Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously during FAD and of the potential risk factors for its development are important observations given the recent launch of amyloid-modifying therapy trials for FAD

Stresses in isostatic granular systems and emergence of force chains

Progress is reported on several questions that bedevil understanding of granular systems: (i) are the stress equations elliptic, parabolic or hyperbolic? (ii) how can the often-observed force chains be predicted from a first-principles continuous theory? (iii) How to relate insight from isostatic systems to general packings? Explicit equations are derived for the stress components in two dimensions including the dependence on the local structure. The equations are shown to be hyperbolic and their general solutions, as well as the Green function, are found. It is shown that the solutions give rise to force chains and the explicit dependence of the force chains trajectories and magnitudes on the local geometry is predicted. Direct experimental tests of the predictions are proposed. Finally, a framework is proposed to relate the analysis to non-isostatic and more realistic granular assemblies.Comment: 4 pages, 2 figures, Corrected typos and clkearer text, submitted to Phys. Rev. Let

Data centric modeling of environmental sensor networks

Meteorological and hydrological sensors deployed over several hundred kilometers of geographical area comprise an environmental sensor network. Large amounts of data need to be processed in minimal time and transmitted over the available low speed and low bandwidth links. This paper describes algorithms for optimal data collection and data fusion. An inductive model using exponential back-off policy is used to collect optimal amount of data. The data measurements for temperature, pH and specific conductance collected for a year from the sensors deployed at Lake Lewisville are used to test the inductive model. Energy savings of 90% are achieved even with 1% of degree of tolerance. The problem of data fusion is addressed by the introduction of a novel concept of a super-sensor, based on self-organization and collaboration among sensors. A histogram application is described that uses recursive doubling for global collaboration between sensors. The performance of the networked super-sensor in comparison to a centralized polling approach is analyzed for optimality on two different geographical areas. ©2004 IEEE

Force correlations and arches formation in granular assemblies

In the context of a simple microscopic schematic scalar model we study the effects of spatial correlations in force transmission in granular assemblies. We show that the parameters of the normalized weights distribution function, $P(v)\sim v^{\alpha}\exp(-v/\phi)$, strongly depend on the spatial extensions, $\xi_V$, of such correlations. We show, then, the connections between measurable macroscopic quantities and microscopic mechanisms enhancing correlations. In particular we evaluate how the exponential cut-off, $\phi(\xi_V)$, and the small forces power law exponent, $\alpha(\xi_V)$, depend on the correlation length, $\xi_V$. If correlations go to infinity, weights are power law distributed.Comment: 6 page

Percolation analysis of force networks in anisotropic granular matter

We study the percolation properties of force networks in an anisotropic model for granular packings, the so-called q-model. Following the original recipe of Ostojic et al. [Nature 439, 828 (2006)], we consider a percolation process in which forces smaller than a given threshold f are deleted in the network. For a critical threshold f_c, the system experiences a transition akin to percolation. We determine the point of this transition and its characteristic critical exponents applying a finite-size scaling analysis that takes explicitly into account the directed nature of the q-model. By means of extensive numerical simulations, we show that this percolation transition is strongly affected by the anisotropic nature of the model, yielding characteristic exponents which are neither those found in isotropic granular systems nor those in the directed version of standard percolation. The differences shown by the computed exponents can be related to the presence of strong directed correlations and mass conservation laws in the model under scrutiny

Packing of Compressible Granular Materials

3D Computer simulations and experiments are employed to study random packings of compressible spherical grains under external confining stress. Of particular interest is the rigid ball limit, which we describe as a continuous transition in which the applied stress vanishes as (\phi-\phi_c)^\beta, where \phi is the (solid phase) volume density. This transition coincides with the onset of shear rigidity. The value of \phi_c depends, for example, on whether the grains interact via only normal forces (giving rise to random close packings) or by a combination of normal and friction generated transverse forces (producing random loose packings). In both cases, near the transition, the system's response is controlled by localized force chains. As the stress increases, we characterize the system's evolution in terms of (1) the participation number, (2) the average force distribution, and (3) visualization techniques.Comment: 4 pages, 7 figures, to appear in Phys. Rev. Let

Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites

β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor

A Model for Force Fluctuations in Bead Packs

We study theoretically the complex network of forces that is responsible for the static structure and properties of granular materials. We present detailed calculations for a model in which the fluctuations in the force distribution arise because of variations in the contact angles and the constraints imposed by the force balance on each bead of the pile. We compare our results for force distribution function for this model, including exact results for certain contact angle probability distributions, with numerical simulations of force distributions in random sphere packings. This model reproduces many aspects of the force distribution observed both in experiment and in numerical simulations of sphere packings

Geometric origin of mechanical properties of granular materials

Some remarkable generic properties, related to isostaticity and potential energy minimization, of equilibrium configurations of assemblies of rigid, frictionless grains are studied. Isostaticity -the uniqueness of the forces, once the list of contacts is known- is established in a quite general context, and the important distinction between isostatic problems under given external loads and isostatic (rigid) structures is presented. Complete rigidity is only guaranteed, on stability grounds, in the case of spherical cohesionless grains. Otherwise, the network of contacts might deform elastically in response to load increments, even though grains are rigid. This sets an uuper bound on the contact coordination number. The approximation of small displacements (ASD) allows to draw analogies with other model systems studied in statistical mechanics, such as minimum paths on a lattice. It also entails the uniqueness of the equilibrium state (the list of contacts itself is geometrically determined) for cohesionless grains, and thus the absence of plastic dissipation. Plasticity and hysteresis are due to the lack of such uniqueness and may stem, apart from intergranular friction, from small, but finite, rearrangements, in which the system jumps between two distinct potential energy minima, or from bounded tensile contact forces. The response to load increments is discussed. On the basis of past numerical studies, we argue that, if the ASD is valid, the macroscopic displacement field is the solution to an elliptic boundary value problem (akin to the Stokes problem).Comment: RevTex, 40 pages, 26 figures. Close to published paper. Misprints and minor errors correcte

Structure, Dynamics and Cellular Insight Into Novel Substrates of the Legionella pneumophila Type II Secretion System

Legionella pneumophila is a Gram-negative bacterium that is able to replicate within a broad range of aquatic protozoan hosts. L. pneumophila is also an opportunistic human pathogen that can infect macrophages and epithelia in the lung and lead to Legionnaires’ disease. The type II secretion system is a key virulence factor of L. pneumophila and is used to promote bacterial growth at low temperatures, regulate biofilm formation, modulate host responses to infection, facilitate bacterial penetration of mucin gels and is necessary for intracellular growth during the initial stages of infection. The L. pneumophila type II secretion system exports at least 25 substrates out of the bacterium and several of these, including NttA to NttG, contain unique amino acid sequences that are generally not observed outside of the Legionella genus. NttA, NttC, and NttD are required for infection of several amoebal species but it is unclear what influence other novel substrates have within their host. In this study, we show that NttE is required for optimal infection of Acanthamoeba castellanii and Vermamoeba vermiformis amoeba and is essential for the typical colony morphology of L. pneumophila. In addition, we report the atomic structures of NttA, NttC, and NttE and through a combined biophysical and biochemical hypothesis driven approach we propose novel functions for these substrates during infection. This work lays the foundation for future studies into the mechanistic understanding of novel type II substrate functions and how these relate to L. pneumophila ecology and disease.The United Kingdom Medical Research Council; The Wellcome Trust