Effect of α-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria

AbstractThe aim of the present study was to evaluate a possible interference of a-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 μM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 μM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to `reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondria) superoxide radicals (O2−) Apart from :ts direct 02-scavenging activities DHLA was also found to control mitochondria) O2− formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondria) O2− generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function

(3R,4R,5S)-4-Hydr­oxy-3-methyl-5-[(2S,3R)-3-methyl­pent-4-en-2-yl]-4,5-dihydro­furan-2(3H)-one

The relative configuration of the title compound, C11H18O3, which was synthesized using a catalytic asymmetric Gosteli–Claisen rearrangement, a diastereoselective reduction with K-Selectride and an Evans aldol addition, was corroborated by single-crystal X-ray diffraction analysis. The five-membered ring has an envelope conformation with a dihedral angle of 29.46 (16)° between the coplanar part and the flap (the hydr­oxy-bearing ring C atom). In the crystal, mol­ecules are connected via bifurcated O—H⋯(O,O) hydrogen bonds, generating [010] chains

(3S,4S,5R)-4-Hydr­oxy-3-methyl-5-[(2S,3R)-3-methyl­pent-4-en-2-yl]-4,5-dihydro­furan-2(3H)-one

The relative configuration of the title compound, C11H18O3, was corroborated by single-crystal X-ray diffraction analysis. In the crystal, mol­ecules are linked via a O—H⋯O hydrogen bond and a chain of mol­ecules is formed along [010]

(±)-syn-Isopropyl 4-(1,1,1,3,3,3-hexa­fluoro­propan-2-yl­oxy)-1-hydr­oxy-3-methyl-2-(prop-1-yn­yl)cyclo­pent-2-ene­carboxyl­ate

The title compound, C16H18F6O4, was obtained through an unprecedented one-pot reaction sequence involving a Gosteli–Claisen rearrangement and a cyclo­isomerization. The constitution and relative configuration were determined by single-crystal X-ray diffraction analysis. In the crystal, mol­ecules are connected via O—H ⋯ O hydrogen bonds

Rationality of quotients by linear actions of affine groups

Let G be the (special) affine group, semidirect product of SL_n and C^n. In this paper we study the representation theory of G and in particular the question of rationality for V/G where V is a generically free G-representation. We show that the answer to this question is positive if the dimension of V is sufficiently large and V is indecomposable. We have a more precise theorem if V is a two-step extension 0 -> S -> V -> Q -> 0 with S, Q completely reducible.Comment: 18 pages; dedicated to Fabrizio Catanese on the occasion of his 60th birthda

(4R)-4-Benzyl-3-{(4S)-4-chloro-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]butano­yl}-1,3-oxazolidin-2-one

The title compound, C19H24ClNO5, was synthesized and subsequently employed in an Evans alkyl­ation. The purpose was to prove the absolute configuration in the projected synthesis of the side chain of (–)-Lytophilippine A. The oxazolidinone and the isopropylidene acetal rings have twisted conformations. The oxazolidinone and side-chain carbonyl groups are orientated in an anti­periplanar arrangement to minimize van der Waals repulsions. Furthermore, the Cl atom and the acetonide-protected secondary alcohol are also in an anti­periplanar arrangement with a torsion angle of 173.64 (14)°. The absolute configuration was determined and agrees with the configuration of the used chiral auxiliary

Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50–99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged 20 adenomas aged T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged 20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing

Diagnosis of Fanconi Anemia: Mutation Analysis by Next-Generation Sequencing

Fanconi anemia (FA) is a rare genetic instability syndrome characterized by developmental defects, bone marrow failure, and a high cancer risk. Fifteen genetic subtypes have been distinguished. The majority of patients (≈85%) belong to the subtypes A (≈60%), C (≈15%) or G (≈10%), while a minority (≈15%) is distributed over the remaining 12 subtypes. All subtypes seem to fit within the “classical” FA phenotype, except for D1 and N patients, who have more severe clinical symptoms. Since FA patients need special clinical management, the diagnosis should be firmly established, to exclude conditions with overlapping phenotypes. A valid FA diagnosis requires the detection of pathogenic mutations in a FA gene and/or a positive result from a chromosomal breakage test. Identification of the pathogenic mutations is also important for adequate genetic counselling and to facilitate prenatal or preimplantation genetic diagnosis. Here we describe and validate a comprehensive protocol for the molecular diagnosis of FA, based on massively parallel sequencing. We used this approach to identify BRCA2, FANCD2, FANCI and FANCL mutations in novel unclassified FA patients

Влияние геометрии вертикальных ребер на производительность емкостей для десублимации газообразного UF6

Объектом исследования является вертикальная погружная емкость с вертикальным оребрением. В процессе исследования проводился расчет зависимостей средней производительности емкостей объемом от 1 до 4 кубометров с вертикальным оребрением от длины и ширины вертикальных ребер. Для данных емкостей были определены оптимальные значения ширины и длины вертикальных ребер.The object of study is a vertical immersion tank with vertical fins. In the course of the study, the dependences of the average productivity of containers with a volume of 1 to 4 cubic meters with vertical ribbing on the length and width of vertical ribs were calculated. For these containers, the optimal values of the width and length of the vertical ribs were determined

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH