Search results for "alternative"
showing 10 items of 1466 documents
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
2018
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformati…
Which non-carbapenem antibiotics are active against extended-spectrum β-lactamase-producing Enterobacteriaceae?
2018
In this study, the activity of 18 non-carbapenem antibiotics was evaluated against 100 extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-Ec) and 50 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) isolated from urinary tract infections and bacteraemia in 2016. Minimum inhibitory concentrations (MICs) were determined using reference methods and the susceptibility profiles were defined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2017 recommendations. All of the ESBL-Ec isolates were susceptible to ceftazidime/avibactam and a great majority of them were susceptible to fosfomycin (98%), piperacillin/tazobactam (97%), amikacin (97%) and nitr…
Medicinal Plants and Natural Products as Potential Sources for Antiparkinson Drugs
2016
Parkinsonʼs disease is a progressive neurodegenerative dysfunction characterized by the loss of pigmented dopaminergic neurons of the nigrostriatal system with a consequent dopamine decrease. The reduction of dopamine levels produces neuronal damage, depigmentation of the substantia nigra, and the presence of intracellular inclusions in dopaminergic neurons. Treatments for Parkinsonʼs disease aim for improving these motor symptoms by increasing the dopaminergic signal in the striatum with levodopa in combination with enzyme inhibitors or anticholinergic drugs. Nevertheless, natural products can act as neuroprotective agents by reducing the progression of the disease and the inflammatory pro…
De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features
2020
IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or with…
Androgen-inducible gene 1 increases the ER Ca(2+) content and cell death susceptibility against oxidative stress.
2016
Androgen-induced gene 1 (AIG1) is a transmembrane protein implicated with survival (its expression level was shown to correlate with the survival of patients suffering from hepatocellular carcinoma) and Ca(2+) signaling (over-expression of AIG1 increased transcription mediated by the Ca(2+)-dependent nuclear factor of activated T cells). We aimed to shed light on this less-studied protein and investigated its tissue expression, genomic organization, intracellular localization and membrane topology as well as its effects on cell death susceptibility and the Ca(2+) content of the endoplasmic reticulum. Immunoblotting of mouse tissues demonstrated highest expression of AIG1 in the liver, lung …
Adolescent sugar-sweetened beverage consumption: An extended Health Action Process Approach.
2019
Abstract Objective Consumption of excess added sugar in the form of sugar-sweetened beverages (SSBs) contributes to a wide range of health concerns in adolescents. Identification of modifiable determinants of SSB consumption based on behavioral theory may inform development of interventions aimed at reducing SSB consumption. The aim of the current study was to test the efficacy of an extended version of the Health Action Process Approach to predict adolescent SSB consumption. Methods Using a prospective design, adolescent students (N = 450) self-reported their outcome expectancies, perceived behavioral control, intentions, habit, action, maintenance, and recovery self-efficacy, action and c…
Sequential cleavage of the proteins encoded by HNOT/ALG3, the human counterpart of the Drosophila NOT and yeast ALG3 gene, results in products acting…
2017
This study provides first insights into the biosynthesis, structure, biochemistry and complex processing of the proteins encoded by hNOT/ALG3, the human counterpart of the Drosophila Neighbour of TID (NOT) and the yeast asparagine linked glycosylation 3 gene (ALG3), which encodes a mannosyltransferase. Unambiguous evidence that both the fly and human proteins act as mannosyltransferases has not been provided yet. Previously, we showed that hNOT/ALG3 encodes two alternatively spliced main transcripts, hNOT-1/ALG3-1 and hNOT-4/ALG3-4, and their 15 truncated derivatives that lack diverse sets of exons and/or carry point mutations that result in premature termination codons. Here we show that t…
Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial
2020
AbstractMyotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3’-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to trans-dysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important…
MTA apical barrier: In vitro study of the use of ultrasonic vibration
2016
Background: The apexification is the first alternative treatment on a permanent tooth when, after a tooth trauma and in the presence of immature apex trauma, pulp necrosis occurs. Many studies have demonstrated the efficacy of mineral trioxide aggregate (MTA) as apical sealing material of choice in these cases, but has a degree of filtration as all other materials. The objective of this study was to analyze the seal ability of MTA on the duct walls in immature teeth unirradicular apexes, using indirect vibration. Material and Methods: The study was conducted on 45 teeth divided into 3 groups: Group A or control group in which no vibration for placing the MTA was used, Group B and C or group…
Immunmodulatory and Antiproliferative Properties of Rhodiola Species.
2016
The traditional medicines of Asia and Europe have long used various Rhodiola species, which are endemic to the subarctic areas of the northern hemisphere, as tonic, adaptogen, antidepressant, and anti-inflammatory drugs. In order to establish the therapeutic uses of these plants in modern medicine, the pharmacological effects of Rhodiola sp. have been widely studied. Indeed, the most amply researched species, Rhodiola rosea, has been shown to possess antioxidant, adaptogenic, antistress, antimicrobial, immunomodulatory, angiomodulatory, and antitumoral effects. Salidroside (p-hydroxyphenethyl-β-D-glucoside), a major compound in Rhodiola, seems to be responsible for many of the effects obser…