The RIX domain defines a class of polymorphic T6SS effectors and secreted adaptors.

Bacteria use the type VI secretion system (T6SS) to deliver toxic effectors into bacterial or eukaryotic cells during interbacterial competition, host colonization, or when resisting predation. Identifying effectors is a challenging task, as they lack canonical secretion signals or universally conserved domains. Here, we identify a protein domain, RIX, that defines a class of polymorphic T6SS cargo effectors. RIX is widespread in the Vibrionaceae family and is located at N-termini of proteins containing diverse antibacterial and anti-eukaryotic toxic domains. We demonstrate that RIX-containing proteins are delivered via T6SS into neighboring cells and that RIX is necessary and sufficient for T6SS-mediated secretion. In addition, RIX-containing proteins can enable the T6SS-mediated delivery of other cargo effectors by a previously undescribed mechanism. The identification of RIX-containing proteins significantly enlarges the repertoire of known T6SS effectors, especially those with anti-eukaryotic activities. Furthermore, our findings also suggest that T6SSs may play an underappreciated role in the interactions between vibrios and eukaryotes.

Metabolomic analysis of Trichophyton rubrum and Microsporum canis during keratin degradation.

Keratin is important and needed for the growth of dermatophytes in the host tissue. In turn, the ability to invade keratinised tissues is defined as a pivotal virulence attribute of this group of medically important fungi. The host-dermatophyte interaction is accompanied by an adaptation of fungal metabolism that allows them to adhere to the host tissue as well as utilize the available nutrients necessary for their survival and growth. Dermatophyte infections pose a significant epidemiological and clinical problem. Trichophyton rubrum is the most common anthropophilic dermatophyte worldwide and its typical infection areas include skin of hands or feet and nail plate. In turn, Microsporum canis is a zoophilic pathogen, and mostly well known for ringworm in pets, it is also known to infect humans. The aim of the study was to compare the intracellular metabolite content in the T. rubrum and M. canis during keratin degradation using liquid chromatography system coupled with tandem mass spectrometer (LC-MS/MS). The metabolite "fingerprints" revealed compounds associated with amino acids metabolism, carbohydrate metabolism related to the glycolysis and the tricarboxylic acid cycle (TCA), as well as nucleotide and energy metabolism. The metabolites such as kynurenic acid, L-alanine and cysteine in case of T. rubrum as well as cysteine and riboflavin in case of M. canis were detected only during keratin degradation what may suggest that these compounds may play a key role in the interactions of T. rubrum and M. canis with the host tissue. The metabolomic results were completed by qPCR gene expression assay. Our findings suggest that metabolomic analysis of T. rubrum and M. canis growing in culture media that mimic the dermatophyte infection could allow the understanding of processes involved in the pathogenesis of dermatophytes.

A sequencing-based survey of functional APAF1 alleles in a large sample of individuals with affective illness and population controls.

Rare apoptosis-promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co-segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re-sequencing in a large sample of northern European and European-American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76-85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European-American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.

Relationship of the Met allele of the brain-derived neurotrophic factor Val66Met polymorphism to memory after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to be related to variability in episodic memory. We studied whether the Met allele is associated with poor learning and memory in survivors of aneurysmal subarachnoid hemorrhage (SAH). METHODS: Ninety-six patients were examined with a neuropsychological test battery approximately 1 year after SAH. Their deoxyribonucleic acid samples were genotyped for the BDNF Val66Met polymorphism. The Met carriers were compared to the Val/Val homozygous patients on the test performances. RESULTS: In the total sample, there was no difference between the genotype groups. However, among the patients with no cerebral infarction, the Met carriers had inferior learning and memory performance than the Val/Val homozygotes, but the groups did not differ on the nonmemory test performances. The patients with left and bilateral infarctions had deficits in verbal memory, which may have concealed the effect of the BDNF Val66Met polymorphism on memory in the total sample. CONCLUSION: As a whole, the BDNF Val66Met polymorphism was not associated with learning and memory performance in patients recovering from SAH. However, the Met allele might predict poor memory function among patients with SAH not complicated by a cerebral infarction. These findings support earlier reports of an association between the Met allele and low memory performance. Longitudinal studies comparing functional recovery from SAH between Met and Val/Val patients without cerebral infarctions are warranted.

The Met allele of the BDNF Val66Met polymorphism predicts poor outcome among survivors of aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF) plays a role in neuronal survival, plasticity and neurogenesis. The BDNF gene contains a common Val66Met polymorphism; the Met allele is associated with lower depolarization-induced BDNF release and differences in memory functions and brain morphology. We hypothesized that the Met allele is associated with poor recovery from subarachnoid hemorrhage. METHODS: A sample of 105 survivors was assessed at 3 months after subarachnoid hemorrhage using Glascow Outcome Scale. Poor outcome was defined as severe disability or worse. DNA samples were genotyped for the Val66Met polymorphism. RESULTS: Higher percentage of the Met carriers had a poor outcome (29%) as compared with the Val/Val group (10%; P=0.011). In multiple logistic regression, this association between the Met allele and poor outcome was independent of several other prognostic factors such as patient age, clinical condition, and radiological severity of the bleeding (odds ratio 8.40; 95% CI, 1.60 to 44.00; P=0.012). CONCLUSIONS: Genetically influenced variation in BDNF function plays a role in recovery from subarachnoid hemorrhage. These data indicate that augmentation of BDNF signaling may be beneficial to recovery from brain injury.