TROY (TNFRSF19) is overexpressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling

A critical problem in the treatment of malignant gliomas is the extensive infiltration of individual tumor cells into adjacent brain tissues. This invasive phenotype severely limits all current therapies, and to date, no treatment is available to control the spread of this disease. Members of the tumor necrosis factor (TNF) ligand superfamily and their cognate receptors regulate various cellular responses including proliferation, migration, differentiation, and apoptosis. Specifically, the TNFRSF19/TROY gene encodes a type I cell surface receptor that is expressed on migrating or proliferating progenitor cells of the hippocampus, thalamus, and cerebral cortex. Here, we show that levels of TROY mRNA expression directly correlate with increasing glial tumor grade. Among malignant gliomas, TROY expression correlates inversely with overall patient survival. In addition, we show that TROY overexpression in glioma cells activates Rac1 signaling in a Pyk2-dependent manner to drive glioma cell invasion and migration. Pyk2 coimmunoprecipitates with the TROY receptor, and depletion of Pyk2 expression by short hairpin RNA interference oligonucleotides inhibits TROY-induced Rac1 activation and subsequent cellular migration. These findings position aberrant expression and/or signaling by TROY as a contributor, and possibly as a driver, of the malignant dispersion of glioma cells.     

What shapes intra‐specific variation in home range size? A case study of female roe deer

Spatial distribution in mammals, and thereby home range size, is influenced by many different factors including body size, sex, age, reproductive status, season, availability of forage, availability of water, fragmentation of landscape, trophic level and intra- and inter-specific competition. Using linear mixed models, we looked for factors shaping the variation in size of spring-summer and winter home ranges for 51 radio-collared adult female roe deer at Trois Fontaines forest, Champagne–Ardenne, France (1996–2005). Home range size of females was larger in winter than in spring–summer, decreased with age, and decreased with increasing quality. Females in low quality areas adjusted the size of their home range to include more patches of habitat so that all female deer obtained similar amounts of food resources (total biomass of 6.73±2.34 tons (mean±SE) for each home range). Such adjustments of home range size in response to patchiness of resources led to marked between-female variation in home range size. Our results demonstrate that roe deer females have different tactics of habitat use according to spatial variations in habitat quality so that females get similar food resources in highly productive environments such as the Trois Fontaines forest.     

BMI, body composition, and physical functioning in older adults

Objective: Recent studies have emphasized the importance of muscle and fat mass in relation to age‐related decline in physical function. Our objective was to determine whether BMI, as a surrogate measurement of fat mass, may be used as a measure of risk factor for physical functioning in older adults and whether body composition measurements confer any advantage over BMI. Research Methods and Procedures: Four thousand men and women ≥65 years of age living in the community, stratified by age and sex, underwent the following measurements: body composition by DXA; grip strength; and timed 6‐m walk. Subjects were grouped into five categories of BMI using Asian criteria for health‐related risks, and between‐group differences in physical performance measures and body composition were analyzed using analysis of covariance adjusting for age, physical activity level, and presence of chronic disease. Results: Subjects in the two obese categories had a significantly greater number of instrumental activities of daily living (IADL) impairments compared with the underweight and normal‐weight groups. Those with BMI ≥30 kg/m² had the worst walking performance, and the groups with BMI in the normal and overweight range had optimal performance. Fat mass, but not appendicular muscle mass, was associated with walking speed after adjusting for BMI. Discussion: Fat mass seems to be a more important factor than appendicular muscle mass in determining walking speed in community‐living older adults, even after adjusting for BMI.     

Insertional inactivation of the lpxA gene involved in the biosynthesis of lipid A in Neisseria meningitidis resulted in lpxA/lpxA::aph-3' heterodiploids

The lpxA gene is known to be involved in the biosynthesis of lipid A in Gram-negative bacteria and thought to be an essential gene. However, viable meningococcal lpxA mutants devoid of detectable endotoxin (lipooligosaccharide) have been reported. We characterised such mutants in strains of Neisseria meningitidis belonging to serogroups B and C using molecular and biochemical analysis. While lpxA mutants with no detectable or a low level of lipooligosaccharide could be obtained in N. meningitidis, the simple insertional inactivation of lpxA was not possible. In all mutants, we obtained lpxA/lpxA::aph-3' heterodiploids harbouring one copy of the wild-type lpxA gene and one copy of the inactivated lpxA gene by insertion of the kanamycin resistance cassette, aph-3'. The absence of lipooligosaccharide in these mutants may result from a negative transdominance effect of a truncated LpxA protein on the wild-type LpxA protein.     

Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening

The human opportunistic pathogen Serratia marcescens is a bacterium with a broad host range, and represents a growing problem for public health. Serratia marcescens kills Caenorhabditis elegans after colonizing the nematode's intestine. We used C.elegans to screen a bank of transposon-induced S.marcescens mutants and isolated 23 clones with an attenuated virulence. Nine of the selected bacterial clones also showed a reduced virulence in an insect model of infection. Of these, three exhibited a reduced cytotoxicity in vitro, and among them one was also markedly attenuated in its virulence in a murine lung infection model. For 21 of the 23 mutants, the transposon insertion site was identified. This revealed that among the genes necessary for full in vivo virulence are those that function in lipopolysaccharide (LPS) biosynthesis, iron uptake and hemolysin production. Using this system we also identified novel conserved virulence factors required for Pseudomonas aeruginosa pathogenicity. This study extends the utility of C.elegans as an in vivo model for the study of bacterial virulence and advances the molecular understanding of S.marcescens pathogenicity.     

The NFP locus of Medicago truncatula controls an early step of Nod factor signal transduction upstream of a rapid calcium flux and root hair deformation

Establishment of the Rhizobium-legume symbiosis depends on a molecular dialogue, in which rhizobial nodulation (Nod) factors act as symbiotic signals, playing a key role in the control of specificity of infection and nodule formation. Using nodulation-defective (Nod-) mutants of Medicago truncatula to study the mechanisms controlling Nod factor perception and signalling, we have previously identified five genes that control components of a Nod factor-activated signal transduction pathway. Characterisation of a new M. truncatula Nod- mutant led to the identification of the Nod Factor Perception (NFP) locus. The nfp mutant has a novel phenotype among Nod- mutants of M. truncatula, as it does not respond to Nod factors by any of the responses tested. The nfp mutant thus shows no rapid calcium flux, the earliest detectable Nod factor response of wild-type plants, and no root hair deformation. The nfp mutant is also deficient in Nod factor-induced calcium spiking and early nodulin gene expression. While certain genes controlling Nod factor signal transduction also control the establishment of an arbuscular mycorrhizal symbiosis, the nfp mutant shows a wild-type mycorrhizal phenotype. These data indicate that the NFP locus controls an early step of Nod factor signal transduction, upstream of previously identified genes and specific to nodulation.     

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.     

Reliability of the circadian rhythm of water and macronutrient-rich diets intake in dietary choice

Rats with ad libitum water and the ability to self-select among three macronutrient-rich diets--carbohydrate (CHO), protein (PRO), and lipid (LIP)--show a circadian rhythmicity in their ingestion. The aim of the present study was to determine whether this circadian rhythmicity is reliable from day to day. Eight rats were offered ad libitum water and a choice of three isoenergetic diet rations providing carbohydrate, protein, and lipid. Water and food intake was recorded every 3 h for 7 days. The reliability of the circadian rhythm of water and food intake was assessed by the Intraclass Correlation Coefficient (ICC) and the test-retest reliability using the Pearson's Correlation Coefficient (r). The results showed that the circadian rhythm of water, CHO, and PRO intake are strongly reliable. However, the circadian rhythm of LIP intake is less reproducible. Among the three reliable parameters-water, CHO, and PRO, the circadian rhythm of water intake was the most reproducible over 7 days. This suggests that water intake may be used as a marker of circadian rhythmicity in ingestive behavior.