TLR signaling is required for Salmonella typhimurium virulence

Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulence mechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S. typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicate that S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.     

Wolbachia in Anastrepha Fruit Flies (Diptera: Tephritidae)

Endosymbiotic bacteria of the genus Wolbachia are widespread among arthropods and cause a variety of reproductive abnormalities, such as cytoplasmic incompatibility, thelytokous parthenogenesis, male-killing, and host feminization. In this study, we used three sets of Wolbachia-specific primers (16S rDNA, ftsZ, and wsp) in conjunction with the polymerase chain reaction (PCR), cloning and sequencing to study the infection of fruit flies (Anastrepha spp. and Ceratitis capitata) by Wolbachia. The flies were collected at several localities in Brazil and at Guayaquil, Ecuador. All of the fruit flies studied were infected with Wolbachia supergroup A, in agreement with the high prevalence of this group in South America. Phylogenetic analysis showed that the wsp gene was the most sensitive gene for studying the relationships among Wolbachia strains. The Wolbachia sequences detected in these fruit flies were similar to those such as wMel reported for other fruit flies. These results show that the infection of Anastrepha fruit flies by Wolbachia is much more widespread than previously thought.     

Polyparasite Helminth Infections and Their Association to Anaemia and Undernutrition in Northern Rwanda

Background

Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals.

Methods

Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished.

Findings

Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting.

Conclusion

The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country.     

Redirection of flux through the phenylpropanoid pathway by increased glucosylation of soluble intermediates

The phenylpropanoid pathway is used in biosynthesis of a wide range of soluble secondary metabolites including hydroxycinnamic acid esters, flavonoids and the precursors of lignin and lignans. In Arabidopsis thaliana a small cluster of three closely related genes, UGT72E1-E3, encode glycosyltransferases (GTs) that glucosylate phenylpropanoids in vitro. This study explores the effect of constitutively over-expressing two of these GTs (UGT72E1 and E3) in planta using the CaMV-35S promoter to determine whether phenylpropanoid homeostasis can be altered in a similar manner to that achieved by over-expression of UGT72E2 as previously reported. The data show that impact of over-expressing UGT72E3 in leaves is highly similar to that of UGT72E2 in that the production of massive levels of coniferyl and sinapyl alcohol 4-O-glucosides and a substantial loss in sinapoyl malate. In contrast, the over-expression of UGT72E1 in leaves led only to minimal changes in coniferyl alcohol 4-O-glucoside and no effect was observed on sinapoyl malate levels. In roots, over-expression of both UGTs led to some increase in the accumulation of the two glucosides. The cell specificity expression of the whole UGT72E gene cluster was investigated and interestingly only UGT72E3 was found to be wound and touch responsive.     

Prematurity and adult minor illness

The long term impact of being born premature has received limited scientific investigation. Studies that have been carried out, focus on outcomes in childhood, with very few considering the impact on adult physical health. Three case studies are presented here, investigating differences in adult minor illness and psychological variables between adult participants born preterm, fullterm but small and fullterm with normal birthweight. This is a retrospective design using questionnaires and checklist to gather relevant information. Minor illness symptoms, daily hassles, anxiety, depression and general self-efficacy were measured. The participant born preterm scored higher on all measures. Data were applied to the Equilibrium Model for Minor Illness. Being born early appears to have a greater impact on later adult outcomes measured than being born fullterm but small or fullterm but of normal weight. In this article the authors reflect upon possible explanations for the different outcomes of each of the participants within the foetal origins of disease theory.     

Discovery of novel PTP1b inhibitors

A small library of 19 compounds was designed based on unique structural features of PTP1b. Utilizing electrospray ionization mass spectrometry (ESI-MS) to provide binding information about complexes of enzyme and small molecule ligands, two classes of lead compounds were discovered.     

Sexes show differential tolerance to spittlebug damage and consequences of damage for multi-species interactions

Antagonists can play a role in sexual system evolution if tolerance or resistance is sex-dependent. Our understanding of this role will be enhanced by consideration of the effects of antagonists on other plant-animal interactions. This study determined whether the sex morphs of a gynodioecious Fragaria virginiana differ in their susceptibility and response to damage by spittlebugs and whether damage altered pollinator attraction traits or interactions with other antagonists. Tolerance, but not resistance, to spittlebugs differed between the sexes. Generally, spittlebugs were more damaging to hermaphrodites than females, a finding in accord with the hypothesis that the pollen-bearing morph is less tolerant of source-damage than the pollen-sterile morph when damage is incurred during flowering. In both sex morphs, spittlebugs reduced inflorescence height, increased petal size, but did not affect the number of open flowers per day, suggesting that the net effect of damage may be to increase pollinator attraction. Spittlebug infestation modified interactions with other antagonists in a sex-dependent manner: spittlebugs reduced attack by bud-clipping weevils in hermaphrodites but increased infection by leaf fungi in females. The complex interactions between plant sex, antagonists, and pollinator attraction documented here emphasize the importance of considering sex-differential multi-species interactions in plant sexual evolution.     

Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator

The growth of an individual is deeply influenced by the regulation of cell growth and division, both of which also contribute to a wide variety of pathological conditions, including cancer, diabetes, and inflammation. To identify a major regulator of human growth, we performed positional cloning in an autosomal recessive type of profound short stature, anauxetic dysplasia. Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis. We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage hair hypoplasia founder mutation affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin messenger RNA (mRNA) levels but do severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.     

Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations

We identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing NSD1 (referred to as "NSD1-positive individuals"), through analyses of 530 subjects with diverse phenotypes. Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (P < 2 x 10(-16)). Sotos syndrome was clinically diagnosed in 99% of NSD1-positive individuals, independent of the molecular analyses, indicating that NSD1 aberrations are essentially specific to this condition. Furthermore, our data suggest that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. We reviewed the clinical phenotypes of 239 NSD1-positive individuals. Facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of the individuals. However, both the height and head circumference of 10% of the individuals were within the normal range, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype, since individuals with identical mutations had different phenotypes. We compared the phenotypes of patients with intragenic NSD1 mutations with those of patients with 5q35 microdeletions. Patients with microdeletions had less-prominent overgrowth (P = .0003) and more-severe learning disability (P = 3 x 10(-9)) than patients with mutations. However, all features present in patients with microdeletions were also observed in patients with mutations, and there was no correlation between deletion size and the clinical phenotype, suggesting that the deletion of additional genes in patients with 5q35 microdeletions has little specific effect on phenotype. We identified only 13 familial cases. The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases (P = .005) to carry missense mutations, suggesting that the underlying NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness.