Characterization of the Drosophila Ortholog of the Human Usher Syndrome Type 1G Protein Sans

BACKGROUND: The Usher syndrome (USH) is the most frequent deaf-blindness hereditary disease in humans. Deafness is attributed to the disorganization of stereocilia in the inner ear. USH1, the most severe subtype, is associated with mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15, and sans. Myosin VIIa, harmonin, cadherin 23, and protocadherin 15 physically interact in vitro and localize to stereocilia tips in vivo, indicating that they form functional complexes. Sans, in contrast, localizes to vesicle-like structures beneath the apical membrane of stereocilia-displaying hair cells. How mutations in sans result in deafness and blindness is not well understood. Orthologs of myosin VIIa and protocadherin 15 have been identified in Drosophila melanogaster and their genetic analysis has identified essential roles in auditory perception and microvilli morphogenesis, respectively. PRINCIPAL FINDINGS: Here, we have identified and characterized the Drosophila ortholog of human sans. Drosophila Sans is expressed in tubular organs of the embryo, in lens-secreting cone cells of the adult eye, and in microvilli-displaying follicle cells during oogenesis. Sans mutants are viable, fertile, and mutant follicle cells appear to form microvilli, indicating that Sans is dispensable for fly development and microvilli morphogenesis in the follicle epithelium. In follicle cells, Sans protein localizes, similar to its vertebrate ortholog, to intracellular punctate structures, which we have identified as early endosomes associated with the syntaxin Avalanche. CONCLUSIONS: Our work is consistent with an evolutionary conserved function of Sans in vesicle trafficking. Furthermore it provides a significant basis for further understanding of the role of this Usher syndrome ortholog in development and disease

Cost of detecting malignant lesions by endoscopy in 2741 primary care dyspeptic patients without alarm symptoms.

BACKGROUND & AIMS: Current guidelines recommend empirical, noninvasive approaches to manage dyspeptic patients without alarm symptoms, but concerns about missed lesions persist; the cost savings afforded by noninvasive approaches must be weighed against treatment delays. We investigated the prevalence of malignancies and other serious abnormalities in patients with dyspepsia and the cost of detecting these by endoscopy. METHODS: We studied 2741 primary-care outpatients, 18-70 years in age, who met Rome II criteria for dyspepsia. Patients with alarm features (dysphagia, bleeding, weight loss, etc) were excluded. All patients underwent endoscopy. The cost and diagnostic yield of an early endoscopy strategy in all patients were compared with those of endoscopy limited to age-defined cohorts. Costs were calculated for a low, intermediate, and high cost environment. RESULTS: Endoscopies detected abnormalities in 635 patients (23%). The most common findings were reflux esophagitis with erosions (15%), gastric ulcers (2.7%), and duodenal ulcers (2.3%). The prevalence of upper gastrointestinal malignancy was 0.22%. If all dyspeptic patients 50 years or older underwent endoscopy, 1 esophageal cancer and no gastric cancers would have been missed. If the age threshold for endoscopy were set at 50 years, at a cost of $500/endoscopy, it would cost$82,900 (95% CI, $35,714-$250,000) to detect each case of cancer. CONCLUSIONS: Primary care dyspeptic patients without alarm symptoms rarely have serious underlying conditions at endoscopy. The costs associated with diagnosing an occult malignancy are large, but an age cut-off of 50 years for early endoscopy provides the best assurance that an occult malignancy will not be missed

mTOR signaling in proteostasis and its relevance to autism spectrum disorders

Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.This review was supported by grant BFU2015-68568-P (MINECO/FEDER, EU) to AO