RAB-5 and RAB-10 cooperate to regulate neuropeptide release in Caenorhabditis elegans

Neurons secrete neuropeptides from dense core vesicles (DCVs) to modulate neuronal activity. Little is known about how neurons manage to differentially regulate the release of synaptic vesicles (SVs) and DCVs. To analyze this, we screened all Caenorhabditis elegans Rab GTPases and Tre2/Bub2/Cdc16 (TBC) domain containing GTPase-activating proteins (GAPs) for defects in DCV release from C. elegans motoneurons. rab-5 and rab-10 mutants show severe defects in DCV secretion, whereas SV exocytosis is unaffected. We identified TBC-2 and TBC-4 as putative GAPs for RAB-5 and RAB-10, respectively. Multiple Rabs and RabGAPs are typically organized in cascades that confer directionality to membrane-trafficking processes. We show here that the formation of release-competent DCVs requires a reciprocal exclusion cascade coupling RAB-5 and RAB-10, in which each of the two Rabs recruits the other’s GAP molecule. This contributes to a separation of RAB-5 and RAB-10 domains at the Golgi–endosomal interface, which is lost when either of the two GAPs is inactivated. Taken together, our data suggest that RAB-5 and RAB-10 cooperate to locally exclude each other at an essential stage during DCV sorting.     

AudioGene: Predicting Hearing Loss Genotypes from Phenotypes to Guide Genetic Screening

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a common and often progressive sensory deficit. ADNSHL displays a high degree of genetic heterogeneity and varying rates of progression. Accurate, comprehensive, and cost‐effective genetic testing facilitates genetic counseling and provides valuable prognostic information to affected individuals. In this article, we describe the algorithm underlying AudioGene, a software system employing machine‐learning techniques that utilizes phenotypic information derived from audiograms to predict the genetic cause of hearing loss in persons segregating ADNSHL. Our data show that AudioGene has an accuracy of 68% in predicting the causative gene within its top three predictions, as compared with 44% for a majority classifier. We also show that AudioGene remains effective for audiograms with high levels of clinical measurement noise. We identify audiometric outliers for each genetic locus and hypothesize that outliers may reflect modifying genetic effects. As personalized genomic medicine becomes more common, AudioGene will be increasingly useful as a phenotypic filter to assess pathogenicity of variants identified by massively parallel sequencing.     

An evaluation of microleakage of various glass ionomer based restorative materials in deciduous and permanent teeth: An in vitro study

AimTo evaluate the microleakage of recently available glass ionomer based restorative materials (GC Fuji IX GP, GC Fuji VII, and Dyract) and compare their microleakage with the previously existing glass ionomer restorative materials (GC Fuji II LC) in primary and permanent teeth.MethodOne hundred and fifty (75 + 75) non-carious deciduous and permanent teeth were restored with glass ionomer based restorative materials after making class I cavities. Samples were subjected to thermocycling after storing in distilled water for 24 h. Two coats of nail polish were applied 1 mm short of restorative margins and samples sectioned buccolingually after storing in methylene blue dye for 24 h. Microleakage was assessed using stereomicroscope.ResultSignificant differences (P < 0.05) were found when inter group comparisons were done. Except when GC Fuji VII (Group III) was compared with GC Fuji II LC (Group II) and Dyract (Group IV), non-significant differences (P > 0.05) were observed. It was found that there was no statistically significant difference when the means of microleakage of primary teeth were compared with those of permanent teeth.ConclusionsGC Fuji IX GP showed maximum microleakage and GC Fuji VII showed least microleakage.     

Prevalence of haptic feedback in robot-mediated surgery: a systematic review of literature

With the successful uptake and inclusion of robotic systems in minimally invasive surgery and with the increasing application of robotic surgery (RS) in numerous surgical specialities worldwide, there is now a need to develop and enhance the technology further. One such improvement is the implementation and amalgamation of haptic feedback technology into RS which will permit the operating surgeon on the console to receive haptic information on the type of tissue being operated on. The main advantage of using this is to allow the operating surgeon to feel and control the amount of force applied to different tissues during surgery thus minimising the risk of tissue damage due to both the direct and indirect effects of excessive tissue force or tension being applied during RS. We performed a two-rater systematic review to identify the latest developments and potential avenues of improving technology in the application and implementation of haptic feedback technology to the operating surgeon on the console during RS. This review provides a summary of technological enhancements in RS, considering different stages of work, from proof of concept to cadaver tissue testing, surgery in animals, and finally real implementation in surgical practice. We identify that at the time of this review, while there is a unanimous agreement regarding need for haptic and tactile feedback, there are no solutions or products available that address this need. There is a scope and need for new developments in haptic augmentation for robot-mediated surgery with the aim of improving patient care and robotic surgical technology further.     

Serum tumor markers and testicular germ cell tumors: a primer for radiologists

Abdominal Radiology - Serum tumor markers (STMs) play a critical role in the diagnosis, staging and follow-up of both seminomatous and nonseminomatous testicular germ cell neoplasms. Levels of...     

beta-lapachone,a novel plant product,overcomes drug resistance in human multiple myeloma cells

OBJECTIVE: To evaluate the anti-tumor potential of beta-lapachone in multiple myeloma (MM) cell lines (U266, RPMI8226, and MM.1S); MM cell lines resistant to dexamethasone (MM.1R), melphalan (RPMI8226/LR5), doxorubicin (RPMI8226/DOX40), and mitoxantrone (RPMI8226/ MR20); and MM cells from patients (MM1-MM4). MATERIALS AND METHODS: Cytotoxicity of beta-lapachone was assessed by MTT and [3H]-thymidine uptake assays. Apoptosis was analyzed using propidium iodide staining, DNA fragmentation, TUNEL assay, caspase-9 colorimetric assay, and immunoblotting for caspase-3, poly (ADP-ribose) polymerase (PARP), and caspase-8 cleavage products. Paracrine growth of MM cells was assessed by [3H]-thymidine uptake in cultures of bone marrow stromal cells (BMSCs) and MM cells. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in the culture supernatants was measured by specific enzyme-linked immunosorbent assays (ELISAs). RESULTS: beta-lapachone showed significant cytotoxicity in MM cells (IC(50): 4-8 microM). In contrast, normal peripheral blood mononuclear cells (PBMCs) and BMSCs from MM patients were relatively resistant (IC(50): 8-16 microM). IL-6 did not protect against beta-lapachone-induced apoptosis in MM.1S cells, and dexamethasone showed additive cytotoxicity. beta-lapachone also decreased binding of MM.1S cells to BMSCs; abrogated IL-6 and VEGF secretion triggered by adhesion of BMSCs to MM.1S cells; reduced proliferation of MM.1S cells adherent to BMSCs; and decreased intracellular adhesion molecule-1 (ICAM-1) expression on MM.1S cells. Furthermore, beta-lapachone induced typical PARP cleavage, increased caspase-9 proteolytic activity, and activation of caspase-3, without activation of caspase-8 in U266 cells. CONCLUSION: These studies provide a framework for clinical evaluation of beta-lapachone to improve the outcome for patients with MM.     

Complications of total hip arthroplasty: periprosthetic fractures of the acetabulum

Periprosthetic fractures of the acetabulum are a rare but potentially disastrous complication of total hip arthroplasty. Such fractures occur either as early perioperative complications or late complications when they are associated with either significant trauma or as a result of the loss of the structural integrity of the bone supporting the prosthesis, such as aseptic osteolysis. The incidence of such fractures appears to be increasing with the increased use of uncemented acetabular components. This article explores the current literature on the epidemiology, etiology, and classification of periprosthetic acetabular fractures as well as offering potential treatment strategies.