A mammalian Wnt5a-Ror2-Vangl2 axis controls the cytoskeleton and confers cellular properties required for alveologenesis.

Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in alveolar epithelial cells and myofibroblasts for alveologenesis in mammals. Our studies uncovered a Wnt5a-Ror2-Vangl2 cascade that endows cellular properties and novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior

Spiral Antenna with Reconfigurable HIS using Liquid Crystals for Monopulse Radar Application

Combined meta-intersections between two algorithms SOM and k-means. This Excel file contains final 23 meta-intersections as described in Results section. Each intersection is in separate tab, which also contains gene-annotation enrichment analysis results. (XLSX 721 kb

Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin

Actively transcribed regions of the genome are vulnerable to genomic instability. Recently, it was discovered that transcription is repressed in response to neighboring DNA double-strand breaks (DSBs). It is not known whether a failure to silence transcription flanking DSBs has any impact on DNA repair efficiency or whether chromatin remodelers contribute to the process. Here, we show that the PBAF remodeling complex is important for DSB-induced transcriptional silencing and promotes repair of a subset of DNA DSBs at early time points, which can be rescued by inhibiting transcription globally. An ATM phosphorylation site on BAF180, a PBAF subunit, is required for both processes. Furthermore, we find that subunits of the PRC1 and PRC2 polycomb group complexes are similarly required for DSB-induced silencing and promoting repair. Cancer-associated BAF180 mutants are unable to restore these functions, suggesting PBAF's role in repressing transcription near DSBs may contribute to its tumor suppressor activity

Entropy of Black Holes in D=5, N=2 Supergravity and AdS Central Charges

We consider general black holes in D=5, N=2 supergravity coupled to vector multiplets, and discuss the issue of microstate counting from various viewpoints. The statistical entropy is computed for the near-extremal case using the central charge of the $AdS_2$ factor appearing in the near-horizon geometry. Furthermore, we explicitly construct the duality transformation connecting electrically charged black holes to magnetically charged black strings, under which the $AdS_2 \times S^3$ near horizon geometry becomes $AdS_3 \times S^2$. For $AdS_3$ the counting of microstates correctly reproduces the Bekenstein-Hawking entropy, thus resolving the discrepancy previously found for $AdS_2$.Comment: 25 pages, Latex, no figures, references adde

Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

T(H)1 and T(H)17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic T(H) cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). T(H) cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here, we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40(−/−)) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(−/−) T(H)1 and T(H)17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40(−/−) mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T cell pathogenicity

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Interventions to optimise the care continuum for chronic viral hepatitis: a systematic review and meta-analyses.

BACKGROUND: Advances in therapy for hepatitis B virus (HBV) and hepatitis C virus (HCV) have ushered in a new era in chronic hepatitis treatment. To maximise the effectiveness of these medicines, individuals must be engaged and retained in care. We analysed operational interventions to enhance chronic viral hepatitis testing, linkage to care, treatment uptake, adherence, and viral suppression or cure. METHODS: We did a systematic review of operational interventions, and did meta-analyses for sufficiently comparable data. We searched PubMed, Embase, WHO library, International Clinical Trials Registry Platform, PsycINFO, and CINAHL for randomised controlled trials and controlled non-randomised studies that examined operational interventions along the chronic viral hepatitis care continuum, published in English up to Dec 31, 2014. We included non-pharmaceutical intervention studies with primary or secondary outcomes of testing, linkage to care, treatment uptake, treatment adherence, treatment completion, treatment outcome, or viral endpoints. We excluded dissertations and studies of children only. Data were extracted by two independent reviewers, with disagreements resolved by a third reviewer. Studies were assessed for bias. Data from similar interventions were pooled and quality of evidence was assessed using GRADE. This study was registered in PROSPERO (42014015094). FINDINGS: We identified 7583 unduplicated studies, and included 56 studies that reported outcomes along the care continuum (41 for HCV and 18 for HBV). All studies except one were from high-income countries. Lay health worker HBV test promotion interventions increased HBV testing rates (relative risk [RR] 2·68, 95% CI 1·82-3·93). Clinician reminders to prompt HCV testing during clinical visits increased HCV testing rates (3·70, 1·81-7·57). Nurse-led educational interventions improved HCV treatment completion (1·14, 1·05-1·23) and cure (odds ratio [OR] 1·93, 95% CI 1·44-2·59). Coordinated mental health, substance misuse, and hepatitis treatment services increased HCV treatment uptake (OR 3·03, 1·24-7·37), adherence (RR 1·22, 1·05-1·41), and cure (RR 1·21, 1·07-1·38) compared with usual care. INTERPRETATION: Several simple, inexpensive operational interventions can substantially improve engagement and retention along the chronic viral hepatitis care continuum. Further operational research to inform scale-up of hepatitis services is needed in low-income and middle-income countries. FUNDING: World Health Organization and US Fulbright Program

Dissolved organic phosphorus utilization by phytoplankton reveals preferential degradation of polyphosphates over phosphomonoesters

The nutritionally available pool of dissolved organic phosphorus (DOP) supports marine primary productivity in a range of ocean ecosystems but remains poorly resolved. Here, the relative lability of model phosphorus (P) compounds representing the major P(V) bond classes of marine DOP – phosphomonoesters (P-O-C) and phosphoanhydrides (P-O-P) – was assessed in diatom cultures of the genus Thalassiosira, as well as coastal field sites of the western North Atlantic. In diatom samples, maximum enzymatic hydrolysis rates revealed that the P-anhydride bonds of inorganic tripolyphosphate (3poly-P), followed by the P-anhydride bonds of adenosine 5′-triphosphate (ATP), were preferentially degraded relative to the P-monoesters adenosine 5′-monophosphate (AMP) and 4-methylumbelliferone phosphate (MUF-P). Consistent with these rate measurements, targeted proteomics analysis demonstrated that the underlying phosphatase diversity present in diatom samples was dominated by P-anhydride degrading enzymes (inorganic pyrophosphatases and nucleoside triphosphatases). Furthermore, biomass-normalized rates of ATP degradation were always suppressed under P-replete conditions in diatom cultures, but the effect of overall P availability on 3poly-P degradation was inconsistent among diatom strains, suggesting that inorganic polyphosphate (poly-P) degradation may persist irrespective of prevailing P levels in the marine environment. Indeed, the majority of field sites examined in the P-replete coastal western North Atlantic exhibited significantly higher maximum rates of inorganic poly-P hydrolysis relative to P-monoester hydrolysis, which was largely driven by phytoplankton dynamics. Based on these results, the possibility that P-anhydride utilization may contribute comparably or even more substantially than P-esters to community-level P demand, phytoplankton growth, and primary productivity should be considered

A Combined Perceptual, Physico-Chemical, and Imaging Approach to ‘Odour-Distances’ Suggests a Categorizing Function of the Drosophila Antennal Lobe

How do physico-chemical stimulus features, perception, and physiology relate? Given the multi-layered and parallel architecture of brains, the question specifically is where physiological activity patterns correspond to stimulus features and/or perception. Perceived distances between six odour pairs are defined behaviourally from four independent odour recognition tasks. We find that, in register with the physico-chemical distances of these odours, perceived distances for 3-octanol and n-amylacetate are consistently smallest in all four tasks, while the other five odour pairs are about equally distinct. Optical imaging in the antennal lobe, using a calcium sensor transgenically expressed in only first-order sensory or only second-order olfactory projection neurons, reveals that 3-octanol and n-amylacetate are distinctly represented in sensory neurons, but appear merged in projection neurons. These results may suggest that within-antennal lobe processing funnels sensory signals into behaviourally meaningful categories, in register with the physico-chemical relatedness of the odours