Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.

Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-α (TNF-α) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin-matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-α-induced VCAM-1 expression within heart vessel-associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-α-induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-α-induced VCAM-1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase-dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover

Forecasting the Population-Level Impact of Reductions in HIV Antiretroviral Therapy in Papua New Guinea

Papua New Guinea (PNG) recently did not secure external funding for the continuation of its antiretroviral treatment (ART) programs meaning that supplies of HIV drugs for the estimated 38,000 people living with HIV in PNG could be completely depleted during 2010. Using a mathematical model of HIV transmission calibrated to available HIV epidemiology data from PNG, we evaluated the expected population-level impact of reductions in ART availability. If the number of people on ART falls to 10% of its current level, then there could be an approximately doubling in annual incidence and an additional 12,848 AIDS-related deaths (100.7% increase) over the next 5 years; if ART provision is halved, then annual incidence would increase by ~68%, and there would be an additional ~10,936 AIDS-related deaths (85.7% increase). These results highlight that maintenance of ART and associated services through external funding is essential for the health and well-being of HIV-positive people in PNG

A conserved circadian function for the Neurofibromatosis 1 gene

Summary: Loss of the Neurofibromatosis 1 (Nf1) protein, neurofibromin, in Drosophila disrupts circadian rhythms of locomotor activity without impairing central clock function, suggesting effects downstream of the clock. However, the relevant cellular mechanisms are not known. Leveraging the discovery of output circuits for locomotor rhythms, we dissected cellular actions of neurofibromin in recently identified substrates. Herein, we show that neurofibromin affects the levels and cycling of calcium in multiple circadian peptidergic neurons. A prominent site of action is the pars intercerebralis (PI), the fly equivalent of the hypothalamus, with cell-autonomous effects of Nf1 in PI cells that secrete DH44. Nf1 interacts genetically with peptide signaling to affect circadian behavior. We extended these studies to mammals to demonstrate that mouse astrocytes exhibit a 24-hr rhythm of calcium levels, which is also attenuated by lack of neurofibromin. These findings establish a conserved role for neurofibromin in intracellular signaling rhythms within the nervous system. : Bai et al. show that the gene mutated in the disease Neurofibromatosis 1 is required for maintaining levels or cycling of calcium in circadian neurons in Drosophila and in mammalian cells. These effects likely account for effects of Nf1 on circadian behavior in Drosophila and may be relevant in explaining sleep phenotypes in patients. Keywords: circadian rhythms, neurofibromatosis 1, Drosophila, peptide signaling, cycling of calcium, mouse astrocyte

An Origami-Inspired Design of a Thermal Mixing Element Within a Concentrated Solar Power System

A Concentrated Solar Power on Demand (CSPonD) system heats a tank of molten salt with sunlight, storing the sun's energy thermally and generating electricity when needed using a heat exchanger. To prevent the heated salt from forming thermal gradients (reducing the heat exchanger's efficiency) or overheating (and becoming corrosive), a thermal mixing element mixes the heated salt both axially and radially. Since the mixing element can only move axially within the tank, it contains internal, radial channels to induce radial flow of the salt. These channels are constructed from tabbed wall-components, whose tabs seat into and extend past slots in the top-and bottom-plates of the mixing element. The top-and bottom-plates are constructed from multiple panels with overlapping slots, allowing the panels to form the plates when the tabs are inserted. This interlocking design allows majority of the mixing element to be rapidly manufactured at a low cost from sheet metal and simplifies transportation. In situ, the assembled components fasten together by bending the overextending tabs, minimizing the number of fasteners needed. Topics: Design, Concentrating solar powerMasdar Institute of Science and Technolog

An Improved Methodology for Multidimensional High- Throughput Preformulation Characterization of Protein Conformational Stability

The Empirical Phase Diagram (EPD) technique is a vector-based multidimensional analysis method for summarizing large data sets from a variety of biophysical techniques. It can be used to provide comprehensive preformulation characterization of a macromolecule’s higher-order structural integrity and conformational stability. In its most common mode, it represents a type of stimulus-response diagram using environmental variables such as temperature, pH, and ionic strength as the stimulus, with alterations in macromolecular structure being the response. Until now EPD analysis has not been available in a high throughput mode because of the large number of experimental techniques and environmental stressor/stabilizer variables typically employed. A new instrument has been developed that combines circular dichroism, UV-absorbance, fluorescence spectroscopy and light scattering in a single unit with a 6-position temperature controlled cuvette turret. Using this multifunctional instrument and a new software system we have generated EPDs for four model proteins. Results confirm the reproducibility of the apparent phase boundaries and protein behavior within the boundaries. This new approach permits two EPDs to be generated per day using only 0.5 mg of protein per EPD. Thus, the new methodology generates reproducible EPDs in high-throughput mode, and represents the next step in making such determinations more routine

Robust estimates of soil moisture and latent heat flux coupling strength obtained from triple collocation

Land surface models (LSMs) are often applied to predict the one-way coupling strength between surface soil moisture (SM) and latent heat (LH) flux. However, the ability of LSMs to accurately represent such coupling has not been adequately established. Likewise, the estimation of SM/LH coupling strength using ground-based observational data is potentially compromised by the impact of independent SM and LH measurements errors. Here we apply a new statistical technique to acquire estimates of one-way SM/LH coupling strength which are nonbiased in the presence of random error using a triple collocation approach based on leveraging the simultaneous availability of independent SM and LH estimates acquired from (1) LSMs, (2) satellite remote sensing, and (3) ground-based observations. Results suggest that LSMs do not generally overestimate the strength of one-way surface SM/LH coupling

Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias