24 varieties were evaluated for three years (2018-2020) at six locations in Telangana state for yield, nutritional characteristics and tolerance to shoot fly and grain mold. The absolute grain yield genetic gain from the base year 1990 is 44.93 kg/ha/yr over the first released variety CSV 15. The realized mean yield increased from 2658 kg/ha of the variety CSV 15 in 1990s to 4069 kg/ha of SPV 2579 developed in 2020s. The absolute genetic gain for grain mold resistance is -0.11 per year with an overall relative gain of 1.46% over CSV 15. The top varieties for grain yield (SPV 2579, SPV 2678 and SPV 2578), fodder yield (PYPS 2, SPV 2769 and SPV 2679), shoot fly tolerance (PYPS 8, PYPS 2 and SPV 2179), mold tolerance (PYPS 8, PYPS 2 and SPV 2579) and high protein (PYPS 8, PYPS 2 and SPV 2769) were identified for possible scale up and further use in reeding program diversification. The study revealed that sorghum varieties bred with diverse genetic backgrounds such as landraces and with tolerance to pests and diseases had stable yield performance. Application of genomics and other precision tools can double genetic gains for these traits to strengthen sorghum cultivation in rainfed areas serving food and nutrition security

Fluorinated musk fragrances : the CF2 group as a conformational bias influencing the odour of civetone and (R)-muscone

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). The authors acknowledge the EPSRC National Mass Spectrometry Facility (Swansea). M.Y. thanks the China Scholarship Council for financial support. D.O'H. thanks the Royal Society for a Wolfson Research Merit Award.The difluoromethylene (CF2) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF2 group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X-ray studies indeed show that the CF2 groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co-workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF2 groups, lose their musk fragrance and become less pleasant.PostprintPeer reviewe

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis

Synthesis of biologically active fluorinated lipids and heterocyclic compounds

Cette thèse concerne la synthèse totale de molécules bioactives et l'évaluation de leur activité biologique. Dans une première partie est décrite la synthèse d'analogues fluorés de métabolites d'acides gras polyinsaturés. Le 5(R)-fluoroheptynoate de méthyle a ainsi été préparé en utilisant une approche via les propargyliques fluorés chiraux. Cette démarche a été ensuite étendue aux composés gemdifluorés correspondants, permettant la synthèse totale des 5,5-difluoro-(12R)- et 12(S)-leucotriènes B3. La seconde partie de la thèse concerne la synthèse et l'évaluation biologique de nouveaux inducteurs d'apoptose de cellules tumorales. Cette étude part d'un composé hétérocyclique connu, le HA 14-1. Grâce à des stratégies appropriées, de nouvelles familles d'analogues du HA 14-1 ont été préparées. Les tests biologiques réalisés sur ces produits ont permis de dégager des relations structure-fonction qui ouvrent des pistes de recherche originales dans le domaine des antitumoraux.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF