HCMV pUL135 remodels the actin cytoskeleton to impair immune recognition of infected cells

Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the UL/b’ domain is associated with loss of virulence. In a screen of UL/b’, we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix

Evolution of Inhomogeneous Condensates after Phase Transitions

Using the O(4) linear $\sigma$ model, we address the topic of non-equilibrium relaxation of an inhomogeneous initial configuration due to quantum and thermal fluctuations. The space-time evolution of an inhomogeneous fluctuation of the condensate in the isoscalar channel decaying via the emission of pions in the medium is studied within the context of disoriented chiral condensates. We use out of equilibrium closed time path methods in field theory combined with the amplitude expansion. We give explicit expressions for the asymptotic space-time evolution of an initial inhomogeneous configuration including the contribution of thresholds at zero and non-zero temperature. At non-zero temperature we find new relaxational processes due to thermal cuts that have no counterpart in the homogeneous case. Within the one-loop approximation, we find that the space time evolution of such inhomogeneous configuration out of equilibrium is effectively described in terms of a rapidity dependent temperature $T(\vartheta)=T/\cosh[\vartheta]$ as well as a rapidity dependent decay rate $\Gamma(\vartheta, T(\vartheta))$. This rate is to be interpreted as the production minus absorption rate of pions in the medium and approaches the zero temperature value at large rapidities. An initial configuration localized on a bounded region spreads and decays in spherical waves with slower relaxational dynamics at large rapidity.Comment: 25 pages Revtex 3.0, two figures available upon reques

Nanometric depth resolution from multi-focal images in microscopy

We describe a method for tracking the position of small features in three dimensions from images recorded on a standard microscope with an inexpensive attachment between the microscope and the camera. The depth-measurement accuracy of this method is tested experimentally on a wide-field, inverted microscope and is shown to give approximately 8 nm depth resolution, over a specimen depth of approximately 6 µm, when using a 12-bit charge-coupled device (CCD) camera and very bright but unresolved particles. To assess low-flux limitations a theoretical model is used to derive an analytical expression for the minimum variance bound. The approximations used in the analytical treatment are tested using numerical simulations. It is concluded that approximately 14 nm depth resolution is achievable with flux levels available when tracking fluorescent sources in three dimensions in live-cell biology and that the method is suitable for three-dimensional photo-activated localization microscopy resolution. Sub-nanometre resolution could be achieved with photon-counting techniques at high flux levels

Oregon 2100: projected climatic and ecological changes

Greenhouse climatic warming is underway and exacerbated by human activities. Future outcomes of these processes can be projected using computer models checked against climatic changes during comparable past atmospheric compositions. This study gives concise quantitative predictions for future climate, landscapes, soils, vegetation, and marine and terrestrial animals of Oregon. Fossil fuel burning and other human activities by the year 2100 are projected to yield atmospheric CO2 levels of about 600-850 ppm (SRES A1B and B1), well above current levels of 400 ppm and preindustrial levels of 280 ppm. Such a greenhouse climate was last recorded in Oregon during the middle Miocene, some 16 million years ago. Oregon’s future may be guided by fossil records of the middle Miocene, as well as ongoing studies on the environmental tolerances of Oregon plants and animals, and experiments on the biological effects of global warming. As carbon dioxide levels increase, Oregon’s climate will move toward warm temperate, humid in the west and semiarid to subhumid to the east, with increased summer and winter drought in the west. Western Oregon lowlands will become less suitable for temperate fruits and nuts and Pinot Noir grapes, but its hills will remain a productive softwood forest resource. Improved pasture and winter wheat crops will become more widespread in eastern Oregon. Tsunamis and stronger storms will exacerbate marine erosion along the Oregon Coast, with significant damage to coastal properties and cultural resources

Full genome sequence and sfRNA interferon antagonist activity of Zika virus from Recife, Brazil

Background: The outbreak of Zika virus (ZIKV) in the Americas has transformed a previously obscure mosquito-transmitted arbovirus of the Flaviviridae family into a major public health concern. Little is currently known about the evolution and biology of ZIKV and the factors that contribute to the associated pathogenesis. Determining genomic sequences of clinical viral isolates and characterization of elements within these are an important prerequisite to advance our understanding of viral replicative processes and virus-host interactions. Methodology/Principal findings: We obtained a ZIKV isolate from a patient who presented with classical ZIKV-associated symptoms, and used high throughput sequencing and other molecular biology approaches to determine its full genome sequence, including non-coding regions. Genome regions were characterized and compared to the sequences of other isolates where available. Furthermore, we identified a subgenomic flavivirus RNA (sfRNA) in ZIKV-infected cells that has antagonist activity against RIG-I induced type I interferon induction, with a lesser effect on MDA-5 mediated action. Conclusions/Significance: The full-length genome sequence including non-coding regions of a South American ZIKV isolate from a patient with classical symptoms will support efforts to develop genetic tools for this virus. Detection of sfRNA that counteracts interferon responses is likely to be important for further understanding of pathogenesis and virus-host interactions

Modulators of 14-3-3 Protein-Protein Interactions

Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein-protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as 'undruggable' targets, the last two decades have seen an increasing number of successful examples of PPI modulators resulting in a growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This Perspective focuses on the hub protein 14-3-3, which has several hundred identified protein interaction partners and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide-mimetics and natural products

Designing count‐based studies in a world of hierarchical models

Abstract: Advances in hierarchical modeling have improved estimation of ecological parameters from count data, especially those quantifying population abundance, distribution, and dynamics by explicitly accounting for observation processes, particularly incomplete detection. Even hierarchical models that account for incomplete detection, however, cannot compensate for data limitations stemming from poorly planned sampling. Ecologists therefore need guidance for planning count‐based studies that follow established sampling theory, collect appropriate data, and apply current modeling approaches to answer their research questions. We synthesize available literature relevant to guiding count‐based studies. Considering the central historical and ongoing contributions of avian studies to ecological knowledge, we focus on birds as a case study for this review, but the basic principles apply to all populations whose members are sufficiently observable to be counted. The sequence of our review represents the thought process in which we encourage ecologists to engage 1) the research question(s) and population parameters to measure, 2) sampling design, 3) analytical framework, 4) temporal design, and 5) survey protocol. We also provide 2 hypothetical demonstrations of these study plan components representing different research questions and study systems. Mirroring the structure of hierarchical models, we suggest researchers primarily focus on the ecological processes of interest when designing their approach to sampling, and wait to consider logistical constraints of data collection and observation processes when developing the survey protocol. We offer a broad framework for researchers planning count‐based studies, while pointing to relevant literature elaborating on particular tools and concepts

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391