Novel, synergistic antifungal combinations that target translation fidelity

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8 fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone

The malarial exported PFA0660w is an Hsp40 co-chaperone of PfHsp70-x

Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentrationdependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria

Sfrp Controls Apicobasal Polarity and Oriented Cell Division in Developing Gut Epithelium

Epithelial tubular morphogenesis leading to alteration of organ shape has important physiological consequences. However, little is known regarding the mechanisms that govern epithelial tube morphogenesis. Here, we show that inactivation of Sfrp1 and Sfrp2 leads to reduction in fore-stomach length in mouse embryos, which is enhanced in the presence of the Sfrp5 mutation. In the mono-cell layer of fore-stomach epithelium, cell division is normally oriented along the cephalocaudal axis; in contrast, orientation diverges in the Sfrps-deficient fore-stomach. Cell growth and apoptosis are not affected in the Sfrps-deficient fore-stomach epithelium. Similarly, cell division orientation in fore-stomach epithelium diverges as a result of inactivation of either Stbm/Vangl2, an Fz/PCP component, or Wnt5a. These observations indicate that the oriented cell division, which is controlled by the Fz/PCP pathway, is one of essential components in fore-stomach morphogenesis. Additionally, the small intestine epithelium of Sfrps compound mutants fails to maintain proper apicobasal polarity; the defect was also observed in Wnt5a-inactivated small intestine. In relation to these findings, Sfrp1 physically interacts with Wnt5a and inhibits Wnt5a signaling. We propose that Sfrp regulation of Wnt5a signaling controls oriented cell division and apicobasal polarity in the epithelium of developing gut

Longitudinal Associations Between Perceived Parent-Adolescent Attachment Relationship Quality and Generalized Anxiety Disorder Symptoms in Adolescence

This longitudinal study examined the direction of effects between adolescents’ generalized anxiety disorder (GAD) symptoms and perceived parent-adolescent attachment relationship quality, as well as the moderating role of gender and age. 1,313 Dutch adolescents (48.5% boys) from two age cohorts of early (n = 923, Mage = 12 at W1) and middle (n = 390, Mage = 16 at W1) adolescents completed questionnaires regarding their attachment relationship to parents and GAD symptoms in four waves. Cross-lagged path analyses demonstrated that adolescents’ GAD symptoms and perceived father-adolescent attachment relationship quality bidirectionally negatively affected each other over time. For mothers, adolescents’ GAD symptoms negatively predicted perceived mother-adolescent attachment relationship quality over time. The within-wave correlated residuals between perceived attachment relationship quality with fathers and GAD symptoms were stronger for boys than for girls and stronger for the cohort of middle adolescents than for the cohort of early adolescents. This study demonstrates that both the parents’ and the adolescents’ gender as well as the adolescents’ age affects the relation between adolescents’ GAD symptoms and perceived parent-adolescent attachment relationship quality

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

BACKGROUND Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation. CONCLUSION This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts

Sosiaalisen median toimenpidesuunnitelma

Opinnäytetyön taustalla oli jyväskyläläisen Finlandia Hotelli Alban tarve kehittää toimintaansa sosiaalisessa mediassa. Tavoitteena oli laatia sosiaalisen median toimenpidesuunnitelma Hotelli Alballe. Toimenpidesuunnitelma konkretisoitui sosiaalisen median vuosikelloksi Hotelli Alban henkilökunnalle. Tutkimuksella pyrittiin selvittämään, miten Alban henkilökunnan toimintaa sosiaalisessa mediassa voidaan helpottaa, ja sitä, millaista sisältöä sosiaaliseen mediaan kannattaa tuottaa. Tutkimus tehtiin laadullisella eli kvalitatiivisella tavalla. Aineiston pohjalta laadittiin vuosikello. Osa tutkimukesta toteutettiin haastattelemalla Hotelli Alban asiakkaita. Kohderyhmänä olivat Alban vapaa-ajan matkustajat. Haastattelut toteutettiin Jyväskylässä, Hotelli Albassa, marraskuussa 2019. Haastateltavia henkilöitä oli yhdeksän. Haastatteluiden lisäksi aineistoa kerättiin tekemällä sosiaalisen median kilpailija-analyysi muille jyväskyläläisille hotelleille. Kilpailija-analyysin tuloksia peilattiin myös Hotelli Alban omien Facebook-sivujen web-analytiikkaan. Tutkimus osoitti, että sosiaalisessa mediassa kiinnostavimpia päivitysaiheita ovat kilpailut, tarjoukset sekä henkilökohtaiset esittelyt esimerkiksi hotellin henkilökunnasta. Päivitysten säännöllisyys nousi myös esiin sekä haastateltavien vastauksissa että kilpailija-analyysin tuloksissa. Selkeästi parhaiten sosiaalisessa mediassa menestyivät sellaiset hotellit, joiden toiminnassa oli havaittavissa suunnitelmallisuus ja säännöllisyys. Toimenpidesuunnitelmaksi Hotelli Alballe saatiin laadittua vuosikello ja yleisiä ohjeita, joiden avulla pystytään helpottamaan henkilökunnan sosiaalisen median päivittämistä