526 research outputs found

    Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia

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    Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia dysfunction generally inherited as an autosomal recessive disease. Genetic testing is increasingly considered an early step in the PCD diagnostic workflow. We used targeted panel next generation sequencing (NGS) for genetic screening of 33 Egyptian families with highly clinically suspected PCD. All variants prioritized were Sanger confirmed in the affected individuals and correctly segregated within the family. Targeted NGS yielded a high diagnostic output (70%) with bi‐allelic mutations identified in known PCD genes. Mutations were identified in 13 genes overall, with CCDC40 and CCDC39 the most frequently mutated genes among Egyptian patients. Most identified mutations were predicted null effect variants (79%) and not reported before (85%). This study reveals that the genetic landscape of PCD among Egyptians is highly heterogeneous, indicating that a targeted NGS approach covering multiple genes will provide a superior diagnostic yield than Sanger sequencing for genetic diagnosis. The high diagnostic output achieved here highlights the potential of placing genetic testing early within the diagnostic workflow for PCD, in particular in developing countries where other diagnostic tests can be less available

    Eficiencia de la extracción asistida por ultrasonido de pétalos de Delonix regia como antioxidante natural en la estabilidad oxidativa del aceite de girasol

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    The possibility of improving the oxidative stability of sunflower oil by enriching it with carotenoids from Delonix regia petals was studied. A combination of ultrasound-assisted extraction and stirring techniques was used. The optimal conditions were material/solvent ratio of 1:20 (w/v), ultrasonic power of 30 W and extraction time of 50 min. Under these conditions, the yield of total carotenoids was 503.0 μg/g dry weight. Increasing the acoustic power density degraded carotenoids. A HPLC analysis was used for the quantification of β-carotene in the extract. The DPPH radical scavenging activity and ferric reducing antioxidant power of the carotenoid-rich extract were found to be superior to the standard Butylated hydroxyl toluene (BHT). The enrichment of sunflower oil with carotenoid-rich extract at 67.46 mg carotenoids/kg oil improved its oxidative stability by more than 50% as measured by the Rancimat method. These results suggest that the investigated extract has the potential to be used as a bio-preservative in food products.Se estudió la posibilidad de mejorar la estabilidad oxidativa del aceite de girasol enriqueciéndolo con carotenoides de pétalos de Delonix regia. Se utilizaron técnicas combinadas de extracción asistida por ultrasonido y técnicas de agitación. Las condiciones óptimas fueron una relación material/ disolvente de 1:20 (p/v), una potencia ultrasónica de 30 W y un tiempo de extracción de 50 min. En estas condiciones, el rendimiento de carotenoides totales fue de 503,0 ?g/g de peso seco. El aumento de la densidad de potencia acústica degrada a los carotenoides. El análisis por HPLC se utilizó para la cuantificación de β-caroteno en el extracto. Se encontró que la actividad de captación de radicales DPPH y el poder antioxidante reductor férrico del extracto rico en carotenoides es superior al del butilhidroxitolueno estándar (BHT). El enriquecimiento de aceite de girasol con extracto rico en carotenoides a 67,46 mg de carotenoides/kg de aceite mejoró su estabilidad oxidativa en más del 50% según lo medido por el método de Rancimat. Estos resultados proponen que el extracto investigado tiene el potencial de ser utilizado como conservante biológico en productos alimenticios

    Design, Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents

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    Three new series of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-yl)-4′-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4′-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4′-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC50 of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for 3c indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1

    Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

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    Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele

    New Paracyclophanylthiazoles with Anti-Leukemia Activity: Design, Synthesis, Molecular Docking, and Mechanistic Studies

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    A new series of methyl 2-(2-(4′-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates 3a–f were synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides 2a–f with dimethyl acetylenedicarboxylate. Based upon nuclear magnetic resonance (NMR), infrared (IR), and mass spectra (HRMS), the structure of the obtained products was elucidated. X-ray structure analysis was also used as unambiguous tool to elucidate the structure of the products. The target compounds 3a–f were screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound 3a was found as the most cytotoxic potency against 60 cancer cell lines. Consequently, it was selected for further five doses analysis according to National Cancer Institute (NCI) protocol. The cytotoxic effect showed selectivity ratios ranging between 0.63 and 1.28 and between 0.58 and 5.89 at the GI50 and total growth inhibition (TGI) levels, respectively. Accordingly, compound 3a underwent further mechanistic study against the most sensitive leukemia RPMI-8226 and SR cell lines. It showed antiproliferation with IC50 = 1.61 ± 0.04 and 1.11 ± 0.03 µM against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 µM/mL. Caspase-3, BAX, and Bcl-2 assays for 3a using annexin V-FITC staining revealed significant pro-apoptotic activity. Furthermore, multidrug-resistant leukemia SR cells were used to show better resistance indices (1.285 ng/mL, 1.15-fold) than the reference. Docking studies with β-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound 3a, which made several interactions better than that of the reference colchicine

    New Paracyclophanylthiazoles with Anti-Leukemia Activity: Design, Synthesis, Molecular Docking, and Mechanistic Studies

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    A new series of methyl 2-(2-(4′-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates 3a–f were synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides 2a–f with dimethyl acetylenedicarboxylate. Based upon nuclear magnetic resonance (NMR), infrared (IR), and mass spectra (HRMS), the structure of the obtained products was elucidated. X-ray structure analysis was also used as unambiguous tool to elucidate the structure of the products. The target compounds 3a–f were screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound 3a was found as the most cytotoxic potency against 60 cancer cell lines. Consequently, it was selected for further five doses analysis according to National Cancer Institute (NCI) protocol. The cytotoxic effect showed selectivity ratios ranging between 0.63 and 1.28 and between 0.58 and 5.89 at the GI50 and total growth inhibition (TGI) levels, respectively. Accordingly, compound 3a underwent further mechanistic study against the most sensitive leukemia RPMI-8226 and SR cell lines. It showed antiproliferation with IC50 = 1.61 ± 0.04 and 1.11 ± 0.03 µM against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 µM/mL. Caspase-3, BAX, and Bcl-2 assays for 3a using annexin V-FITC staining revealed significant pro-apoptotic activity. Furthermore, multidrug-resistant leukemia SR cells were used to show better resistance indices (1.285 ng/mL, 1.15-fold) than the reference. Docking studies with β-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound 3a, which made several interactions better than that of the reference colchicine

    IN VITRO EVALUATION OF ENSILING AND /OR EXOGENOUS FIBROLYTIC ENZYME SUPPLEMENTATION OF DATE PRESS CAKE

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    This study was conducted to evaluate the effect of ensiling and /or exogenous fibrolytic enzyme supplementation date press cake using in vitro batch culture technique . Untreated date press cake (DPC) and ensiled DPC with exogenous fibrolytic enzymes (ZAD1 and ZAD2) and with or without adding urea compared to corn grains were in vitro evaluated using batch culture technique. DM, NDF and ADF degradation and total gas production as well as fermentation parameters of the incubated samples were determined after 24 h of fermentation. Total VFAs, proportions are not affected (P > 0.05) by any of the treatments. However, value of ammonia concentration was higher (P 0.05) with the ensiling treatments. There were no significant differences in the values of DMD and OMD between the different treatments. But, the values of NDFD and ADFD were increased (P0.05) between the corn grain and the DPC without any treatments. While, values of metabolizable protein (MP) and efficiency of microbial biomass production (EMP) were increased (p<0.05) with DPC compared to corn grains . There was no significant difference in the rumen activity when using date press cake (DPC) or corn grains. Moreover, the ensiling process did not cause a clear improvement in rumen fermentation
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