Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency

Heterozygous variants in GBA1 encoding glucocerebrosidase (GCase) are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants in SMPD1 are also overrepresented in PD cohorts, whilst a reduction of its encoded enzyme (ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how combined deficiencies of both enzymes may interact to modulate PD has yet to be explored. Therefore, we created a double knock out (DKO) zebrafish line for both gba1 and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO compared to single mutants. Unexpectedly, DKOs maintained conventional swimming behaviour and had normalised neuronal gene expression signatures when compared to single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKOs. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo

Detection and monitoring of cancers with biosensors in Vietnam

Biosensors are able to provide fast, accurate and reliable detec-tions and monitoring of cancer cells, as well as to determine the effectiveness of anticancer chemotherapy agents in cancer treatments. These have attracted a great attention of research communities, especially in the capabilities of detecting the path-ogens, viruses and cancer cells in narrow scale that the conven-tional apparatus and techniques do not have. This paper pre-sents technologies and applications of biosensors for detections of cancer cells and related diseases, with the focus on the cur-rent research and technology development about biosensors in Vietnam, a typical developing country with a very high number of patients diagnosed with cancers in recent years, but having a very low cancer survival rate. The role of biosensors in early detections of diseases, cancer screening, diagnosis and treat-ment, is more and more important; especially it is estimated that by 2020, 60-70% new cases of cancers and nearly 70% of cancer deaths will be in economically disadvantaged countries. The paper is also aimed to open channels for the potential R&D collaborations with partners in Vietnam in the areas of innovative design and development of biosensors in particular and medical technology devices in general

DNA-Mediated Patterning of Single Quantum Dot Nanoarrays: A Reusable Platform for Single-Molecule Control

D.H. is financially supported by the Chinese Scholarship Council. We further gratefully acknowledge financial support from Queen Mary University of London

Rapid tooling for injection moulding process

3rd International Symposium on Designing, Processing and Properties of Advanced Engineering Materials, Jeju, SOUTH KOREA, NOV 05-08, 2003International audienceCROMeP (Research Centre on Tools, Materials and Processes) experience in rapid tooling development is related. Focus is placed on two processes, namely the Direct Metal Laser Sintering/DMLS(R) and STRATOCONCEPT(R) currently under consideration for the manufacturing of thermoplastic injection moulds. The principle of the two processing routes as well as the benefits attainable by using those processes will be briefly reviewed. Recent results on the microstructure and the mechanical performances of sample tools built up using both processes are presented

Efficacy of second-line antiretroviral therapy among people living with HIV/AIDS in Asia: Results from the TREAT Asia HIV observational database

Roughly 4% of the 1.25 million patients on antiretroviral therapy (ART) in Asia are using second-line therapy. To maximize patient benefit and regional resources, it is important to optimize the timing of second-line ART initiation and use the most effective compounds available. METHODS:: HIV-positive patients enrolled in the TREAT Asia HIV Observational Database who had used second-line ART for 6 months were included. ART use and rates and predictors of second-line treatment failure were evaluated. RESULTS:: There were 302 eligible patients. Most were male (76.5%) and exposed to HIV via heterosexual contact (71.5%). Median age at second-line initiation was 39.2 years, median CD4 cell count was 146 cells per cubic millimeter, and median HIV viral load was 16,224 copies per milliliter. Patients started second-line ART before 2007 (n = 105), 2007-2010 (n = 147) and after 2010 (n = 50). Ritonavir-boosted lopinavir and atazanavir accounted for the majority of protease inhibitor use after 2006. Median follow-up time on second-line therapy was 2.3 years. The rates of treatment failure and mortality per 100 patient/years were 8.8 (95% confidence interval: 7.1 to 10.9) and 1.1 (95% confidence interval: 0.6 to 1.9), respectively. Older age, high baseline viral load, and use of a protease inhibitor other than lopinavir or atazanavir were associated with a significantly shorter time to second-line failure. CONCLUSIONS:: Increased access to viral load monitoring to facilitate early detection of first-line ART failure and subsequent treatment switch is important for maximizing the durability of second-line therapy in Asia. Although second-line ART is highly effective in the region, the reported rate of failure emphasizes the need for third-line ART in a small portion of patients

Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria.

For the treatment of patients with acute falciparum malaria, the combination of artemisinin as a single dose with a single dose of mefloquine was studied in 4 separate prospective trials, comprising 405 adults and 139 children with uncomplicated falciparum malaria in 2 in-patient and 2 rural out-patient studies in Viet Nam. Adults received oral artemisinin and children artemisinin suppositories. Randomized comparative treatment schedules were: artemisinin alone for 5 d, mefloquine-sulfadoxine-pyrimethamine (MSP), or quinine plus sulfadoxine-pyrimethamine (SP). Parasite clearance times (PCT) were rapid for artemisinin treated inpatients (90%: 14.8-20.4 h) but also for patients receiving MSP (PCT 90%: 18.0 h) and quinine (PCT 90%: 22.5 h). The recrudescence rate (RI) during a 28 d follow-up period among the patients given artemisinin plus mefloquine was 15% in the adult in-patients and zero in the adult and children out-patients. RI in the artemisinin 5 d treatment group was 33.3%; among those given artemisinin plus SP it was 47.3% in in-patients and in out-patients 46.1%. In the MSP treated out-patients RI was 1.5% in adults and zero in children. Artemisinin as a single dose (oral in adults and as a suppository in children) in combination with mefloquine was effective in rapidly lowering parasitaemia and in preventing recrudescence in hospital in-patients and in out-patients attending a rural health clinic. MSP alone as a single dose also rapidly reduced parasitaemia (but not as quickly as the artemisinin-mefloquine combination in out-patient children) and prevented recrudescence

Projection Based Model Reduction for Optimal Design of the Time-Dependent Stokes System

The optimal design of structures and systems described by partial differential equations (PDEs) often gives rise to large-scale optimization problems, in particular if the underlying system of PDEs represents a multi-scale, multi-physics problem. Therefore, reduced order modeling techniques such as balanced truncation model reduction, proper orthogonal decomposition, or reduced basis methods are used to significantly decrease the computational complexity while maintaining the desired accuracy of the approximation. In particular, we are interested in such shape optimization problems where the design issue is restricted to a relatively small portion of the computational domain. In this case, it appears to be natural to rely on a full order model only in that specific part of the domain and to use a reduced order model elsewhere. A convenient methodology to realize this idea consists in a suitable combination of domain decomposition techniques and balanced truncation model reduction. We will consider such an approach for shape optimization problems associated with the time-dependent Stokes system and derive explicit error bounds for the modeling error. As an application in life sciences, we will be concerned with the optimal design of capillary barriers as part of a network of microchannels and reservoirs on microfluidic biochips that are used in clinical diagnostics, pharmacology, and forensics for high-throughput screening and hybridization in genomics and protein profiling in proteomics