Cell Invasion by Neisseria meningitidis Requires a Functional Interplay between the Focal Adhesion Kinase, Src and Cortactin

Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells

An upper limit to the photon fraction in cosmic rays above 10^19 eV from the Pierre Auger Observatory

An upper limit of 16% (at 95% c.l.) is derived for the photon fraction in cosmic rays with energies above 10^19 eV, based on observations of the depth of shower maximum performed with the hybrid detector of the Pierre Auger Observatory. This is the first such limit on photons obtained by observing the fluorescence light profile of air showers. This upper limit confirms and improves on previous results from the Haverah Park and AGASA surface arrays. Additional data recorded with the Auger surface detectors for a subset of the event sample, support the conclusion that a photon origin of the observed events is not favoured

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Memory for Emotional Pictures in Patients with Alzheimer's Dementia: Comparing Picture-Location Binding and Subsequent Recognition

Emotional content typically facilitates subsequent memory, known as the emotional enhancement effect. We investigated whether emotional content facilitates spatial and item memory in patients with Alzheimer's dementia (AD). Twenty-three AD patients, twenty-three healthy elderly, and twenty-three young adults performed a picture relocation task and a delayed recognition task with positive, negative, and neutral stimuli. AD patients showed a benefit in immediate spatial memory for positive pictures, while healthy young and older participants did not benefit from emotional content. No emotional enhancement effects on delayed item recognition were seen. We conclude that AD patients may have a memory bias for positive information in spatial memory. Discrepancies between our findings and earlier studies are discussed

Bar graphs of the results of the delayed-match-to sample (WM) task.

<p>(a) Hit – False Alarm Rates for pairs consisting of one neutral and either another neutral or a low- or high arousal picture. (b) Corrected Recognition when considering Valence levels. Particularly pairs containing a low-arousal positive picture were more likely to be correctly remembered. Error bars represent the standard error of mean.</p

Bar graphs of the results of the single-item LTM task.

<p>(a) ‘Hit – False Alarm Rates’ for neutral, low-arousal and high-arousal items in the single item LTM task. No significant differences were found. (b) Corrected Recognition when considering Valence levels. No statistically reliable differences were found.</p

Bar graphs of the results of the associative LTM task.

<p>(a) Proportion Correct for pairs consisting of one neutral picture and another neutral or a low- or high arousal picture. Pairs consisting of high-arousal picture were less likely to be remembered in the LTM task. (b) Proportion Correct when considering Valence levels. Particularly pairs containing high-arousal positive picture were less likely to be remembered. Error bars represent the standard error of mean.</p