Small-molecule inhibitors of phosphatidylcholine transfer protein/StarD2 identified by high-throughput screening

Phosphatidylcholine transfer protein (PC–TP, also referred to as StarD2) is a highly specific intracellular lipid-binding protein that catalyzes the transfer of phosphatidylcholines between membranes in vitro. Recent studies have suggested that PC–TP in vivo functions to regulate fatty acid and glucose metabolism, possibly via interactions with selected other proteins. To begin to address the relationship between activity in vitro and biological function, we undertook a high-throughput screen to identify small-molecule inhibitors of the phosphatidylcholine transfer activity of PC–TP. After adapting a fluorescence quench assay to measure phosphatidylcholine transfer activity, we screened 114,752 compounds of a small-molecule library. The high-throughput screen identified 14 potential PC–TP inhibitors. Of these, 6 compounds exhibited characteristics consistent with specific inhibition of PC–TP activity, with IC50 values that ranged from 4.1 to 95.0 ?M under conditions of the in vitro assay. These compounds should serve as valuable reagents to elucidate the biological function of PC–TP. Because mice with homozygous disruption of the PC–TP gene (Pctp) are sensitized to insulin action and relatively resistant to the development of atherosclerosis, these inhibitors may also prove to be of value in the management of diabetes and atherosclerotic cardiovascular diseases

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. [Results]: We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. [Conclusions]: In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.RF and JL received funding from EU FP7 (PREDICT project), EB is a Rosetrees Trust fellow, NM received funding from the Rosetrees Trust, MG is funded by the UK Medical Research Council, IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal, and CS is a senior Cancer Research UK clinical research fellow and is funded by Cancer Research UK, the Rosetrees Trust, EU FP7 (projects PREDICT and RESPONSIFY, ID:259303), the Prostate Cancer Foundation, and the Breast Cancer Research Foundation. This study was supported by researchers at the National Institute for Health Research Biomedical Research Centres at University College London Hospitals and at the Royal Marsden Hospital.Peer Reviewe

Utveckla modell av laddare i fordon för realtidssimulering

Electrification of vehicles is now one of the top priorities of automotive manufacturers in orderto comply with the sustainability goals and standards set by the United Nations. One of thedisadvantages faced by electric vehicles is a longer time required for charging the vehicles ascompared to refuelling a conventional vehicle. To speed up the charging, it is necessary toimprove the power rating to charge the vehicle at charging stations. Developing an efficient OnBoard Charger (OBC) that converts Alternating Current (AC) power to Direct Current (DC)power to charge the battery is one of the contributing factors for faster charging. In order to protect the electricity grid from power failures, a bidirectional OBC can beimplemented in the vehicle. This bidirectional OBC is able to transfer power to the electricitygrid as well by discharging the battery. This technique helps to stabilise the grid during highpower demand. Having an efficient OBC ensures minimal losses during power conversion fromthe charging station to the battery in the vehicle. Therefore, this thesis deals with the development of an OBC model to be incorporated ina Hardware in Loop (HIL) simulation. This model is only an emulation of the actual OBChardware for HIL test and is therefore limited. The model is mainly developed in Simulinkand consists of control logic and power conversion stages like Precharge and Power FactorCorrection that successfully imitate the actual hardware. Further, in order to validate the model, it was run in Model in Loop (MIL) simulationwherein the model was tested under scenarios similar to the ones in the HIL setup. A successfulconversion of AC power to DC power was performed and a demonstration of the flexibility andthe adaptability of the model to different test cases is documented in the report. Some of theoutputs of the model are DC current for charging, model stateflow and AC current drawn fromthe grid.Elektrifiering av fordon är nu en av fordonstillverkarnas högsta prioriteringar för att följade hållbarhetsmål och standarder som fastställts av Förenta Nationer. En av nackdelarna förelfordon är att det tar längre tid att ladda elfordonen jämfört med att tanka ett konventionelltfordon. För att snabba på laddningen är det nödvändigt att förbättra märkeffekten för att laddafordonet vid laddningsstationer. Att utveckla en effektiv ombordladdare (OBC) som omvandlarväxelström (AC) till likström (DC) för att ladda batteriet är en av de bidragande faktorerna försnabbare laddning. För att skydda elnätet från strömavbrott kan en dubbelriktad OBC implementeras i fordonet.Denna dubbelriktade OBC kan också överföra ström till elnätet genom att ladda ur batteriet.Denna teknik hjälper till att stabilisera nätet under höga effektbehov. Att ha en effektiv OBCsäkerställer minimala förluster under kraftomvandling från laddstationen till batteriet i fordonet. Därför handlar detta examensarbete om utvecklingen av en OBC-modell som skainkorporeras i en Hardware in Loop (HIL) simulering. Denna modell är bara en emulering avden faktiska OBC hårdvaran för HIL-test och är därför begränsad. Modellen är huvudsakligenutvecklad i Simulink och består av styrlogik och effektomvandlingssteg som ‘Precharge’ ocheffektfaktorkorrigering som framgångsrikt imiterar den faktiska hårdvaran. Vidare, för att validera modellen, kördes den i Model in Loop (MIL) simulering därmodellen testades under scenarier som liknar de i HIL-inställningen. En framgångsrikomvandling av växelström till likström utfördes och en demonstration av flexibiliteten ochmodellens anpassningsförmåga till olika testfall dokumenteras i rapporten. Några av modellensutsignaler är likström för laddning, modelltillstånd och växelström som tas från elnätet