From heritability to probability

Can a heritability value tell us something about the weight of genetic versus environmental causes that have acted in the development of a particular individual? Two possible questions arise. Q1: what portion of the phenotype of X is due to its genes and what portion to its environment? Q2: what portion of X’s phenotypic deviation from the mean is a result of its genetic deviation and what portion a result of its environmental deviation? An answer to Q1 provides the full information about X’s development, while an answer to Q2 leaves out a large portion unexplained—that portion which corresponds to the phenotypic mean. Q1 is unanswerable, but I show it is nevertheless legitimate under certain quantitative genetics models. With regard to Q2, opinions in the philosophical and biological literature differ as to its legitimacy. I argue that not only is it legitimate, but in particular, under a few simplifying assumptions, it allows for a quantitative probabilistic answer: for normally distributed quantitative traits with no G-E correlation or statistical G × E interaction, we can assess the probability that X’s genes had a greater effect than its environment on its deviation from the mean population value. This probability is expressed as a function the heritability and the individual’s phenotypic value; we can also provide a quantitative probabilistic answer to Q2 for an arbitrary individual where the probability is a function only of heritability.     

Yersinia pestis Endowed with Increased Cytotoxicity Is Avirulent in a Bubonic Plague Model and Induces Rapid Protection against Pneumonic Plague

An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica O∶8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10⁷-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD₅₀ of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.     

The involvement of sand disturbance, cannibalism and intra-guild predation in competitive interactions among pit-building antlion larvae

Competition in trap-building predators such as antlion larvae is a complex biotic interaction, potentially involving exploitation competition, sand throwing (i.e., interference competition), cannibalism and intra-guild predation. We investigated the short-term behavioral and developmental responses of the strict sit-and-wait antlion predator Myrmeleon hyalinus to sand disturbance (i.e., quantification of the impact of severe sand throwing), and to con- and hetero-specific competition by a larger sit-and-pursue antlion species Lopezus fedtschenkoi. We found that antlions subjected to sand disturbances reduced their pit construction activity and relocated less often. Furthermore, the reduction in pit construction activity was stronger among antlions subjected to disturbances prior to feeding. Almost no death occurred during the sand disturbance experiment, but as expected, disturbances caused reductions in the relative growth rates of antlions. This negative effect was stronger in the group exposed to sand disturbances prior to feeding. The presence of the sit-and-pursue competitor led to reductions both in pit construction and in relocation activities of M. hyalinus. Although the per-capita food supply was identical in both experiments, only 48% of M. hyalinus larvae survived the competition experiment, and this pattern was consistent between the con- and hetero-specific treatments. However, in the presence of hetero-specific competitors, the relative growth rate of surviving larvae was significantly lower than that measured in the presence of con-specific competitors. Our study demonstrates that investigating the different components of complex biotic interactions can markedly improve our understanding of how these different factors interact to influence the behavior and life history of organisms.     

Effectiveness of liposomal paclitaxel against MCF-7 breast cancer cells

Paclitaxel is an effective chemotherapeutic agent that is widely used for the treatment of several cancers, including breast, ovarian, and non-small-cell lung cancer. Due to its high lipophilicity, paclitaxel is difficult to administer and requires solubilization with Cremophor EL (polyethoxylated castor oil) and ethanol, which often lead to adverse side effects, including life-threatening anaphylaxis. Incorporation of paclitaxel in dimyristoylphosphatidylcholine:dimyristoylphosphatidylglycerol (DPPC:DMPG) liposomes can facilitate its delivery to cancer cells and eliminate the adverse reactions associated with the Cremophor EL vehicle. Accordingly, the effectiveness of liposomal paclitaxel on MCF-7 breast cancer cells was examined. The results from this study showed that (i) the lipid components of the liposomal formulation were nontoxic, (ii) the cytotoxic effects of liposomal paclitaxel were improved when compared with those seen with conventional paclitaxel, and (iii) the intracellular paclitaxel levels were higher in MCF-7 cells treated with the liposomal paclitaxel formulation. The results of these studies showed that delivery of paclitaxel as a liposomal formulation could be a promising strategy for enhancing its chemotherapeutic effects.     

Levels of Selected Trace Elements, Phytohormones, and Sugars in Pseudomonas-Infected Lycopersicum esculantum Mill Plants

The present study investigated the levels of trace elements (Zn, Cu, Fe, Pb, and Cd), major elements (Ca and K), phytohormones (trans-Zeatin [t-Z] and gibberellic acid [GA]), and sugars (sucrose and glucose) following inoculation with Pseudomonas syringae pv. tomato strain. The results of the trace elements analysis showed that Fe (in the first, fourth, eighth, and tenth study days), Cd (in the fourth, eighth, and tenth study days), Cu (in the fourth and eighth study days), and Zn (in the eighth and tenth study days) increased in bacterium-infected tomato plants, compared to healthy plants. The levels of Pb, Ca, and K did not meaningfully determine a change after inoculation with pathogen. In this vein, the increase accumulation rates of Cu, Zn, and Fe in the injured plants can be an important indicator for the plant defense processes towards pathogen attack. Furthermore, in the first, fourth, eighth, and tenth study days, the glucose and sucrose contents crucially decreased in bacterium-infected plants compared to the control groups. The lowest level of sucrose in bacterium-infected plants was observed on the first day. The findings displayed that, when endogenous t-Z levels did not change after inoculation with virulent bacterium strain, there was a reduction in the first, fourth, eighth, and tenth days in the level of GA when compared with the control group levels. Therefore, there may be a link between lower GA level and enhancement in the expression of defense-related genes. The results of this study showed that there are complex relationships among levels of sugar, trace element, and endogenous phytohormone in the regulation of defense mechanisms against bacterial pathogen attacks.     

The Involvement of IL-17A in the Murine Response to Sub-Lethal Inhalational Infection with Francisella tularensis

Background

Francisella tularensis is an intercellular bacterium often causing fatal disease when inhaled. Previous reports have underlined the role of cell-mediated immunity and IFNγ in the host response to Francisella tularensis infection.

Methodology/Principal Findings

Here we provide evidence for the involvement of IL-17A in host defense to inhalational tularemia, using a mouse model of intranasal infection with the Live Vaccine Strain (LVS). We demonstrate the kinetics of IL-17A production in lavage fluids of infected lungs and identify the IL-17A-producing lymphocytes as pulmonary γδ and Th17 cells. The peak of IL-17A production appears early during sub-lethal infection, it precedes the peak of immune activation and the nadir of the disease, and then subsides subsequently. Exogenous airway administration of IL-17A or of IL-23 had a limited yet consistent effect of delaying the onset of death from a lethal dose of LVS, implying that IL-17A may be involved in restraining the infection. The protective role for IL-17A was directly demonstrated by in vivo neutralization of IL-17A. Administration of anti IL-17A antibodies concomitantly to a sub-lethal airway infection with 0.1×LD₅₀ resulted in a fatal disease.

Conclusion

In summary, these data characterize the involvement and underline the protective key role of the IL-17A axis in the lungs from inhalational tularemia.     

Iterative Structure-Based Peptide-Like Inhibitor Design against the Botulinum Neurotoxin Serotype A

The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their K_i values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2′ position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors.     

Infusion of a Lipid Emulsion Modulates AMPK and Related Proteins in Rat Liver,Muscle, and Adipose Tissues

The primary objective of this study was to investigate the impact of lipid oversupply on the AMPK pathway in skeletal muscle, liver, and adipose tissue. Male Wistar rats were infused with lipid emulsion (LE) or phosphate‐buffered saline for 5 h/day for 6 days. Muscles exposed to LE for 6 days exhibited increased AMPK and acetyl‐CoA carboxylase (ACC) phosphorylation, along with a greater association between AMPK and Ca²⁺/calmodulin‐dependent protein kinase kinase (CaMKK). No differences in muscle protein phosphatase 2C (PP2C) activity, LKB1 phosphorylation or AMPK and LKB1 association were observed. Muscle ACCβ, and adiponectin receptor 1 (AdipoR1) mRNA levels and PPARγ‐co‐activator 1α (PGC1α) protein levels were also increased in LE‐treated rats. In contrast, AMPK and ACC phosphorylation decreased and PP2C activity increased in rat livers exposed to LE. Hepatic mRNA levels of ACCα, PPARα, AdipoR1, AdipoR2, and sterol regulatory element–binding protein‐1c (SREBP1c) were also reduced after LE infusion. In adipose tissue, there was no significant alteration in AMPK or ACC phosphorylation. These results demonstrate that following lipid oversupply the AMPK pathway was enhanced in rat skeletal muscle while diminished in the liver and was unchanged in adipose tissue. CaMKK in skeletal muscle and PP2C in the liver, at least in part, appear to mediate these alterations. Alterations in AMPK pathway in the liver induced metabolic defects associated with lipid oversupply.     

Migration of zebrafish primordial germ cells: a role for myosin contraction and cytoplasmic flow

The molecular and cellular mechanisms governing cell motility and directed migration in response to the chemokine SDF-1 are largely unknown. Here, we demonstrate that zebrafish primordial germ cells whose migration is guided by SDF-1 generate bleb-like protrusions that are powered by cytoplasmic flow. Protrusions are formed at sites of higher levels of free calcium where activation of myosin contraction occurs. Separation of the acto-myosin cortex from the plasma membrane at these sites is followed by a flow of cytoplasm into the forming bleb. We propose that polarized activation of the receptor CXCR4 leads to a rise in free calcium that in turn activates myosin contraction in the part of the cell responding to higher levels of the ligand SDF-1. The biased formation of new protrusions in a particular region of the cell in response to SDF-1 defines the leading edge and the direction of cell migration.     

The role of PKCζ in NMDA-induced retinal ganglion cell death: Prevention by aspirin

Intravitreal NMDA injection has been shown to induce the excitotoxic loss of retinal cells. The retinal ganglion cell apoptosis induced by NMDA is thought to play an important role in retinal ischemia injury and NMDA-injected rat has been used as a model of neuronal loss in diseases such as glaucoma. In this experimental model, we studied the early effects of NMDA leading to the degeneration of retinal ganglion cells. PKCζ regulates the NF-κB pathway in cellular responses to various stresses and we have shown that aspirin inhibits purified human PKCζ. We therefore investigated the molecular mechanism by which retinal cells limit ocular injury following NMDA treatment. We found that the NMDA-induced apoptosis of ganglion cells was mediated, at least partly, by PKCζ. This enzyme was activated early in the cellular response to NMDA. Prolonged activation was followed by PKCζ cleavage, and nuclear translocation of the C-terminal region of this protein—a critical event for the survival of retinal cells. We also found that pretreatment with aspirin or the coinjection of NMDA with a specific PKCζ inhibitor counteracted the effects of NMDA. These findings provide new insight into the role played by PKCζ in neuronal loss in glaucoma.