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    • Enzyme parameters obtained for GC E variants can

    2021-11-11

    Enzyme parameters obtained for GC-E variants can further be introduced in kinetic models of phototransduction using computational approaches. A similar approach has been successfully applied in the investigation of disease causing mutations of GCAP1 to simulate rod and cone photoresponses under disease conditions (Dell'Orco et al., 2014). With proof of concept for gene augmentation therapy now established in GC-E deficient mouse models, and verification that and AAV5 vector carrying the GRK1 promoter is capable of driving transgene exclusively in rods and Y-27632 of a clinically relevant species (non-human primate), it is expected that the next step would be a phase I/II clinical trial for testing safety concerns followed by phase III for testing treatment efficacy. One should take into account the long-term results obtained in RPE65-treated LCA patients, showing that gene therapy does not stop the process of photoreceptor degeneration. However, because LCA1 is a more stationary disease, and because the therapy will be aimed directly at the disease target (photoreceptors) rather than a neighboring epithelial layer, treatment might yield better long-term results. Applying the same treatment strategy to cure adCRD due to a heterozygous GUCY2D mutation is unlikely to be efficient since the mutated allele produced an abnormal protein that affect GC-E biochemical properties. Knocking down the mutant allele (without interfering the wt allele) is therefore needed to prevent the effect of the mutant allele, assuming a haplosufficieny mechanism in which 50% of the wt protein amount is sufficient for normal photoreceptor function. Although a large number of LCA and CRD patients were found to harbor pathogenic mutations in GUCY2D, it is likely that many additional patients were misdiagnosed and were not screened for mutations in this gene. Misdiagnosis can occur for both LCA cases (who might not be available for clinical assessment at a young age and therefore might be diagnosed with RP or a cone-dominated disease) and CRD cases (who might be diagnosed with CD, maculopathy, and Stargardt disease). Moreover, clinical variability among patients who carry mutations in the same gene or even carry the same mutation, can lead to different clinical diagnoses, for example RP/CRD versus LCA (Avila-Fernandez et al., 2007, Perrault et al., 2005, Ugur Iseri et al., 2010). Therefore, regardless the retinal phenotype of a patient, genetic testing should include GUCY2D for both recessive and dominant inheritance patterns as well as isolate cases. Indeed, next generation sequencing techniques that are now available for either a specific gene-panel or the whole exome, revealed unexpected genetic findings and should be preferred over screening a specific single gene for mutations.
    Acknowledgements
    Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder and studies show that about 7%–15% of North Americans and about 11.5% of Europeans are affected , , , . IBS patients have frequent and intermittent abdominal pain and discomfort, which not only adversely affect the patient’s health, but also reduce work efficiency and increase the use of related medical resources , . IBS with constipation (IBS-C) patients Y-27632 account for about one-third of the total number of IBS patients, and the number of female patients is more than male . Apart from abdominal pain and reduced the frequency of stool, IBS-C patients also suffer from bloating, straining and incomplete sense of evacuation , . Because traditional therapies have poor efficacy on the main symptoms of IBS-C patients, more treatment options will be valuable . Linaclotide is a 14-amino acid peptide approved by the FDA for the treatment of IBS-C, which not only accelerates intestinal transit but also improves abdominal pain , . This peptide belongs to heat-stable enterotoxin analog of , which activates GC-C on the surface of intestinal epithelium, resulting in increased level of cyclic guanosine monophosphate (cGMP). Increased cGMP could activate cystic fibrosis transmembrane conductance regulator (CFTR). This activation results in the secretion of bicarbonate and chloride into the lumen, increasing intracavital fluid secretion and accelerating intestinal transit , . Although linaclotide is effective for the treatment of IBS-C, there are some side effects such as dose-dependent diarrhoea, abdominal discomfort and flatulence in clinical trials , . Therefore, it is still necessary to improve the activity of linaclotide based on drug molecule design , . However, the PDB files of linaclotide remains unknown. For this reason, the determination of the three-dimensional structure of linaclotide is of importance.