The Loss of Functional Caspase-12 in Europe Is a Pre-Neolithic Event

Contains fulltext : 109878.pdf (publisher's version ) (Open Access)BACKGROUND: Caspase-12 (CASP12) modulates the susceptibility to sepsis. In humans, the "C" allele at CASP12 rs497116 has been associated with an increased risk of sepsis. Instead, the derived "T" allele encodes for an inactive caspase-12. Interestingly, Eurasians are practically fixed for the inactive variant, whereas in Sub-Saharan Africa the active variant is still common (~24%). This marked structure has been explained as a function of the selective advantage that the inactive caspase-12 confers by increasing resistance to infection. As regards to both when positive selection started acting and as to the speed with which fixation was achieved in Eurasia, estimates depend on the method and assumptions used, and can vary substantially. Using experimental evidence, we propose that, least in Eurasia, the increase in the frequency of the T allele might be related to the selective pressure exerted by the increase in zoonotic diseases transmission caused by the interplay between increased human population densities and a closer contact with animals during the Neolithic. METHODOLOG/PRINCIPAL FINDINGS: We genotyped CASP12 rs497116 in prehistoric individuals from 6 archaeological sites from the North of the Iberian Peninsula that date from Late Upper Paleolithic to Late Neolithic. DNA extraction was done from teeth lacking cavities or breakages using standard anti-contamination procedures, including processing of the samples in a positive pressure, ancient DNA-only chamber, quantitation of DNAs by qPCR, duplication, replication, genotyping of associated animals, or cloning of PCR products. Out of 50, 24 prehistoric individuals could finally be genotyped for rs497116. Only the inactive form of CASP12 was found. CONCLUSIONS/SIGNIFICANCE: We demonstrate that the loss of caspase-12 in Europe predates animal domestication and that consequently CASP12 loss is unlikely to be related to the impact of zoonotic infections transmitted by livestock

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors

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V-akt murine thymoma viral oncogene homolog 3 (AKT3) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Here, we have performed a prospective nationwide genetic association study using the Human Exome BeadChip and identified gene variants in encoding dynactin 4 (DCTN4), retinoic acid early transcript 1E (RAET1E), and V-akt murine thymoma viral oncogene homolog 3 (AKT3) to be associated with unfavourable outcome in patients with pneumococcal meningitis. No clinical replication cohort is available, so we validated the role of one of these targets, AKT3, in a pneumococcal meningitis mouse model. Akt3 deficient mice had worse survival and increased histopathology scores for parenchymal damage (infiltration) and vascular infiltration (large meningeal artery inflammation) but similar bacterial loads, cytokine responses, compared to wild-type mice. We found no differences in cerebrospinal fluid cytokine levels between patients with risk or non-risk alleles. Patients with the risk genotype (rs10157763, AA) presented with low scores on the Glasgow Coma Scale and high rate of epileptic seizures. Thus, our results show that AKT3 influences outcome of pneumococcal meningiti

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts

Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery

Viininmaistelun alkeet -tapahtuma Maria P:ssä

Tiivistelmä Tekijät: Paananen Riina ja Korkiakoski Merika Työn nimi: Viininmaistelun alkeet -tapahtuma Maria P:ssä Tutkintonimike: Restonomi (AMK), matkailun koulutus Asiasanat: tapahtuma, viini, viininmaistelu, Chile Opinnäytetyön tarkoituksena oli suunnitella ja järjestää Viininmaistelun alkeet -tapahtuma. Tapahtuman toimeksiantajana toimi kajaanilainen yritys Viinibaari Maria P. Tapahtuma haluttiin toteuttaa baarin imagoon sopivaksi. Opinnäytetyön tavoitteena oli saada Viini-baarille lisää asiakkaita tutustuttamalla kokemattomia viininmaistajia viineihin. Työ oli toiminnallinen opinnäytetyö, jonka tuotoksena oli Viininmaistelun alkeet -tapahtuma. Opinnäytetyöhön kerättiin teoriapohjaa viininmaistelusta sekä viinin ja ruoan yhdistämisestä, Chilestä viinimaana ja tapahtuman järjestämisestä. Näitä kaikkia käytettiin lopullisen tuotoksen valmistumiseen. Toteutuksen arviointina toimi tapahtumaan osallistuneilta saatu kirjallinen palaute. Palautteen mukaan kehittämistehtävän toteutuksessa onnistuttiin hyvin, sillä opinnäytetyön ennalta määritellyt tavoitteet saavutettiin. Opinnäytetyötä voidaan käyttää apuna jatkossa vastaavien tapahtumien suunnittelussa.Abstract Authors: Paananen Riina & Korkiakoski Merika Title of the Publication: Basics of wine tasting- event Degree title: Bachelor of Hospitality Management Keywords: event, wine, tasting, Chile The purpose for this thesis was to plan and arrange Basics of wine tasting –event. The commissioner for this thsesis was a local bar in Kajaani called Viinibaari Maria P. The event was planned to suit the imago of the bar. The objective of the thesis was to gain more customers to Viinibaari Maria P by introducing various wines to novice wine tasters. This research was a functional thesis which produced the Basics wine tasting event. The theory of this thesis focused on wine tasting, combining wine and food, Chile as a wine producer, and on planning and arranging an event. The feedback for the execution consists of the feedback forms that the customers of the event were asked to fill in. In addition observation method was used for evaluation. According to the feedback the event was successful because the objective of the thesis was reached. Our conclusion is that this thesis can be used as a guide in planning similar events

Large scale genomic analysis shows no evidence for pathogen adaptation between the blood and cerebrospinal fluid niches during bacterial meningitis.

Recent studies have provided evidence for rapid pathogen genome diversification, some of which could potentially affect the course of disease. We have previously described such variation seen between isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis. Here, we performed whole-genome sequencing of paired isolates from the blood and CSF of 869 meningitis patients to determine whether such variation frequently occurs between these two niches in cases of bacterial meningitis. Using a combination of reference-free variant calling approaches, we show that no genetic adaptation occurs in either invaded niche during bacterial meningitis for two major pathogen species, Streptococcus pneumoniae and Neisseria meningitidis. This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood-brain barrier. Our findings place the focus back on bacterial evolution between nasopharyngeal carriage and invasion, or diversity of the host, as likely mechanisms for determining invasiveness

Recognition and blocking of innate immunity cells by Candida albicans chitin

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STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency

Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel