Mixed model approaches for the identification of QTLs within a maize hybrid breeding program

Two outlines for mixed model based approaches to quantitative trait locus (QTL) mapping in existing maize hybrid selection programs are presented: a restricted maximum likelihood (REML) and a Bayesian Markov Chain Monte Carlo (MCMC) approach. The methods use the in-silico-mapping procedure developed by Parisseaux and Bernardo (2004) as a starting point. The original single-point approach is extended to a multi-point approach that facilitates interval mapping procedures. For computational and conceptual reasons, we partition the full set of relationships from founders to parents of hybrids into two types of relations by defining so-called intermediate founders. QTL effects are defined in terms of those intermediate founders. Marker based identity by descent relationships between intermediate founders define structuring matrices for the QTL effects that change along the genome. The dimension of the vector of QTL effects is reduced by the fact that there are fewer intermediate founders than parents. Furthermore, additional reduction in the number of QTL effects follows from the identification of founder groups by various algorithms. As a result, we obtain a powerful mixed model based statistical framework to identify QTLs in genetic backgrounds relevant to the elite germplasm of a commercial breeding program. The identification of such QTLs will provide the foundation for effective marker assisted and genome wide selection strategies. Analyses of an example data set show that QTLs are primarily identified in different heterotic groups and point to complementation of additive QTL effects as an important factor in hybrid performance

Crisis Visits and Psychiatric Hospitalizations Among Patients Attending a Community Clinic in Rural Southern California

Ethnic minorities from disadvantaged socioeconomic backgrounds report increased utilization of mental health emergency services; however findings have been inconsistent across ethnic/racial groups. In this study we describe patients who present to a rural crisis unit in Southern California, examine rates of psychiatric hospitalizations across ethnic/racial groups, and investigate factors that are associated with increased psychiatric hospitalizations in this sample. This is a retrospective study of 451 racially and ethnically diverse patients attending a crisis unit in Imperial County, California. Chart review and data abstraction methods were used to characterize the sample and identify factors associated with psychiatric crises and subsequent hospitalizations. The sample was predominantly Latino/Hispanic (58.5%). Based on chart review, common psychosocial stressors which prompted a crisis center visit were: (a) financial problems; (b) homelessness; (c) partner or family conflict; (d) physical and health problems; (e) problems at school/work; (f) medication compliance; (g) aggressive behavior; (h) delusional behavior; (i) addiction and (j) anxiety/depression. Bivariate analyses revealed that Hispanics had a disproportionately lower rate of psychiatric hospitalizations while African Americans had a higher rate. Multivariate analyses which included demographic, clinical and psychosocial stressor variables revealed that being African American, having a psychotic disorder, and presenting as gravely disabled were associated with a higher likelihood of hospitalization while partner/family conflict was associated with a lesser likelihood in this rural community. These data elucidate the need for longitudinal studies to understand the interactions between psychosocial stressors, ethnicity and social support as determinants of psychiatric hospitalizations

Clutch Frequency Affects the Offspring Size-Number Trade-Off in Lizards

Background: Studies of lizards have shown that offspring size cannot be altered by manipulating clutch size in species with a high clutch frequency. This raises a question of whether clutch frequency has a key role in influencing the offspring sizenumber trade-off in lizards. Methodology/Principal Findings: To test the hypothesis that females reproducing more frequently are less likely to tradeoff offspring size against offspring number, we applied the follicle ablation technique to female Eremias argus (Lacertidae) from Handan (HD) and Gonghe (GH), the two populations that differ in clutch frequency. Follicle ablation resulted in enlargement of egg size in GH females, but not in HD females. GH females switched from producing a larger number of smaller eggs in the first clutch to a smaller number of larger eggs in the second clutch; HD females showed a similar pattern of seasonal shifts in egg size, but kept clutch size constant between the first two clutches. Thus, the egg sizenumber trade-off was evident in GH females, but not in HD females. Conclusions/Significance: As HD females (mean = 3.1 clutches per year) reproduce more frequently than do GH females (mean = 1.6 clutches per year), our data therefore validate the hypothesis tested. Our data also provide an inference that maximization of maternal fitness could be achieved in females by diverting a large enough, rather than a higher-than-usual

Heterosis as Investigated in Terms of Polyploidy and Genetic Diversity Using Designed Brassica juncea Amphiploid and Its Progenitor Diploid Species

Fixed heterosis resulting from favorable interactions between the genes on their homoeologous genomes in an allopolyploid is considered analogous to classical heterosis accruing from interactions between homologous chromosomes in heterozygous plants of a diploid species. It has been hypothesized that fixed heterosis may be one of the causes of low classical heterosis in allopolyploids. We used Indian mustard (Brassica juncea, 2n = 36; AABB) as a model system to analyze this hypothesis due to ease of its resynthesis from its diploid progenitors, B. rapa (2n = 20; AA) and B. nigra (2n = 16; BB). Both forms of heterosis were investigated in terms of ploidy level, gene action and genetic diversity. To facilitate this, eleven B. juncea genotypes were resynthesized by hybridizing ten near inbred lines of B. rapa and nine of B. nigra. Three half diallel combinations involving resynthesized B. juncea (11×11) and the corresponding progenitor genotypes of B. rapa (10×10) and B. nigra (9×9) were evaluated. Genetic diversity was estimated based on DNA polymorphism generated by SSR primers. Heterosis and genetic diversity in parental diploid species appeared not to predict heterosis and genetic diversity at alloploid level. There was also no association between combining ability, genetic diversity and heterosis across ploidy. Though a large proportion (0.47) of combinations showed positive values, the average fixed heterosis was low for seed yield but high for biomass yield. The genetic diversity was a significant contributor to fixed heterosis for biomass yield, due possibly to adaptive advantage it may confer on de novo alloploids during evolution. Good general/specific combiners at diploid level did not necessarily produce good general/specific combiners at amphiploid level. It was also concluded that polyploidy impacts classical heterosis indirectly due to the negative association between fixed heterosis and classical heterosis

Projected Loss of a Salamander Diversity Hotspot as a Consequence of Projected Global Climate Change

Background: Significant shifts in climate are considered a threat to plants and animals with significant physiological limitations and limited dispersal abilities. The southern Appalachian Mountains are a global hotspot for plethodontid salamander diversity. Plethodontids are lungless ectotherms, so their ecology is strongly governed by temperature and precipitation. Many plethodontid species in southern Appalachia exist in high elevation habitats that may be at or near their thermal maxima, and may also have limited dispersal abilities across warmer valley bottoms. Methodology/Principal Findings: We used a maximum-entropy approach (program Maxent) to model the suitable climatic habitat of 41 plethodontid salamander species inhabiting the Appalachian Highlands region (33 individual species and eight species included within two species complexes). We evaluated the relative change in suitable climatic habitat for these species in the Appalachian Highlands from the current climate to the years 2020, 2050, and 2080, using both the HADCM3 and the CGCM3 models, each under low and high CO 2 scenarios, and using two-model thresholds levels (relative suitability thresholds for determining suitable/unsuitable range), for a total of 8 scenarios per species. Conclusion/Significance: While models differed slightly, every scenario projected significant declines in suitable habitat within the Appalachian Highlands as early as 2020. Species with more southern ranges and with smaller ranges had larger projected habitat loss. Despite significant differences in projected precipitation changes to the region, projections did no

PKCδ Sensitizes Neuroblastoma Cells to L-Buthionine-Sulfoximine and Etoposide Inducing Reactive Oxygen Species Overproduction and DNA Damage

Neuroblastoma is a type of pediatric cancer. The sensitivity of neuroblastoma (NB) cancer cells to chemotherapy and radiation is inhibited by the presence of antioxidants, such as glutathione (GSH), which is crucial in counteracting the endogenous production of reactive oxygen species (ROS). We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and Protein kinase C (PKC) δ activation. In the present study, we transfected PKCδ in NB cells resistant to oxidative death induced by L-buthionine-S,R-sulfoximine (BSO), a GSH-depleting agent. Cell responses, in terms of ROS production, apoptosis and DNA damage were evaluated. Moreover, PKCδ activation was monitored by analyzing the phosphorylation status of threonine 505 residue, carrying out PKC activity assay and investigating the subcellular localization of the kinase. The cell responses obtained in BSO-resistant cells were also compared with those obtained in BSO-sensitive cells subjected to the same experimental protocol. Our results demonstrate, for the first time, that PKCδ induces DNA oxidation and ROS overproduction leading to apoptosis of BSO-resistant NB cells and potentiates the cytotoxic effects induced by BSO in sensitive cells. Moreover, PKCδ overexpression enhances the sensitivity of NB cells to etoposide, a well-characterised drug, commonly used in neuroblastoma therapy. Altogether our data provide evidence of a pro-oxidant role of PKCδ that might be exploited to design new therapeutic strategies aimed at selective killing of cancer cells and overcoming drug resistance. However, it becomes evident that a more detailed understanding of ROS-mediated signaling in cancer cells is necessary for the development of redox-modulated therapeutic approaches

Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome

Agent-Based Modeling of Endotoxin-Induced Acute Inflammatory Response in Human Blood Leukocytes

Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context. In order to study the underlying complexity of the acute inflammatory response, an agent-based framework is developed that models the emerging host response as the outcome of orchestrated interactions associated with intricate signaling cascades and intercellular immune system interactions.An agent-based modeling (ABM) framework is proposed to study the nonlinear dynamics of acute human inflammation. The model is implemented using NetLogo software. Interacting agents involve either inflammation-specific molecules or cells essential for the propagation of the inflammatory reaction across the system. Spatial orientation of molecule interactions involved in signaling cascades coupled with the cellular heterogeneity are further taken into account. The proposed in silico model is evaluated through its ability to successfully reproduce a self-limited inflammatory response as well as a series of scenarios indicative of the nonlinear dynamics of the response. Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.The ABM framework developed in this study provides insight on the stochastic interactions of the mediators involved in the propagation of endotoxin signaling at the cellular response level. The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components. The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system