Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (-) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations. © 2012 Elsevier Inc.postprin

Oxidative coupling between C(sp2)-H and C(sp3)-H bonds of indoles and cyclic ethers/cycloalkanes

2015-2016 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer

Aim: Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer. Methods: HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis. Results: Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients. Conclusions: HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance

Flexible High-Conductivity Carbon-Nanotube Interconnects Made by Rolling and Printing

Applications of carbon nanotubes (CNTs) in flexible and complementary metal-oxide-semiconductor (CMOS)-based electronic and energy devices are impeded due to typically low CNT areal densities, growth temperatures that are incompatible with device substrates, and challenges in large-area alignment and interconnection. A scalable method for continuous fabrication and transfer printing of dense horizontally aligned CNT (HA-CNT) ribbon interconnects is presented. The process combines vertically aligned CNT (VA-CNT) growth by thermal chemical vapor deposition, a novel mechanical rolling process to transform the VA-CNTs to HA-CNTs, and adhesion-controlled transfer printing without needing a carrier film. The rolling force determines the HA-CNT packing fraction and the HA-CNTs are processed by conventional lithography. An electrical resistivity of 2 mΩ · cm is measured for ribbons having 800-nm thickness, while the resistivity of copper is 100 times lower, a value that exceeds most CNT assemblies made to date, and significant improvements can be made in CNT structural quality. This rolling and printing process could be scaled to full wafer areas and more complex architectures such as continuous CNT sheets and multidirectional patterns could be achieved by straightforward design of the CNT growth process and/or multiple rolling and printing sequences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64295/1/2467_ftp.pd

Plasmonically Enhanced Reflectance of Heat Radiation from Low-Bandgap Semiconductor Microinclusions

Increased reflectance from the inclusion of highly scattering particles at low volume fractions in an insulating dielectric offers a promising way to reduce radiative thermal losses at high temperatures. Here, we investigate plasmonic resonance driven enhanced scattering from microinclusions of low-bandgap semiconductors (InP, Si, Ge, PbS, InAs and Te) in an insulating composite to tailor its infrared reflectance for minimizing thermal losses from radiative transfer. To this end, we compute the spectral properties of the microcomposites using Monte Carlo modeling and compare them with results from Fresnel equations. The role of particle size-dependent Mie scattering and absorption efficiencies, and, scattering anisotropy are studied to identify the optimal microinclusion size and material parameters for maximizing the reflectance of the thermal radiation. For composites with Si and Ge microinclusions we obtain reflectance efficiencies of 57 - 65% for the incident blackbody radiation from sources at temperatures in the range 400 - 1600 {\deg}C. Furthermore, we observe a broadbanding of the reflectance spectra from the plasmonic resonances due to charge carriers generated from defect states within the semiconductor bandgap. Our results thus open up the possibility of developing efficient high-temperature thermal insulators through use of the low-bandgap semiconductor microinclusions in insulating dielectrics.Comment: Main article (8 Figures and 2 Tables) + Supporting Information (8 Figures

M2Net: Multi-modal Multi-channel Network for Overall Survival Time Prediction of Brain Tumor Patients

Early and accurate prediction of overall survival (OS) time can help to obtain better treatment planning for brain tumor patients. Although many OS time prediction methods have been developed and obtain promising results, there are still several issues. First, conventional prediction methods rely on radiomic features at the local lesion area of a magnetic resonance (MR) volume, which may not represent the full image or model complex tumor patterns. Second, different types of scanners (i.e., multi-modal data) are sensitive to different brain regions, which makes it challenging to effectively exploit the complementary information across multiple modalities and also preserve the modality-specific properties. Third, existing methods focus on prediction models, ignoring complex data-to-label relationships. To address the above issues, we propose an end-to-end OS time prediction model; namely, Multi-modal Multi-channel Network (M2Net). Specifically, we first project the 3D MR volume onto 2D images in different directions, which reduces computational costs, while preserving important information and enabling pre-trained models to be transferred from other tasks. Then, we use a modality-specific network to extract implicit and high-level features from different MR scans. A multi-modal shared network is built to fuse these features using a bilinear pooling model, exploiting their correlations to provide complementary information. Finally, we integrate the outputs from each modality-specific network and the multi-modal shared network to generate the final prediction result. Experimental results demonstrate the superiority of our M2Net model over other methods.Comment: Accepted by MICCAI'2

Chemogenetic fingerprinting by analysis of cellular growth dynamics

<p>Abstract</p> <p>Background</p> <p>A fundamental goal in chemical biology is the elucidation of on- and off-target effects of drugs and biocides. To this aim chemogenetic screens that quantify drug induced changes in cellular fitness, typically taken as changes in composite growth, is commonly applied.</p> <p>Results</p> <p>Using the model organism <it>Saccharomyces cerevisiae </it>we here report that resolving cellular growth dynamics into its individual components, growth lag, growth rate and growth efficiency, increases the predictive power of chemogenetic screens. Both in terms of drug-drug and gene-drug interactions did the individual growth variables capture distinct and only partially overlapping aspects of cell physiology. In fact, the impact on cellular growth dynamics represented functionally distinct chemical fingerprints.</p> <p>Discussion</p> <p>Our findings suggest that the resolution and quantification of all facets of growth increases the informational and interpretational output of chemogenetic screening. Hence, by facilitating a physiologically more complete analysis of gene-drug and drug-drug interactions the here reported results may simplify the assignment of mode-of-action to orphan bioactive compounds.</p

A novel Family Dignity Intervention (FDI) for enhancing and informing holistic palliative care in Asia: study protocol for a randomized controlled trial

Background The lack of a holistic approach to palliative care can lead to a fractured sense of dignity at the end of life, resulting in depression, hopelessness, feelings of being a burden to others, and the loss of the will to live among terminally ill patients. Building on the clinical foundation of Dignity Therapy, together with the empirical understanding of dignity-related concerns of Asian families facing terminal illness, a novel Family Dignity Intervention (FDI) has been developed for Asian palliative care. FDI comprises a recorded interview with a patient and their primary family caregiver, which is transcribed, edited into a legacy document, and returned to the dyads for sharing with the rest of the patient’s family. The aims of this study are to assess the feasibility, acceptability and potential effectiveness of FDI in reducing psychosocial, emotional, spiritual, and psychophysiological distress in community-dwelling and in-patient, Asian, older terminally ill patients and their families living in Singapore. Methods/design An open-label randomized controlled trial. One hundred and twenty-six patient-family dyads are randomly allocated to one of two groups: (1) an intervention group (FDI offered in addition to standard psychological care) and (2) a control group (standard psychological care). Both quantitative and qualitative outcomes are assessed in face-to-face interviews at baseline, 3 days and 2 weeks after intervention, as well as during an exit interview with family caregivers at 2 months post bereavement. Primary outcome measures include sense of dignity for patients and psychological distress for caregivers. Secondary outcomes include meaning in life, quality of life, spirituality, hopefulness, perceived support, and psychophysiological wellbeing, as well as bereavement outcomes for caregivers. Qualitative data are analyzed using the Framework method. Discussion To date, there is no available palliative care intervention for dignity enhancement in Asia. This first-of-its-kind study develops and tests an evidence-based, family driven, psycho-socio-spiritual intervention for enhancing dignity and wellbeing among Asian patients and families facing mortality. It addresses a critical gap in the provision of holistic palliative care. The expected outcomes will contribute to advancements in both theories and practices of palliative care for Singapore and its neighboring regions while serving to inform similar developments in other Asian communities. Trial registration ClinicalTrials.gov, ID: NCT03200730. Registered on 26 June 2017

Novel, synergistic antifungal combinations that target translation fidelity

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8 fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone