Cryptococcus neoformans escape From Dictyostelium amoeba by both WASH-mediated constitutive exocytosis and vomocytosis

Cryptococcus neoformans is an environmental yeast that can cause opportunistic infections in humans. As infecting animals does not form part of its normal life-cycle, it has been proposed that the virulence traits that allow cryptococci to resist immune cells were selected through interactions with environmental phagocytes such as amoebae. Here, we investigate the interactions between C. neoformans and the social amoeba Dictyostelium discoideum. We show that like macrophages, D. discoideum is unable to kill C. neoformans upon phagocytosis. Despite this, we find that the yeast pass through the amoebae with an apparently normal phagocytic transit and are released alive by constitutive exocytosis after ~80 min. This is the canonical pathway in amoebae, used to dispose of indigestible material after nutrient extraction. Surprisingly however, we show that upon either genetic or pharmacological blockage of constitutive exocytosis, C. neoformans still escape from D. discoideum by a secondary mechanism. We demonstrate that constitutive exocytosis-independent egress is stochastic and actin-independent. This strongly resembles the non-lytic release of cryptococci by vomocytosis from macrophages, which do not perform constitutive exocytosis and normally retain phagocytosed material. Our data indicate that vomocytosis is functionally redundant for escape from amoebae, which thus may not be the primary driver for its evolutionary selection. Nonetheless, we show that vomocytosis of C. neoformans is mechanistically conserved in hosts ranging from amoebae to man, providing new avenues to understand this poorly-understood but important virulence mechanism

Nernst branes from special geometry

We construct new black brane solutions in $U(1)$ gauged ${\cal N}=2$ supergravity with a general cubic prepotential, which have entropy density $s\sim T^{1/3}$ as $T \rightarrow 0$ and thus satisfy the Nernst Law. By using the real formulation of special geometry, we are able to obtain analytical solutions in closed form as functions of two parameters, the temperature $T$ and the chemical potential $\mu$. Our solutions interpolate between hyperscaling violating Lifshitz geometries with $(z,\theta)=(0,2)$ at the horizon and $(z,\theta)=(1,-1)$ at infinity. In the zero temperature limit, where the entropy density goes to zero, we recover the extremal Nernst branes of Barisch et al, and the parameters of the near horizon geometry change to $(z,\theta)=(3,1)$.Comment: 37 pages. v2: numerical pre-factors of scalar fields q_A corrected in Section 3. No changes to conclusions. References adde

Physical Activity and Trajectory of Cognitive Change in Older Persons: Mayo Clinic Study of Aging

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) epsilon 4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged >= 70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE epsilon 4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex

Nernst branes in gauged supergravity

We study static black brane solutions in the context of N = 2 U(1) gauged supergravity in four dimensions. Using the formalism of first-order flow equations, we construct novel extremal black brane solutions including examples of Nernst branes, i.e. extremal black brane solutions with vanishing entropy density. We also discuss a class of non-extremal generalizations which is captured by the first-order formalism.Comment: 44 pages, 3 figures, v2: added appendix B and references, minor typographic changes, v3: added some clarifying remarks, version published in JHE

In vivo biomolecular imaging of zebrafish embryos using confocal Raman spectroscopy

Zebrafish embryos provide a unique opportunity to visualize complex biological processes, yet conventional imaging modalities are unable to access intricate biomolecular information without compromising the integrity of the embryos. Here, we report the use of confocal Raman spectroscopic imaging for the visualization and multivariate analysis of biomolecular information extracted from unlabeled zebrafish embryos. We outline broad applications of this method in: (i) visualizing the biomolecular distribution of whole embryos in three dimensions, (ii) resolving anatomical features at subcellular spatial resolution, (iii) biomolecular profiling and discrimination of wild type and ΔRD1 mutant Mycobacterium marinum strains in a zebrafish embryo model of tuberculosis and (iv) in vivo temporal monitoring of the wound response in living zebrafish embryos. Overall, this study demonstrates the application of confocal Raman spectroscopic imaging for the comparative bimolecular analysis of fully intact and living zebrafish embryos

On the IR completion of geometries with hyperscaling violation

We study solutions to Einstein-Maxwell-dilaton gravity with a constant magnetic flux which describe, in the holographic AdS/CFT framework, field theories characterized by a dynamical critical exponent and a hyperscaling violation exponent. Such solutions are known to be IR-incomplete due to the presence of a running dilaton, which drives the theory towards strong coupling in the IR, where quantum corrections become important. After introducing generic corrections, in this note we examine the conditions for the emergence of an AdS_2 x R^2 region close to the horizon, which provides an IR-completion for the hyperscaling violating solutions. In the presence of these corrections, we construct explicit numerical solutions where the geometry flows from AdS_4 in the UV to AdS_2 x R^2 in the deep IR, with an intermediate region which exhbits both hyperscaling violation and Lifshitz scaling.We also provide constraints on the structure of Einstein-Maxwell-dilaton theories that admit such solutions, as well as an emergent AdS_2 x R^2 region in the infrared.Comment: Typos fixed, references added, improved discussio

Big issues for small feet : developmental, biomechanical and clinical narratives on children's footwear

The effects of footwear on the development of children's feet has been debated for many years and recent work from the developmental and biomechanical literature has challenged long-held views about footwear and the impact on foot development. This narrative review draws upon existing studies from developmental, biomechanical and clinical literature to explore the effects of footwear on the development of the foot. The emerging findings from this support the need for progress in [children's] footwear science and advance understanding of the interaction between the foot and shoe. Ensuring clear and credible messages inform practice requires a progressive evidence base but this remains big issue in children's footwear research

Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner.

Autophagy is a eukaryotic catabolic process also participating in cell-autonomous defence. Infected host cells generate double-membrane autophagosomes that mature in autolysosomes to engulf, kill and digest cytoplasmic pathogens. However, several bacteria subvert autophagy and benefit from its machinery and functions. Monitoring infection stages by genetics, pharmacology and microscopy, we demonstrate that the ESX-1 secretion system of Mycobacterium marinum, a close relative to M. tuberculosis, upregulates the transcription of autophagy genes, and stimulates autophagosome formation and recruitment to the mycobacteria-containing vacuole (MCV) in the host model organism Dictyostelium. Antagonistically, ESX-1 is also essential to block the autophagic flux and deplete the MCV of proteolytic activity. Activators of the TORC1 complex localize to the MCV in an ESX-1-dependent manner, suggesting an important role in the manipulation of autophagy by mycobacteria. Our findings suggest that the infection by M. marinum activates an autophagic response that is simultaneously repressed and exploited by the bacterium to support its survival inside the MCV

Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging

© 2019, The Author(s). In this study derived from the population-based Mayo Clinic Study of Aging, we investigated whether non-exercise physical activity (PA) was associated with global and domain-specific cognitive trajectories (memory, language, visuospatial skills, attention) and whether the association differed by apolipoprotein E (APOE) ε4 genotype status. We included 2061 community-dwelling individuals aged ≥ 70 years (50.5% males, 26.7% APOE ε4 carriers) who were cognitively unimpaired at baseline and on whom serial cognitive data and self-reported information on non-exercise PA were available. We specifically inquired about non-exercise PA carried out at two time points, i.e., midlife (between 50 and 65 years of age) and late-life (within 1 year prior to assessment) and three intensity levels, i.e., light (e.g., laundry), moderate (e.g., scrubbing floors) and heavy (e.g., hard manual labor). Linear mixed-effect models revealed that engaging in midlife PA of moderate or heavy intensity was associated with significantly less-pronounced decline of z-scores in all cognitive domains. Similarly, participants that engaged in late-life moderate or heavy PA had less decline in visuospatial, attention and global z-scores than non-active peers. These associations varied depending on APOE ε4 carrier status, i.e., APOE ε4 non-carriers but not APOE ε4 carriers that engaged in late-life PA had less decline in cognitive z-scores. In contrast, engaging in midlife PA, irrespective of intensity, was significantly associated with less decline in memory function only among APOE ε4 carriers