Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM) host defense and production of lipid mediators during the neonatal period compared to adult AMs.</p> <p>Methods</p> <p>AMs were harvested from young (day 7 and day 14) and adult (~10 week) rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR.</p> <p>Results</p> <p>AMs from young animals (day 7 and 14) were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF)- α. In addition, young AMs produce more prostaglandin (PG) E₂, a suppressor of host defense, and less leukotriene (LT) B₄, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE₂and LTB₄; however, there was no change in the expression of E prostanoid (EP) receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE₂as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE₂by aspirin nor the addition of exogenous LTB₄rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7) AMs compared to adult AMs.</p> <p>Conclusion</p> <p>These results suggest that elevated production of PGE₂and decreased production of LTB₄do not contribute to impaired opsonized macrophage phagocytosis and highlight an important difference between young and adult AMs.</p

Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase

BACKGROUND: For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally.The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. RESULTS: In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. CONCLUSION: These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency &gt;3%, and were also present in the mutant library, had fitness levels that were &gt;40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Satisfaction with Creativity: A Study of Organizational Characteristics and Individual Motivation

In answering the question of what influences satisfaction with creativity in the workplace, this work takes into account the extent to which the organization supports human aspiration to act creatively. The work throughout reflects a pragmatist approach to creativity and fulfillment, bridging it with needs theory in psychology. The empirical model uses survey data encompassing over 4,000 workers in Italian social enterprises. Results show that satisfaction with creativity is supported, at organizational level, by teamwork, autonomy, domain-relevant competences, as well as by inclusive, fair processes and relationships. At the individual level, satisfaction with creativity is enhanced by the strength of intrinsic initial motivations. The analysis of interaction terms shows that teamwork and workers' initial motivations are complementary in enhancing satisfaction with creativity, while a high degree of domain-relevant competences appears to substitute advice and supervision by superiors in accomplishing the desired level of creative action

Public Versus Private: Does It Matter for Water Conservation? Insights from California

This article asks three connected questions: First, does the public view private and public utilities differently, and if so, does this affect attitudes to conservation? Second, do public and private utilities differ in their approaches to conservation? Finally, do differences in the approaches of the utilities, if any, relate to differences in public attitudes? We survey public attitudes in California toward (hypothetical but plausible) voluntary and mandated water conservation, as well as to price increases, during a recent period of shortage. We do this by interviewing households in three pairs of adjacent public and private utilities. We also survey managers of public and private urban water utilities to see if they differ in their approaches to conservation and to their customers. On the user side we do not find pronounced differences, though a minority of customers in all private companies would be more willing to conserve or pay higher prices under a public operator. No respondent in public utility said the reverse. Negative attitudes toward private operators were most pronounced in the pair marked by a controversial recent privatization and a price hike. Nonetheless, we find that California’s history of recurrent droughts and the visible role of the state in water supply and drought management undermine the distinction between public and private. Private utilities themselves work to underplay the distinction by stressing the collective ownership of the water source and the collective value of conservation. Overall, California’s public utilities appear more proactive and target-oriented in asking their customers to conserve than their private counterparts and the state continues to be important in legitimating and guiding conservation behavior, whether the utility is in public hands or private

Prevalence of bullying and aggressive behavior and their relationship to mental health problems among 12- to 15-year-old Norwegian adolescents

The aim of this study was to examine the relationships between being bullied and aggressive behavior and self-reported mental health problems among young adolescents. A representative population sample of 2,464 young Norwegian adolescents (50.8% girls) aged 12–15 years was assessed. Being bullied was measured using three items concerning teasing, exclusion, and physical assault. Self-esteem was assessed by Harter’s self-perception profile for adolescents. Emotional and behavioral problems were measured by the Moods and Feelings Questionnaire (MFQ) and the youth self-report (YSR). Aggressive behavior was measured by four items from the YSR. One-tenth of the adolescents reported being bullied, and 5% reported having been aggressive toward others during the past 6 months. More of the students being bullied and students being aggressive toward others reported parental divorce, and they showed higher scores on all YSR subscales and on the MFQ questions, and lower scores on the global self-worth subscale (Harter) than students not being bullied or aggressive. A few differences emerged between the two groups being bullied or being aggressive toward others: those who were aggressive showed higher total YSR scores, higher aggression and delinquency scores, and lower social problems scores, and reported higher scores on the social acceptance subscale (Harter) than bullied students. However, because social problems were demonstrated in both the involved groups, interventions designed to improve social competence and interaction skills should be integrated in antibullying programs

Is Mate Choice in Humans MHC-Dependent?

In several species, including rodents and fish, it has been shown that the Major Histocompatibility Complex (MHC) influences mating preferences and, in some cases, that this may be mediated by preferences based on body odour. In humans, the picture has been less clear. Several studies have reported a tendency for humans to prefer MHC-dissimilar mates, a sexual selection that would favour the production of MHC-heterozygous offspring, who would be more resistant to pathogens, but these results are unsupported by other studies. Here, we report analyses of genome-wide genotype data (from the HapMap II dataset) and HLA types in African and European American couples to test whether humans tend to choose MHC-dissimilar mates. In order to distinguish MHC-specific effects from genome-wide effects, the pattern of similarity in the MHC region is compared to the pattern in the rest of the genome. African spouses show no significant pattern of similarity/dissimilarity across the MHC region (relatedness coefficient, R = 0.015, p = 0.23), whereas across the genome, they are more similar than random pairs of individuals (genome-wide R = 0.00185, p<10−3). We discuss several explanations for these observations, including demographic effects. On the other hand, the sampled European American couples are significantly more MHC-dissimilar than random pairs of individuals (R = −0.043, p = 0.015), and this pattern of dissimilarity is extreme when compared to the rest of the genome, both globally (genome-wide R = −0.00016, p = 0.739) and when broken into windows having the same length and recombination rate as the MHC (only nine genomic regions exhibit a higher level of genetic dissimilarity between spouses than does the MHC). This study thus supports the hypothesis that the MHC influences mate choice in some human populations

A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients.</p> <p>Methods</p> <p>The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays.</p> <p>Results</p> <p>Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; <it>p </it>= 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; <it>p </it>= 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (<it>p</it>-values > 0.05).</p> <p>Conclusions</p> <p>For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.</p