Curvature Sensing by a Viral Scission Protein

Membrane scission is the final step in all budding processes wherein a membrane neck is sufficiently constricted so as to allow for fission and the release of the budded particle. For influenza viruses, membrane scission is mediated by an amphipathic helix (AH) domain in the viral M2 protein. While it is known that the M2AH alters membrane curvature, it is not known how the protein is localized to the center neck of budding virions where it would be able to cause membrane scission. Here, we use molecular dynamics simulations on buckled lipid bilayers to show that the M2AH senses membrane curvature and preferentially localizes to regions of high membrane curvature, comparable to that seen at the center neck of budding influenza viruses. These results were then validated using in vitro binding assays to show that the M2AH senses membrane curvature by detecting lipid packing defects in the membrane. Our results show that the M2AH senses membrane curvature and suggest that the AH domain may localize the protein at the viral neck where it can then mediate membrane scission and the release of budding viruses

Risks Posed by Reston, the Forgotten Ebolavirus

Out of the five members of the Ebolavirus family, four cause lifethreatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans. The reasons for this discrepancy remain unclear. In this review, we analyze the currently available information to provide a state-of-the-art summary of the factors that determine the human pathogenicity of Ebolaviruses. RESTV causes sporadic infections in cynomolgus monkeys and is found in domestic pigs throughout the Philippines and China. Phylogenetic analyses revealed that RESTV is most closely related to the Sudan virus, which causes a high mortality rate in humans. Amino acid sequence differences between RESTV and the other Ebolaviruses are found in all nine Ebolavirus proteins, though no one residue appears sufficient to confer pathogenicity. Changes in the glycoprotein contribute to differences in Ebolavirus pathogenicity but are not sufficient to confer pathogenicity on their own. Similarly, differences in VP24 and VP35 affect viral immune evasion and are associated with changes in human pathogenicity. A recent in silico analysis systematically determined the functional consequences of sequence variations between RESTV and human-pathogenic Ebolaviruses. Multiple positions in VP24 were differently conserved between RESTV and the other Ebolaviruses and may alter human pathogenicity. In conclusion, the factors that determine the pathogenicity of Ebolaviruses in humans remain insufficiently understood. An improved understanding of these pathogenicity-determining factors is of crucial importance for disease prevention and for the early detection of emergent and potentially human-pathogenic RESTVs

Successor-Invariant First-Order Logic on Classes of Bounded Degree

We study the expressive power of successor-invariant first-order logic, which is an extension of first-order logic where the usage of an additional successor relation on the structure is allowed, as long as the validity of formulas is independent on the choice of a particular successor. We show that when the degree is bounded, successor-invariant first-order logic is no more expressive than first-order logic

Ebola outbreak highlights the need for wet and dry laboratory collaboration

The recent Ebola outbreak in Western Africa taught us that Ebolaviruses can cause much larger outbreaks and represent a much greater health threat than many of us believed (or wanted to believe). As of 30th March, the outbreak had resulted in 28,646 confirmed cases and 11,323 deaths. Although the WHO stated that the Ebola epidemic in West Africa no longer represents a Public Health Emergency of International Concern, since Guinea, Liberia, and Sierra are now capable of controlling and maintaining further small outbreaks, flare-ups still occur, most recently, on 4th April when two new cases were reported in Liberia (www.who.int)

The RalB Small GTPase Mediates Formation of Invadopodia through a GTPase-Activating Protein-Independent Function of the RalBP1/RLIP76 Effector

Our recent studies implicated key and distinct roles for the highly related RalA and RalB small GTPases (82% sequence identity) in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and invasive and metastatic growth, respectively. How RalB may promote PDAC invasion and metastasis has not been determined. In light of known Ral effector functions in regulation of actin organization and secretion, we addressed a possible role for RalB in formation of invadopodia, actin-rich membrane protrusions that contribute to tissue invasion and matrix remodeling. We determined that a majority of KRAS mutant PDAC cell lines exhibited invadopodia and that expression of activated K-Ras is both necessary and sufficient for invadopodium formation. Invadopodium formation was not dependent on the canonical Raf-MEK-ERK effector pathway and was instead dependent on the Ral effector pathway. However, this process was more dependent on RalB than on RalA. Surprisingly, RalB-mediated invadopodium formation was dependent on RalBP1/RLIP76 but not Sec5 and Exo84 exocyst effector function. Unexpectedly, the requirement for RalBP1 was independent of its best known function as a GTPase-activating protein for Rho small GTPases. Instead, disruption of the ATPase function of RalBP1 impaired invadopodium formation. Our results identify a novel RalB-mediated biochemical and signaling mechanism for invadopodium formation

Electro-Magnetic Earthquake Bursts and Critical Rupture of Peroxy Bond Networks in Rocks

We propose a mechanism for the low frequency electromagnetic emissions and other electromagnetic phenomena which have been associated with earthquakes. The mechanism combines the critical earthquake concept and the concept of crust acting as a charging electric battery under increasing stress. The electric charges are released by activation of dormant charge carriers in the oxygen anion sublattice, called peroxy bonds or positive hole pairs (PHP), where a PHP represents an $O_3X/^{OO}\backslash YO_3$ with $X,Y = Si^{4+}, Al^{3+}...$, i.e. an $O^-$ in a matrix of $O^{2-}$ of silicates. We propose that PHP are activated by plastic deformations during the slow cooperative build-up of stress and the increasingly correlated damage culminating in a large ``critical'' earthquake. Recent laboratory experiments indeed show that stressed rocks form electric batteries which can release their charge when a conducting path closes the equivalent electric circuit. We conjecture that the intermittent and erratic occurrences of EM signals are a consequence of the progressive build-up of the battery charges in the Earth crust and their erratic release when crack networks are percolating throughout the stressed rock volumes, providing a conductive pathway for the battery currents to discharge. EM signals are thus expected close to the rupture, either slightly before or after, that is, when percolation is most favored.Comment: 17 pages with 3 figures, extended discussion with 1 added figure and 162 references. The new version provides both a synthesis of two theories and a review of the fiel

Personalising airway clearance in chronic lung disease

This review describes a framework for providing a personalised approach to selecting the most appropriate airway clearance technique (ACT) for each patient. It is based on a synthesis of the physiological evidence that supports the modulation of ventilation and expiratory airflow as a means of assisting airway clearance. Possession of a strong understanding of the physiological basis for ACTs will enable clinicians to decide which ACT best aligns with the individual patient's pathology in diseases with anatomical bronchiectasis and mucus hypersecretion. The physiological underpinning of postural drainage is that by placing a patient in various positions, gravity enhances mobilisation of secretions. Newer ACTs are based on two other physiological premises: the ability to ventilate behind obstructed regions of the lung and the capacity to achieve the minimum expiratory airflow bias necessary to mobilise secretions. After reviewing each ACT to determine if it utilises both ventilation and expiratory flow, these physiological concepts are assessed against the clinical evidence to provide a mechanism for the effectiveness of each ACT. This article provides the clinical rationale necessary to determine the most appropriate ACT for each patient, thereby improving care

Transport of water into the lower mantle: Role of stishovite

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95319/1/jgrb13563.pd