Tetherin Restricts Herpes Simplex Virus 1 and Is Antagonized by Glycoprotein M

Tetherin is a broadly active antiviral effector that works by tethering nascent enveloped virions to a host cell membrane, thus preventing their release. In this study, we demonstrate that herpes simplex virus 1 (HSV-1) is targeted by tetherin. We identify the viral envelope glycoprotein M (gM) as having moderate anti-tetherin activity. We show that gM but not gB or gD efficiently removes tetherin from the plasma membrane and can functionally substitute for the human immunodeficiency virus type 1 (HIV-1) Vpu protein, the prototypic viral tetherin antagonist, in rescuing HIV-1 release from tetherin-expressing cells. Our data emphasize that tetherin is a broadly active antiviral effector and contribute to the emerging hypothesis that viruses must suppress or evade an array of host cell countermeasures in order to establish a productive infection.     

Gastric intrinsic factor: The gastric and small intestinal stages of cobalamin absorption. A personal journey

Intrinsic factor (IF) was first identified as a component of the gastric mucosa that reacted with an extrinsic factor, later discovered to be vitamin B12 (VB12). IF has been extensively characterized, and its cloned cDNA used to produce sufficient IF to produce high quality antibodies, and to elucidate its 3-dimensional structure bound to cobalamin (Cbl, VB12). The absorption of the IF–Cbl complex involves internalization by endocytosis, incorporation into multivesicular/lysosomal bodies, release of Cbl by lysosomal proteolysis and pH effects, with subsequent binding to transcobalamin (TC). Hereditary IF deficiency is rare, consistent with the need for IF to absorb Cbl, a vitamin essential for cell replication. When mutations occur, they are most often associated with loss of function, but some mutations occur outside the coding region. The IF-mediated intestinal uptake of Cbl has been harnessed for use as a transporter for peptides, proteins and even nanoparticles. Nanoparticle (NP) technology has produced Cbl-coated NPs that can incorporate peptides (insulin, IgG) that can be absorbed orally to function as hormones and antibodies in rodent models, but these systems are not yet ready for clinical use.     

Food Intake in Healthy Young Adults: Effects of Time Pressure and Social Factors

Some factors influencing food intake and subjective responses to meals were assessed in 2 groups (n=40 and n=36) of healthy university students. Both groups were studied for 6 days and included both “structured” and “unstructured” times. A questionnaire was completed by all subjects at 3 h intervals while awake. The questionnaires asked the subjects to state the factors that led them to choose to eat or not to eat a meal in the previous 3 h. If they ate a meal, they were required to describe the type of meal eaten and their responses to it—their hunger before it, their enjoyment of the meal itself, and their degree of satisfaction afterwards. Subjects were also asked to describe the type of meal that they would like to have eaten (the desired meal) in the absence of any restraints due to time pressure, cost, and so on. In the first group, 3 “structured” (working) and 3 “unstructured” (rest) days were chosen. Consistant with our previous studies, structured days, as compared to unstructured days, were associated with smaller meals and less positive subjective responses to them. Also, the meals that were eaten were often smaller than those that were desired, or were even missed altogether, due to time pressure. Not only were the meals eaten on unstructured days larger and rated, to by the subjects more positively, but also there was an additional positive effect if the meal played a social role. In the second group, 6 days were chosen, during which there were structured and unstructured 3 h periods. Many of the findings (with regard to reasons for eating or not eating a meal, and the effect of meal size upon subjective responses to it, for example) were the same as in the first group. However, the effect of structured vs. unstructured 3 h periods was significantly less marked than the effect of structured vs. unstructured days that had been found in the first group, and effects due to social factors and time pressure were less reliably present. The results indicate that food intake is affected by whether the whole or only part of the day is “structured” or “unstructured.” These findings might be relevant to some problems faced by the workforce, in general, and by night workers, in particular.     

Uterine histotroph and conceptus development: select nutrients and secreted phosphoprotein 1 affect mechanistic target of rapamycin cell signaling in ewes

Interferon tau (IFNT), the pregnancy recognition signal in ruminants, abrogates the uterine luteolytic mechanism to ensure maintenance of function for the corpora lutea to produce progesterone (P4). IFNT also suppresses expression of classical IFN-stimulated genes by uterine lumenal epithelium (LE) and superficial glandular (sGE) epithelium but, acting in concert with progesterone, affects expression of a multitude of genes critical to growth and development of the conceptus. The LE and sGE secrete proteins and transport nutrients into the uterine lumen necessary for conceptus development, pregnancy recognition signaling, and implantation. Secretions include arginine and secreted phosphoprotein 1 (SPP1). Arginine can be metabolized to nitric oxide and to polyamines or act directly to activate the mechanistic target of rapamycin cell signaling pathway to stimulate proliferation, migration, and mRNA translation in trophectoderm cells. SPP1 binds alphavbeta3 and alpha5beta1 integrins to induce focal adhesion assembly, adhesion, and migration of conceptus trophectoderm cells during implantation. Thus, arginine and SPP1 mediate growth, migration, cytoskeletal remodeling, and adhesion of trophectoderm essential for pregnancy recognition signaling and implantation. This minireview focuses on components of histotroph that affect conceptus development in the ewe.     

PKCθ activation in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors is needed for stimulation of numerous important cellular signaling cascades

The novel PKCθ isoform is highly expressed in T-cells, brain and skeletal muscle and originally thought to have a restricted distribution. It has been extensively studied in T-cells and shown to be important for apoptosis, T-cell activation and proliferation. Recent studies showed its presence in other tissues and importance in insulin signaling, lung surfactant secretion, intestinal barrier permeability, platelet and mast-cell functions. However, little information is available for PKCθ activation by gastrointestinal (GI) hormones/neurotransmitters and growth factors. In the present study we used rat pancreatic acinar cells to explore their ability to activate PKCθ and the possible interactions with important cellular mediators of their actions. Particular attention was paid to cholecystokinin (CCK), a physiological regulator of pancreatic function and important in pathological processes affecting acinar function, like pancreatitis. PKCθ-protein/mRNA was present in the pancreatic acini, and T538-PKCθ phosphorylation/activation was stimulated only by hormones/neurotransmitters activating phospholipase C. PKCθ was activated in time- and dose-related manner by CCK, mediated 30% by high-affinity CCK(A)-receptor activation. CCK stimulated PKCθ translocation from cytosol to membrane. PKCθ inhibition (by pseudostrate-inhibitor or dominant negative) inhibited CCK- and TPA-stimulation of PKD, Src, RafC, PYK2, p125(FAK) and IKKα/β, but not basal/stimulated enzyme secretion. Also CCK- and TPA-induced PKCθ activation produced an increment in PKCθ's direct association with AKT, RafA, RafC and Lyn. These results show for the first time the PKCθ presence in pancreatic acinar cells, its activation by some GI hormones/neurotransmitters and involvement in important cell signaling pathways mediating physiological responses (enzyme secretion, proliferation, apoptosis, cytokine expression, and pathological responses like pancreatitis and cancer growth).     

A comparison of various mating disruption technologies for control of two internally feeding Lepidoptera in apples

Sex pheromone mating disruption (MD) is an approach used to control several moth pest species of pome fruit by disrupting the ability of the males to find females and consequently prevent mating. The following experiments were performed to determine the effectiveness of several new and experimental sex pheromone MD technologies, and dispenser densities for simultaneous control of the codling moth (CM), Cydia pomonella (L.), and the oriental fruit moth (OFM), Grapholita molesta (Busck) (both Lepidoptera: Tortricidae), in Pennsylvania apple orchards. In one study, three MD approaches to control CM and oriental fruit moth – CM and OFM Disrupt Micro‐Flakes, Isomate CM/OFM TT, and both a CideTrak OFM and a CideTrak CM dispenser containing both codlemone and pear ester – and an insecticides‐only treatment were compared over the course of 2 years. In the other studies, the efficacy of several CheckMate Duel dispenser densities (i.e., 250, 375, 425, and 500 dispensers ha^?1) were compared against Isomate CM/OFM TT, and an insecticides‐only treatment. The CideTrak CM/pear ester combination and Isomate CM/OFM TT treatments both substantially reduced CM captures in traps in 2007 and 2008. Meanwhile, OFM trap shutdown was highest in the CheckMate Duel densities of 375 (99.9 ± 0.08%) and 500 dispensers ha^?1 (98.9 ± 0.07%) and the Isomate CM/OFM TT treatment (98.0 ± 1.13%), and lowest in the 250 dispensers ha^?1 density treatment (94.3 ± 3.23%). In orchards where OFM is the dominant pest species, a CheckMate Duel dispenser density of 375 ha^?1 is necessary for effective control, whereas higher densities are needed to control CM.     

A reduced‐tillering trait shows small but important yield gains in dryland wheat production

Reducing the number of tillers per plant using a t iller in hibition (tin) gene has been considered as an important trait for wheat production in dryland environments. We used a spatial analysis approach with a daily time‐step coupled radiation and transpiration efficiency model to simulate the impact of the reduced‐tillering trait on wheat yield under different climate change scenarios across Australia's arable land. Our results show a small but consistent yield advantage of the reduced‐tillering trait in the most water‐limited environments both under current and likely future conditions. Our climate scenarios show that whilst elevated [CO₂] (e[CO₂]) alone might limit the area where the reduced‐tillering trait is advantageous, the most likely climate scenario of e[CO₂] combined with increased temperature and reduced rainfall consistently increased the area where restricted tillering has an advantage. Whilst long‐term average yield advantages were small (ranged from 31 to 51 kg ha^?1 year^?1), across large dryland areas the value is large (potential cost‐benefits ranged from Australian dollar 23 to 60 MIL/year). It seems therefore worthwhile to further explore this reduced‐tillering trait in relation to a range of different environments and climates, because its benefits are likely to grow in future dry environments where wheat is grown around the world.     

Complex Genetic Architecture of Cardiac Disease in a Wild Type Inbred Strain of Drosophila melanogaster

Natural populations of the fruit fly, Drosophila melanogaster, segregate genetic variation that leads to cardiac disease phenotypes. One nearly isogenic line from a North Carolina peach orchard, WE70, is shown to harbor two genetically distinct heart phenotypes: elevated incidence of arrhythmias, and a dramatically constricted heart diameter in both diastole and systole, with resemblance to restrictive cardiomyopathy in humans. Assuming the source to be rare variants of large effect, we performed Bulked Segregant Analysis using genomic DNA hybridization to Affymetrix chips to detect single feature polymorphisms, but found that the mutant phenotypes are more likely to have a polygenic basis. Further mapping efforts revealed a complex architecture wherein the constricted cardiomyopathy phenotype was observed in individual whole chromosome substitution lines, implying that variants on both major autosomes are sufficient to produce the phenotype. A panel of 170 Recombinant Inbred Lines (RIL) was generated, and a small subset of mutant lines selected, but these each complemented both whole chromosome substitutions, implying a non-additive (epistatic) contribution to the “disease” phenotype. Low coverage whole genome sequencing was also used to attempt to map chromosomal regions contributing to both the cardiomyopathy and arrhythmia, but a polygenic architecture had to be again inferred to be most likely. These results show that an apparently simple rare phenotype can have a complex genetic basis that would be refractory to mapping by deep sequencing in pedigrees. We present this as a cautionary tale regarding assumptions related to attempts to map new disease mutations on the assumption that probands carry a single causal mutation.