Electronic energy spectra and wave functions on the square Fibonacci tiling

We study the electronic energy spectra and wave functions on the square Fibonacci tiling, using an off-diagonal tight-binding model, in order to determine the exact nature of the transitions between different spectral behaviors, as well as the scaling of the total bandwidth as it becomes finite. The macroscopic degeneracy of certain energy values in the spectrum is invoked as a possible mechanism for the emergence of extended electronic Bloch wave functions as the dimension changes from one to two

A molecular overlayer with the Fibonacci square grid structure

Quasicrystals differ from conventional crystals and amorphous materials in that they possess long-range order without periodicity. They exhibit orders of rotational symmetry which are forbidden in periodic crystals, such as five-, ten-, and twelve-fold, and their structures can be described with complex aperiodic tilings such as Penrose tilings and Stampfli-Gaehler tilings. Previous theoretical work explored the structure and properties of a hypothetical four-fold symmetric quasicrystal-the so-called Fibonacci square grid. Here, we show an experimental realisation of the Fibonacci square grid structure in a molecular overlayer. Scanning tunnelling microscopy reveals that fullerenes (C ) deposited on the two-fold surface of an icosahedral Al-Pd-Mn quasicrystal selectively adsorb atop Mn atoms, forming a Fibonacci square grid. The site-specific adsorption behaviour offers the potential to generate relatively simple quasicrystalline overlayer structures with tunable physical properties and demonstrates the use of molecules as a surface chemical probe to identify atomic species on similar metallic alloy surfaces

Poly (A) binding protein cytoplasmic 1 is a novel co-regulator of the androgen receptor

The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silicoanalysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation correlates to increased disease recurrence. Co-immunoprecipitation assays confirmed the association of PABPC1 with a.a. 50-250 of the NTD of the AR. Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells. Additionally, knockdown of PABPC1 inhibited transactivation of the PSA promoter by NAR (AR lacking the LBD) and attenuated proliferation of AR-positive prostate cancer cells. These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC

Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

ELL-associated factor 2 (EAF2) is an androgen-responsive tumor suppressor frequently deleted in advanced prostate cancer that functions as a transcription elongation factor of RNA Pol II through interaction with the ELL family proteins. EAF2 knockout mice on a 129P2/OLA-C57BL/6J background developed late-onset lung adenocarcinoma, hepatocellular carcinoma, B-cell lymphoma and high-grade prostatic intraepithelial neoplasia. In order to further characterize the role of EAF2 in the development of prostatic defects, the effects of EAF2 loss were compared in different murine strains. In the current study, aged EAF2-/- mice on both the C57BL/6J and FVB/NJ backgrounds exhibited mPIN lesions as previously reported on a 129P2/OLA-C57BL/6J background. In contrast to the 129P2/OLA-C57BL/6J mixed genetic background, the mPIN lesions in C57BL/6J and FVB/NJ EAF2-/- mice were associated with stromal defects characteristic of a reactive stroma and a statistically significant increase in prostate microvessel density. Stromal inflammation and increased microvessel density was evident in EAF2-deficient mice on a pure C57BL/6J background at an early age and preceded the development of the histologic epithelial hyperplasia and neoplasia found in the prostates of older EAF2 -/- animals. Mice deficient in EAF2 had an increased recovery rate and a decreased overall response to the effects of androgen deprivation. EAF2 expression in human cancer was significantly down-regulated and microvessel density was significantly increased compared to matched normal prostate tissue; furthermore EAF2 expression was negatively correlated with microvessel density. These results suggest that the EAF2 knockout mouse on the C57BL/6J and FVB/NJ genetic backgrounds provides a model of PIN lesions associated with an altered prostate microvasculature and reactive stromal compartment corresponding to that reported in human prostate tumors. © 2013 Pascal et al

Predicting Distribution of Aedes Aegypti and Culex Pipiens Complex, Potential Vectors of Rift Valley Fever Virus in Relation to Disease Epidemics in East Africa.

The East African region has experienced several Rift Valley fever (RVF) outbreaks since the 1930s. The objective of this study was to identify distributions of potential disease vectors in relation to disease epidemics. Understanding disease vector potential distributions is a major concern for disease transmission dynamics. DIVERSE ECOLOGICAL NICHE MODELLING TECHNIQUES HAVE BEEN DEVELOPED FOR THIS PURPOSE: we present a maximum entropy (Maxent) approach for estimating distributions of potential RVF vectors in un-sampled areas in East Africa. We modelled the distribution of two species of mosquitoes (Aedes aegypti and Culex pipiens complex) responsible for potential maintenance and amplification of the virus, respectively. Predicted distributions of environmentally suitable areas in East Africa were based on the presence-only occurrence data derived from our entomological study in Ngorongoro District in northern Tanzania. Our model predicted potential suitable areas with high success rates of 90.9% for A. aegypti and 91.6% for C. pipiens complex. Model performance was statistically significantly better than random for both species. Most suitable sites for the two vectors were predicted in central and northwestern Tanzania with previous disease epidemics. Other important risk areas include western Lake Victoria, northern parts of Lake Malawi, and the Rift Valley region of Kenya. Findings from this study show distributions of vectors had biological and epidemiological significance in relation to disease outbreak hotspots, and hence provide guidance for the selection of sampling areas for RVF vectors during inter-epidemic periods

Feasibility and acceptability of NIDUS-Professional, a training and support intervention for homecare workers caring for clients living with dementia: a cluster-randomised feasibility trial protocol.

INTRODUCTION: Most people living with dementia want to remain living in their own homes, and are supported to do so by family carers and homecare workers. There are concerns that homecare is often unable to meet the needs of this client group, with limited evidence regarding effective interventions to improve it for people living with dementia. We have developed a training and support programme for homecare workers (NIDUS-Professional) to be delivered alongside support sessions for people living with dementia and their family carers (NIDUS-Family). We aim to assess (1) its acceptability among homecare workers and employing agencies, and (2) the feasibility of homecare workers, people living with dementia and their family carers completing the outcomes of intervention in a future randomised controlled trial. METHODS AND ANALYSIS: This is a cluster-randomised (2:1) single-blind, multisite feasibility trial. We aim to recruit 60-90 homecare workers, 30-60 clients living with dementia and their family carers through 6-9 English homecare agencies. In the intervention arm, homecare staff will be offered six group sessions on video call over three months, followed by monthly group sessions over the subsequent three-month period. Outcome measures will be collected at baseline and at six months. ETHICS AND DISSEMINATION: The study received ethical approval on 7 January 2020 from the Camden & King's Cross Research Ethics Committee. Study reference: 19/LO/1667. Findings will be disseminated through a peer-reviewed journal, conference presentation and blog to research and clinical audiences; we will attend forums to present findings to participating homecare agencies and their clients. TRIAL REGISTRATION NUMBER: ISRCTN15757555

GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.

Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington's disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

High carbohydrate–low protein consumption maximizes Drosophila lifespan

Dietary restriction extends lifespan in a variety of organisms, but the key nutritional components driving this process and how they interact remain uncertain. In Drosophila, while a substantial body of research suggests that protein is the major dietary component affecting longevity, recent studies claim that carbohydrates also play a central role. To clarify how nutritional factors influence longevity, nutrient consumption and lifespan were measured on a series of diets with varying yeast and sugar content. We show that optimal lifespan requires both high carbohydrate and low protein consumption, but neither nutrient by itself entirely predicts lifespan. Increased dietary carbohydrate or protein concentration does not always result in reduced feeding—the regulation of food consumption is best described by a constant daily caloric intake target. Moreover, due to differences in food intake, increased concentration of a nutrient within the diet does not necessarily result in increased consumption of that particular nutrient. Our results shed light on the issue of dietary effects on lifespan and highlight the need for accurate measures of nutrient intake in dietary manipulation studies