MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway

Entropic Upper Bound on Gravitational Binding Energy

We prove that the gravitational binding energy {\Omega} of a self gravitating system described by a mass density distribution {\rho}(x) admits an upper bound B[{\rho}(x)] given by a simple function of an appropriate, non-additive Tsallis' power-law entropic functional Sq evaluated on the density {\rho}. The density distributions that saturate the entropic bound have the form of isotropic q-Gaussian distributions. These maximizer distributions correspond to the Plummer density profile, well known in astrophysics. A heuristic scaling argument is advanced suggesting that the entropic bound B[{\rho}(x)] is unique, in the sense that it is unlikely that exhaustive entropic upper bounds not based on the alluded Sq entropic measure exit. The present findings provide a new link between the physics of self gravitating systems, on the one hand, and the statistical formalism associated with non-additive, power-law entropic measures, on the other hand

Three Dimensional Electrical Impedance Tomography

The electrical resistivity of mammalian tissues varies widely and is correlated with physiological function. Electrical impedance tomography (EIT) can be used to probe such variations in vivo, and offers a non-invasive means of imaging the internal conductivity distribution of the human body. But the computational complexity of EIT has severe practical limitations, and previous work has been restricted to considering image reconstruction as an essentially two-dimensional problem. This simplification can limit significantly the imaging capabilities of EIT, as the electric currents used to determine the conductivity variations will not in general be confined to a two-dimensional plane. A few studies have attempted three-dimensional EIT image reconstruction, but have not yet succeeded in generating images of a quality suitable for clinical applications. Here we report the development of a three-dimensional EIT system with greatly improved imaging capabilities, which combines our 64-electrode data-collection apparatus with customized matrix inversion techniques. Our results demonstrate the practical potential of EIT for clinical applications, such as lung or brain imaging and diagnostic screening

Deconstructed cat communities: quantifying the threat to felids from prey defaunation

Aim: Defaunation, the emptying of ecosystems of fauna, has been highlighted as a likely threat to the conservation of carnivores, but the magnitude of this threat has yet to be quantified. We quantify the potential threat defaunation presents to wild felids. Location: Global Methods: For the 32 wild felids that feed primarily on mammals, we used 5,330 prey records from 237 published sources to compile a new diet dataset, FelidDIET. This dataset was used to determine the relative importance of mammalian species as prey for each felid. These data were used to quantify the relationship between felid and prey species-richness, and to estimate the potential threat to wild felids from the loss of their prey. Results: Our analyses reveal that models that include adjusted prey species-richness as a predictor of felid-richness outperform those with less precise measures of prey-richness (potential prey-richness and total mammal-richness). This is true both when examined collectively and when split into those felids that prey upon large-bodied prey and those that prey upon small-bodied prey. For seven felid species, including six large felids (over 15 kg), 33% or more of their primary prey-species are threatened. Of most concern is the Sunda clouded leopard Neofelis diardi, for which 66.0% of its primary prey-species are threatened. In total, 57.6% of large felids’ primary prey-species are threatened or declining, compared with 26.5% for small felids. Large felids are particularly vulnerable to primary prey decline in Indo-Malaya and East and Central Africa. Main conclusions: Our findings indicate that imminent prey loss is likely to have substantial negative effects on large felids, many of which are already highly threatened. Considering the trophic cascades associated with large predators, the threat to large felids through the loss of prey diversity presents an ecosystem-scale threat

The role of mutation rate variation and genetic diversity in the architecture of human disease

Background We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Results Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees, and they are predicted to have similar rates of non-synonymous mutation as other genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Conclusions Our results suggest that gene length contributes to whether a gene is associated with disease. However, the mutation rate and the genetic architecture of the locus appear to play only a minor role in determining whether a gene is associated with disease

Constraining Dark Energy and Cosmological Transition Redshift with Type Ia Supernovae

The property of dark energy and the physical reason for acceleration of the present universe are two of the most difficult problems in modern cosmology. The dark energy contributes about two-thirds of the critical density of the present universe from the observations of type-Ia supernova (SNe Ia) and anisotropy of cosmic microwave background (CMB).The SN Ia observations also suggest that the universe expanded from a deceleration to an acceleration phase at some redshift, implying the existence of a nearly uniform component of dark energy with negative pressure. We use the ``gold'' sample containing 157 SNe Ia and two recent well-measured additions, SNe Ia 1994ae and 1998aq to explore the properties of dark energy and the transition redshift. For a flat universe with the cosmological constant, we measure $\Omega_{M}=0.28_{-0.05}^{+0.04}$, which is consistent with Riess et al. The transition redshift is $z_{T}=0.60_{-0.08}^{+0.06}$. We also discuss several dark energy models that define the $w(z)$ of the parameterized equation of state of dark energy including one parameter and two parameters ($w(z)$ being the ratio of the pressure to energy density). Our calculations show that the accurately calculated transition redshift varies from $z_{T}=0.29_{-0.06}^{+0.07}$ to $z_{T}=0.60_{-0.08}^{+0.06}$ across these models. We also calculate the minimum redshift $z_{c}$ at which the current observations need the universe to accelerate.Comment: 16 pages, 5 figures, 1 tabl

Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells

Breaking Open the Black Boxes: media archaeology, anarchaeology and media materiality

An essay on the emergent methodology of media archaeology, in relation to the material turn in approaches to digital media. In particular, this article advocates taking up Siegfried Zielinski's concept of 'anarchaeology', but in a different sense to the way it was originally proposed, in order to emphasise the political potentials of a media (an)archaeological methodological approach

Evaluation of drugs for potential repurposing against COVID-19 using a tier-based scoring system

Embargo removed due to subject matter