Macropinocytotic uptake and infection of human epithelial cells with species B2 adenovirus type 35

The human adenovirus serotype 35 (HAdV-35, short Ad35) causes kidney and urinary tract infections, and infects respiratory organs of immunocompromised individuals. Unlike other adenoviruses, Ad35 has a low seroprevalence which makes Ad35-based vectors promising candidates for gene therapy. Ad35 utilizes CD46 and integrins as receptors for infection of epithelial and hematopoietic cells. Here, we show that infectious entry of Ad35 into HeLa, human kidney HK-2 cells and normal human lung fibroblasts strongly depended on CD46 and integrins but not heparan sulfate, and variably required the large GTPase dynamin. Ad35 infections were independent of expression of the carboxy-terminal domain of AP180 which effectively blocks clathrin-mediated uptake. Ad35 infections were inhibited by small chemicals against the serine/threonine kinase Pak1 (p21-activated kinase), protein kinase C (PKC), sodium-proton exchangers, actin and acidic organelles. Remarkably, the F-actin inhibitor jasplakinolide, the Pak1 inhibitor IPA-3 or the sodium-proton exchange inhibitor EIPA blocked the endocytic uptake of Ad35. Dominant-negative proteins or small interfering RNAs against factors driving macropinocytosis, including the small GTPase Rac1, Pak1 or the Pak1 effector C-terminal binding protein 1 (CtBP1) potently inhibited Ad35 infection. Confocal laser scanning microscopy, electron microscopy and live cell imaging showed that Ad35 colocalized with fluid phase markers in large endocytic structures that were positive for CD46, alpha v integrins and also CtBP1. Our results extend earlier observations with HAdV-3 (Ad3), and establish macropinocytosis as an infectious pathway for species B human adenoviruses in epithelial and hematopoietic cells

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD

Regulating Assisted Reproduction in Canada, Switzerland, and the USA: Comparing the Judicialization of Policy-making

This article analyses the extent to which courts shape policies for assisted reproduction. While the USA is considered to be the most litigious country, Canada has observed a growing involvement of the courts from the 1980’s onward, and Switzerland is characterized by a modest degree of judicialization. Based on national patterns, we would expect litigation and court impact to vary across these three countries. As this paper demonstrates, policy-process specific variables such as the structure of policy conflicts, the novelty of regulation, self-regulation by key stakeholders, and the policies in place better explain the variation in the judicialization of policy-making

Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer\u27s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, \u27shape connections\u27 between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus

hHSS1: a novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33

The completion of the Human Genome Project resulted in discovery of many unknown novel genes. This feat paved the way for the future development of novel therapeutics for the treatment of human disease based on novel biological functions and pathways. Towards this aim, we undertook a bioinformatics analysis of in-house microarray data derived from purified hematopoietic stem cell populations. This effort led to the discovery of HSS1 (Hematopoietic Signal peptide-containing Secreted 1) and its splice variant HSM1 (Hematopoietic Signal peptide-containing Membrane domain-containing 1). HSS1 gene is evolutionarily conserved across species, phyla and even kingdoms, including mammals, invertebrates and plants. Structural analysis showed no homology between HSS1 and known proteins or known protein domains, indicating that it was a truly novel protein. Interestingly, the human HSS1 (hHSS1) gene is located at chromosome 19q13.33, a genomic region implicated in various cancers, including malignant glioma. Stable expression of hHSS1 in glioma-derived A172 and U87 cell lines greatly reduced their proliferation rates compared to mock-transfected cells. hHSS1 expression significantly affected the malignant phenotype of U87 cells both in vitro and in vivo. Further, preliminary immunohistochemical analysis revealed an increase in hHSS1/HSM1 immunoreactivity in two out of four high-grade astrocytomas (glioblastoma multiforme, WHO IV) as compared to low expression in all four low-grade diffuse astrocytomas (WHO grade II). High-expression of hHSS1 in high-grade gliomas was further supported by microarray data, which indicated that mesenchymal subclass gliomas exclusively up-regulated hHSS1. Our data reveal that HSS1 is a truly novel protein defining a new class of secreted factors, and that it may have an important role in cancer, particularly glioma

A new species of Argyromys (Rodentia, Mammalia) from the oligocene of the valley of lakes (Mongolia): its importance for palaeobiogeographical homogeneity across Mongolia, China and Kazakhstan

We describe a new species of Rodentia (Mammalia), Argyromys cicigei sp. nov. from Toglorhoi (fossil bed TGW-A/2a) in Mongolia and Ulantatal (fossil beds UTL 1 and UTL 7) in China. Its tooth morphology differs from the type species Argyromys aralensis from Akespe in Kazakhstan by smaller size and simpler structures. Argyromys has been assigned in different families of Muroidea, such as Tachyoryctoididae and Spalacidae. However, the presence of common characters indicates a closer relationship of Argyromys with the genera of Cricetidae s.l. (subfamilies Eucricetodontinae; Cricetopinae; Cricetodontinae and Gobicricetodontinae among others) from Asia than with the earliest representatives of Spalacidae or the endemic Tachyoryctoididae. Argyromys cicigei sp. nov. possesses a simple anterocone and anteroconid in the upper and lower first molars, respectively, which is characteristic for Cricetidae s.l. It has a flat occlusal surface in worn specimens; weakly-developed posterolophs; an oblique protolophule and metaloph on the upper molars and it lacks a labial anterolophid on the m1. These traits are also typical of the Oligocene genera Aralocricetodon and Plesiodipus, included in the subfamilies Cricetodontinae and Gobicricetodontinae respectively. The cladistic analysis performed here supports this hypothesis. The clade formed by Argyromys species is grouped with other cricetid taxa (s.l). Spalacids, however, form a different clade, as do the tachyoryctoids. Previous authors state that the Aral Formation (Kazakhstan) should be dated to the Oligocene instead of the Miocene, based on the presence of several taxa. The finds of Argyromys in both regions supports the statement that they are closer in age than previously thought. The occurrence of Argyromys in Kazakhstan, Mongolia and China evidences the biogeographic unity of the Central Asian bioprovince during the Oligocene

The Weyl double copy from twistor space

The Weyl double copy is a procedure for relating exact solutions in biadjoint scalar, gauge and gravity theories, and relates fields in spacetime directly. Where this procedure comes from, and how general it is, have until recently remained mysterious. In this paper, we show how the current form and scope of the Weyl double copy can be derived from a certain procedure in twistor space. The new formalism shows that the Weyl double copy is more general than previously thought, applying in particular to gravity solutions with arbitrary Petrov types. We comment on how to obtain anti-self-dual as well as self-dual fields, and clarify some conceptual issues in the twistor approach