Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

Changes in Cognition and Mortality in Relation to Exercise in Late Life: A Population Based Study

BACKGROUND: On average, cognition declines with age but this average hides considerable variability, including the chance of improvement. Here, we investigate how exercise is associated with cognitive change and mortality in older people and, particularly, whether exercise might paradoxically increase the risk of dementia by allowing people to live longer. METHODS AND PRINCIPAL FINDINGS: In the Canadian Study of Health and Aging (CSHA), of 8403 people who had baseline cognition measured and exercise reported at CSHA-1, 2219 had died and 5376 were re-examined at CSHA-2. We used a parametric Markov chain model to estimate the probabilities of cognitive improvement, decline, and death, adjusted for age and education, from any cognitive state as measured by the Modified Mini-Mental State Examination. High exercisers (at least three times per week, at least as intense as walking, n = 3264) had more frequent stable or improved cognition (42.3%, 95% confidence interval: 40.6-44.0) over 5 years than did low/no exercisers (all other exercisers and non exercisers, n = 4331) (27.8% (95% CI 26.4-29.2)). The difference widened as baseline cognition worsened. The proportion whose cognition declined was higher amongst the high exercisers but was more similar between exercise groups (39.4% (95% CI 37.7-41.1) for high exercisers versus 34.8% (95% CI 33.4-36.2) otherwise). People who did not exercise were also more likely to die (37.5% (95% CI 36.0-39.0) versus 18.3% (95% CI 16.9-19.7)). Even so, exercise conferred its greatest mortality benefit to people with the highest baseline cognition. CONCLUSIONS: Exercise is strongly associated with improving cognition. As the majority of mortality benefit of exercise is at the highest level of cognition, and declines as cognition declines, the net effect of exercise should be to improve cognition at the population level, even with more people living longer

Effects of Attractiveness and Social Status on Dating Desire in Heterosexual Adolescents: An Experimental Study

The present study examined to what extent adolescent dating desire is based on attractiveness and social status of a potential short-term partner. Further, we tested whether self-perceived mate value moderated the relationship between dating desire and attractiveness of a potential partner. Data were used from a sample of 1,913 adolescents aged 13–18. Participants rated the importance of various characteristics of a potential partner and also participated in an experimental vignette study in which dating desire was measured with either low or high attractive potential partners having either a high or low social status. The results showed that boys rated attractiveness as more important than girls, while social status was rated as relatively unimportant by both sexes. In addition, in the experimental vignette study, it was found that attractiveness was the primary factor for boys’ dating desire. Only when a potential partner was attractive, social status became important for boys’ dating desire. For girls, on the other hand, it appeared that both attractiveness and social status of a potential partner were important for their dating desire. Finally, boys and girls who perceived themselves as having a high mate value showed more dating desire toward an attractive potential partner compared to adolescents who perceived themselves as having a low mate value. The present results extend previous research by showing that attractiveness of a potential partner is important to both adolescent boys and girls, but social status does not strongly affect dating desire during this particular age period

Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration.

Understanding the molecular mechanisms that promote successful tissue regeneration is critical for continued advancements in regenerative medicine. Vertebrate amphibian tadpoles of the species Xenopus laevis and Xenopus tropicalis have remarkable abilities to regenerate their tails following amputation, through the coordinated activity of numerous growth factor signalling pathways, including the Wnt, Fgf, Bmp, Notch and TGF-β pathways. Little is known, however, about the events that act upstream of these signalling pathways following injury. Here, we show that Xenopus tadpole tail amputation induces a sustained production of reactive oxygen species (ROS) during tail regeneration. Lowering ROS levels, using pharmacological or genetic approaches, reduces the level of cell proliferation and impairs tail regeneration. Genetic rescue experiments restored both ROS production and the initiation of the regenerative response. Sustained increased ROS levels are required for Wnt/β-catenin signalling and the activation of one of its main downstream targets, fgf20 (ref. 7), which, in turn, is essential for proper tail regeneration. These findings demonstrate that injury-induced ROS production is an important regulator of tissue regeneration

Monascus-Fermented Dioscorea Enhances Oxidative Stress Resistance via DAF-16/FOXO in Caenorhabditis elegans

BACKGROUND: Monascus-fermented products are mentioned in an ancient Chinese pharmacopoeia of medicinal food and herbs. Monascus-fermented products offer valuable therapeutic benefits and have been extensively used in East Asia for several centuries. Several biological activities of Monascus-fermented products were recently described, and the extract of Monascus-fermented products showed strong antioxidant activity of scavenging DPPH radicals. To evaluate whether Monascus-fermented dioscorea products have potential as nutritional supplements, Monascus-fermented dioscorea's modulation of oxidative-stress resistance and associated regulatory mechanisms in Caenorhabditis elegans were investigated. PRINCIPAL FINDINGS: We examined oxidative stress resistance of the ethanol extract of red mold dioscorea (RMDE) in C. elegans, and found that RMDE-treated wild-type C. elegans showed an increased survival during juglone-induced oxidative stress compared to untreated controls, whereas the antioxidant phenotype was absent from a daf-16 mutant. In addition, the RMDE reduced the level of intracellular reactive oxygen species in C. elegans. Finally, the RMDE affected the subcellular distribution of the FOXO transcription factor, DAF-16, in C. elegans and induced the expression of the sod-3 antioxidative gene. CONCLUSIONS: These findings suggest that the RMDE acts as an antioxidative stress agent and thus may have potential as a nutritional supplement. Further studies in C. elegans suggest that the antioxidant effect of RMDE is mediated via regulation of the DAF-16/FOXO-dependent pathway

The implementation of the serial trial intervention for pain and challenging behaviour in advanced dementia patients (STA OP!): a clustered randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Pain (physical discomfort) and challenging behaviour are highly prevalent in nursing home residents with dementia: at any given time 45-80% of nursing home residents are in pain and up to 80% have challenging behaviour. In the USA Christine Kovach developed the serial trial intervention (STI) and established that this protocol leads to less discomfort and fewer behavioural symptoms in moderate to severe dementia patients. The present study will provide insight into the effects of implementation of the Dutch version of the STI-protocol (STA OP!) in comparison with a control intervention, not only on behavioural symptoms, but also on pain, depression, and quality of life. This article outlines the study protocol.</p> <p>Methods/Design</p> <p>The study is a cluster randomized controlled trial in 168 older people (aged >65 years) with mild or moderate dementia living in nursing homes. The clusters, Dutch nursing homes, are randomly assigned to either the intervention condition (training and implementation of the STA OP!-protocol) or the control condition (general training focusing on challenging behaviour and pain, but without the step-wise approach). Measurements take place at baseline, after 3 months (end of the STA OP! training period) and after 6 months.</p> <p>Primary outcome measures are symptoms of challenging behaviour (measured with the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory-Nursing Home version (NPI-NH)), and pain (measure with the Dutch version of the Pain Assessment Checklist for Seniors (PACSLAC-D) and the Minimum Data Set of the Resident Assessment Instrument (MDS-RAI) pain scale). Secondary outcome measures include symptoms of depression (Cornell and MDS-RAI depression scale), Quality of Live (Qualidem), changes in prescriptions of analgesics and psychotropic drugs, and the use of non-pharmacological comfort interventions (e.g. snoezelen, reminiscence therapy).</p> <p>Discussion</p> <p>The transfer from the American design to the Dutch design involved several changes due to the different organisation of healthcare systems. Specific strengths and limitations of the study are discussed.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1967">NTR1967</a></p

Comparing the Invasibility of Experimental “Reefs” with Field Observations of Natural Reefs and Artificial Structures

Natural systems are increasingly being modified by the addition of artificial habitats which may facilitate invasion. Where invaders are able to disperse from artificial habitats, their impact may spread to surrounding natural communities and therefore it is important to investigate potential factors that reduce or enhance invasibility. We surveyed the distribution of non-indigenous and native invertebrates and algae between artificial habitats and natural reefs in a marine subtidal system. We also deployed sandstone plates as experimental ‘reefs’ and manipulated the orientation, starting assemblage and degree of shading. Invertebrates (non-indigenous and native) appeared to be responding to similar environmental factors (e.g. orientation) and occupied most space on artificial structures and to a lesser extent reef walls. Non-indigenous invertebrates are less successful than native invertebrates on horizontal reefs despite functional similarities. Manipulative experiments revealed that even when non-indigenous invertebrates invade vertical “reefs”, they are unlikely to gain a foothold and never exceed covers of native invertebrates (regardless of space availability). Community ecology suggests that invertebrates will dominate reef walls and algae horizontal reefs due to functional differences, however our surveys revealed that native algae dominate both vertical and horizontal reefs in shallow estuarine systems. Few non-indigenous algae were sampled in the study, however where invasive algal species are present in a system, they may present a threat to reef communities. Our findings suggest that non-indigenous species are less successful at occupying space on reef compared to artificial structures, and manipulations of biotic and abiotic conditions (primarily orientation and to a lesser extent biotic resistance) on experimental “reefs” explained a large portion of this variation, however they could not fully explain the magnitude of differences

The Interaction Between Pubertal Timing and Peer Popularity for Boys and Girls: An Integration of Biological and Interpersonal Perspectives on Adolescent Depression

The transition to adolescence marks a time of sharply increased vulnerability to the development of depression, particularly among girls. Past research has examined isolated risk factors from individual theoretical models (e.g., biological, interpersonal, and cognitive) of depression, but few have examined integrative models. This study investigated the conjoint effects of early pubertal timing and popularity in the longitudinal prediction of depressive symptoms. A total of 319 girls and 294 boys (ages 11–14) provided information on their pubertal status, depressive symptoms, and the social status (i.e., popularity) of their peers. Adolescents completed a second measure of depressive symptoms 11 months after the initial time point. Findings supported an integrated biological-interpersonal model in explaining the development of depressive symptoms during adolescence. Early pubertal development was associated with increase in depressive symptoms only when accompanied by low levels of popularity. High levels of popularity buffered the association between early pubertal development and later depressive symptoms. Unexpectedly, these results were significant both for girls and boys. Results are discussed in terms of dynamic systems theories