2��-O Methylation of the Viral mRNA Cap by West Nile Virus Evades Ifit1-Dependent and -Independent Mechanisms of Host Restriction In Vivo

Prior studies have shown that 2′-O methyltransferase activity of flaviviruses, coronaviruses, and poxviruses promotes viral evasion of Ifit1, an interferon-stimulated innate immune effector protein. Viruses lacking 2′-O methyltransferase activity exhibited attenuation in primary macrophages that was rescued in cells lacking Ifit1 gene expression. Here, we examined the role of Ifit1 in restricting pathogenesis in vivo of wild type WNV (WNV-WT) and a mutant in the NS5 gene (WNV-E218A) lacking 2′-O methylation of the 5′ viral RNA cap. While deletion of Ifit1 had marginal effects on WNV-WT pathogenesis, WNV-E218A showed increased replication in peripheral tissues of Ifit1^−/− mice after subcutaneous infection, yet this failed to correlate with enhanced infection in the brain or lethality. In comparison, WNV-E218A was virulent after intracranial infection as judged by increased infection in different regions of the central nervous system (CNS) and a greater than 16,000-fold decrease in LD₅₀ values in Ifit1^−/− compared to wild type mice. Ex vivo infection experiments revealed cell-type specific differences in the ability of an Ifit1 deficiency to complement the replication defect of WNV-E218A. In particular, WNV-E218A infection was impaired in both wild type and Ifit1^−/− brain microvascular endothelial cells, which are believed to participate in blood-brain barrier (BBB) regulation of virus entry into the CNS. A deficiency of Ifit1 also was associated with increased neuronal death in vivo, which was both cell-intrinsic and mediated by immunopathogenic CD8⁺ T cells. Our results suggest that virulent strains of WNV have largely evaded the antiviral effects of Ifit1, and viral mutants lacking 2′-O methylation are controlled in vivo by Ifit1-dependent and -independent mechanisms in different cell types.     

A Salience Theory of Learning and Behavior: With Perspectives on Neurobiology and Cognition

Traditional behaviorists have described behaviors fundamentally as responses to stimuli or, perhaps more liberally, as behaviors under the control of discriminative stimuli or contexts. They have held responses or behaviors to be established, strengthened, sustained, and inhibited or extinguished by contingent events: notably reinforcers, punishers, or the absence of either. In addition, they believed reinforcement acts on the response, the behavior, not on the organism. Here, and in support of Hebb’s view, we advance a contrarian view. A key principle of our framework is that species’ brains are uniquely designed to perceive and to relate stimulus events that are contiguous, salient, and relevant to adaptation. In accordance with what we here view as the constructive biases of species’ brains, stimuli are differentially organized into amalgams that reflect an exchange of salience and response-eliciting properties of component units, which are then integrated to form a basis of knowledge about the organism and its ecological niche. One can then base adaptation on overarching principles and rules, not just on simple associations. Species may create emergent behaviors with no history of specific training, and even new capacities, to service adaptation to both familiar and novel challenges.     

Movement and mortality of invasive suckermouth armored catfish during a spearfishing control experiment

Biological Invasions - Control of non-native, invasive species in groundwater-dependent ecosystems that are also inhabited by regionally endemic or at-risk species represents a key challenge in...     

Immunological responses can have both pro- and antitumour effects: implications for immunotherapy

Immune responses influence the development and progression of a malignancy. The tumour can also manipulate the immune system to its own ends, often resulting in an ineffective or transient antitumour response. An appreciation of the complexity of these host-tumour interactions is therefore important for the development of more-effective cancer therapies. This article highlights some prominent mechanisms whereby tumours escape recognition and destruction by the host immune system, thus facilitating disease progression. One important consequence of tumour escape is that an antitumour immune response may unintentionally lead to the outgrowth of less immunogenic or more apoptosis-resistant tumour escape variants, which possess enhanced tumourigenic potential. Insights into the molecular mechanisms of cancer evasion and the complexity of the ever-changing interactions between host and tumour will enable a more rational design of antitumour therapies and may help not only explain disease recurrence, but also identify potential targets for therapeutic interventions. This article also offers a brief review of preclinical animal models, which are essential tools in the study of tumour immunology and cancer biology, particularly those that recapitulate the chronic nature of host-tumour interactions and help guide the development and testing of new therapies.     

Natural Fiber Welded Electrode Yarns for Knittable Textile Supercapacitors

Natural fiber welded (NFW) yarns embedded with porous carbon ­materials are described for applications as electrodes in textile electrochemical capacitors. With this fabrication technique, many kinds of carbons can be embedded into cellulose based yarns and subsequently knitted into full ­fabrics on industrial knitting machines. Yarns welded with carbon and ­stainless steel have device capacitances as high as 37 mF cm^‐1, one of the highest reported values for carbon‐based yarns. The versatility of this ­technique to weld any commercially available cellulose yarn with any ­micro‐ or nanocarbon means properties can be tuned for specific applications. Most importantly, it is found that despite having full flexibility, increased strength, and good electrochemical performance, not all of the electrode yarns are ­suitable for knitting. Therefore, it is recommended that all works reporting on fiber/yarn capacitors for wearables attempt processing into full fabrics.     

Short-chain fatty acid mediated phosphorylation of heat shock protein 25: effects on camptothecin-induced apoptosis

Although short-chain fatty acid (SCFA)-induced heat shock protein 25 (Hsp25) is associated with increased cellular resistance to injury, withdrawal of lumenal butyrate in vivo is associated with intestinal epithelial injury and apoptosis. Recognizing that SCFA-dependent posttranslational modification of Hsp25 may involve altered Hsp25 phosphorylation, we hypothesized that butyrate regulates Hsp25 phosphorylation and secondarily affects cellular responses to apoptosis-inducing agents. Intestinal epithelial crypt IEC-18 cells were treated with butyrate, propionate, or the histone deacetylase inhibitor trichostatin A for 6-24 h. Immunolocalization of Hsp25 was examined by confocal laser microscopy. Hsp25 phosphorylation was characterized using two-dimensional isoelectric focusing gel electrophoresis. Hsp25 accumulation in cytoskeletal- and mitochondrial-enriched fractions was examined by immunoblotting. The activation of p38 MAP kinase was determined using phospho-specific antibodies and MAPKAPK 2 kinase assays. The effects of SCFA on apoptosis were studied by ELISA detection of cleaved DNA and using antibodies recognizing cleaved caspase-3. Five-millimolar butyrate induced no significant injury to IEC-18 cells. Hsp25 did not accumulate in Triton X-100-insoluble cytoskeletal fractions with butyrate treatment but did localize to mitochondria in a p38 MAP kinase-dependent manner. Hsp25 phosphorylation was induced by butyrate, propionate, and trichostatin A. Butyrate-mediated changes in Hsp25 phosphorylation coincide with the activation of the p38 MAP kinase and MAPKAPK 2. Butyrate, propionate, and low-dose trichostatin A confer significant protection from camptothecin-induced apoptosis, which was not reversed by the p38 inhibitor SB203580. We conclude that butyrate-mediated phosphorylation of Hsp25 is associated with significant resistance to apoptosis, which appears to be independent of p38-mediated targeting of Hsp25 to mitochondria.     

Physiological responses of skilled players during a competitive wheelchair tennis match

The purpose of this study was to determine heart rate (HR, b.min(-1)) response during competitive match play of 6 men who were skilled wheelchair (WC) tennis players. Each participant completed an arm crank ergometer test that measured HR via a telemetry device and O2 via open circuit spirometry from rest until fatigue (.V(O2)peak). Each athlete participated in 2 competitive singles matches during which HRs were recorded in 5-second intervals and O2 was estimated using the corresponding HR values recorded during the arm ergometer tests. Data analysis revealed an average playing intensity of 69.4 +/- 8.9% of HRpeak and 49.9 +/-14.5% of .V(O2)peak. In conclusion, it is recommended that skilled adult WC tennis players perform off-court aerobic conditioning as part of their training program, because the intensity of a competitive WC tennis match is sufficiently high enough to stress the cardiovascular system.     

MicroRNA‐455 regulates brown adipogenesis via a novel HIF1an‐AMPK‐PGC1α signaling network

Brown adipose tissue (BAT) dissipates chemical energy as heat and can counteract obesity. MicroRNAs are emerging as key regulators in development and disease. Combining microRNA and mRNA microarray profiling followed by bioinformatic analyses, we identified miR‐455 as a new regulator of brown adipogenesis. miR‐455 exhibits a BAT‐specific expression pattern and is induced by cold and the browning inducer BMP7. In vitro gain‐ and loss‐of‐function studies show that miR‐455 regulates brown adipocyte differentiation and thermogenesis. Adipose‐specific miR‐455 transgenic mice display marked browning of subcutaneous white fat upon cold exposure. miR‐455 activates AMPKα1 by targeting HIF1an, and AMPK promotes the brown adipogenic program and mitochondrial biogenesis. Concomitantly, miR‐455 also targets the adipogenic suppressors Runx1t1 and Necdin, initiating adipogenic differentiation. Taken together, the data reveal a novel microRNA‐regulated signaling network that controls brown adipogenesis and may be a potential therapeutic target for human metabolic disorders.