Dendrimer-Encapsulated Nanoparticles: New Synthetic and Characterization Methods and Catalytic Applications

In this article we describe the synthesis, characterization, and applications of dendrimer-encapsulated nanoparticles (DENs). These materials are synthesized using a template approach in which metal ions are extracted into the interior of dendrimers and then subsequently reduced chemically to yield nearly size-monodisperse particles having diameters in the 1-2 nm range. Monometallic, bimetallic (alloy and core@shell), and semiconductor nanoparticles have been prepared by this route. The dendrimer component of these composites serves not only as a template for preparing the nanoparticle replica, but also as a stabilizer for the nanoparticle. In this perspective, we report on progress in the synthesis, characterization, and applications of these materials since our last review in 2005. Significant advances in the synthesis of core@shell DENs, characterization, and applications to homogeneous and heterogeneous catalysis (including electrocatalysis) are emphasized.U.S. Department of Energy, Office of Basic Energy Sciences DE-FG02-09ER16090U.S. National Science Foundation 0847957Robert A. Welch Foundation F-0032Chemistr

Different Conformations of Phosphatase and Tensin Homolog, Deleted on Chromosome 10 (PTEN) Protein within the Nucleus and Cytoplasm of Neurons

PTEN is a critical gene involved in the regulation of many cellular processes. The product of this gene has dual phosphatase activity and is able to dephosphorylate the 5′ end of the phosphatidylinositol (3,4,5)-trisphosphate. Within the cellular nucleus, this protein has been associated with regulation of the expression of many genes, although the mechanism of this regulation remains unclear. In this paper, two specific oligonucleotide aptamers were developed and selected, using the SELEX procedure, according to their ability to detect the PTEN protein in different subcellular compartments of neurons. While one aptamer was able to detect PTEN in the nucleus, the other recognized PTEN in the cytoplasm. The recognition pattern of PTEN by both aptamers was confirmed using antibodies in western blots of the proteins purified from mouse cerebellar homogenates and subcellular fractions. Additionally, we demonstrated that the two aptamers recognized different epitopes of the target peptide. The results presented here could not be fully explained by the canonical phosphatase structure of PTEN, suggesting the existence of different conformations of phosphatase in the nucleus and the cytoplasm

Short term effects of exercise training on exercise capacity and quality of life in patients with pulmonary arterial hypertension: protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Advances in the understanding and management of pulmonary arterial hypertension have enabled earlier diagnosis and improved prognosis. However, despite best available therapy, symptoms of exertional dyspnoea and fatigue are commonly reported and result in a reduced capacity to perform daily activities and impaired quality of life. Exercise training has demonstrated efficacy in individuals with other respiratory and cardiovascular diseases. Historically, however, exercise training has not been utilised as a form of therapy in pulmonary arterial hypertension due to the perceived risk of sudden cardiac death and the theoretical possibility that exercise would lead to worsening pulmonary vascular haemodynamics and deterioration in right heart function. Now, with the advances in pharmaceutical management, determining the safety and benefits of exercise training in this population has become more relevant. Only three studies of supervised exercise training in pulmonary arterial hypertension have been published. These studies demonstrated improvements in exercise capacity and quality of life, in the absence of adverse events or clinical deterioration. However, these studies have not utilised an outpatient-based, whole body exercise training program, the most common format for exercise programs within Australia. It is uncertain whether this form of training is beneficial and capable of producing sustained benefits in exercise capacity and quality of life in this population.</p> <p>Design/Methods</p> <p>This randomised controlled trial will determine whether a 12 week, outpatient-based, supervised, whole body exercise training program, followed by a home-based exercise program, is safe and improves exercise capacity and quality of life in individuals with pulmonary arterial hypertension. This study aims to recruit 34 subjects who will be randomly allocated to the exercise group (supervised exercise training 3 times a week for 12 weeks, followed by 3 sessions per week of home exercise for 12 weeks) or the control group (usual medical care). Subjects will be assessed at baseline, 12 weeks and 24 weeks.</p> <p>Discussion</p> <p>This study will determine whether outpatient-based, whole body exercise training is beneficial and safe in individuals with pulmonary arterial hypertension. Additionally, this study will contribute to clinical practice guidelines for this patient population.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000502235.aspx">ACTRN12609000502235</a></p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

A preliminary investigation into the prevalence and prediction of problematic cell phone use

Abstract Background and aims Likening mobile phone use dependency to the classification of excessive behaviors may be necessarily equivalent in seriousness to previously established addictions such as problematic computing or excessive gambling. The aim of the study explores into the behavior of excessive use of mobile phones as a pathological behavior. Methods Two studies investigated criteria for problematic mobile phone usage by examining student (Study 1, N = 301) and nonstudent (Study 2, N = 362) responses to a set of adapted mobile phone addiction inventories. Study 1 investigated cell phone addiction inventories as constructs designed to measure problematic cell phone use. Additionally, Study 2 sought to predict age, depression, extraversion, emotional stability, impulse control, and self-esteem as independent variables that augment respondents' perceptions of problematic use. Results The results from Study 1 and Study 2 indicate that 10 to 25% of the participants tested exhibited problematic cell phone usage. Additionally, age, depression, extraversion, and low impulse control are the most suitable predictors for problematic use. Conclusions The results of the two studies indicate that problematic mobile phone use does occur and ought to be taken seriously by the psychological community. Presently, there is limited data providing conclusive evidence for a comprehensible categorization of cell phone addiction, as well as a unified explanatory model specific to problematic mobile phone use. Studies such as this one may contribute substantial findings, adding scientific significance, and offering a valuable submission for the ongoing progress of creating intervention frameworks relative to “virtual addictions”

Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations

The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer's disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer's disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66-107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer's disease processes