Candida albicans Hyphal Extracellular Vesicles Are Different from Yeast Ones, Carrying an Active Proteasome Complex and Showing a Different Role in Host Immune Response.

Candida albicans is the principal causative agent of lethal fungal infections, predominantly in immunocompromised hosts. Extracellular vesicles (EVs) have been described as crucial in the interaction of microorganisms with their host. Since the yeast-to-hypha transition is an important virulence trait with great impact in invasive candidiasis (IC), we have addressed the characterization of EVs secreted by hyphal cells (HEVs) from C. albicans, comparing them to yeast EVs (YEVs). YEVs comprised a larger population of bigger EVs with mainly cell wall proteins, while HEVs were smaller, in general, and had a much higher protein diversity. YEVs were able to rescue the sensitivity of a cell wall mutant against calcofluor white, presumably due to the larger amount of cell wall proteins they contained. On the other hand, HEVs also contained many cytoplasmic proteins related to protein metabolism and intracellular protein transport and the endosomal sorting complexes required for transport (ESCRT) pathway related to exosome biogenesis, pointing to an intracellular origin of HEVs. Interestingly, an active 20S proteasome complex was secreted exclusively in HEVs. Moreover, HEVs contained a greater number of virulence-related proteins. As for their immunogenic role, both types of EV presented immune reactivity with human sera from patients suffering invasive candidiasis; however, under our conditions, only HEVs showed a cytotoxic effect on human macrophages and could elicit the release of tumor necrosis factor alpha (TNF-α) by these macrophages. IMPORTANCE This first analysis of HEVs of C. albicans has shown clear differences between them and the YEVs of C. albicans, showing their relevance and possible use in the discovery of new diagnostic markers and treatment targets against C. albicans infections. The data obtained point to different mechanisms of biogenesis of YEVs and HEVs, as well as different involvements in cell biology and host interaction. YEVs played a more relevant role in cell wall maintenance, while HEVs were more closely related to virulence, as they had greater effects on human immune cells. Importantly, an active 20S proteosome complex was described as a fungal-EV cargo. A deeper study of its role and those of many other proteins exclusively detected in HEVs and involved in different relevant biological processes of this fungus could open up interesting new areas of research in the battle against C. albicans

Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment

BACKGROUND: Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD. METHODS: rCBF was investigated in 54 MCI subjects using Tc-99m hexamethylpropyleneamine oxime (HMPAO). An automated analysis software (BRASS) was applied to analyze the relative blood flow (cerebellar ratios) of 24 cortical regions. After the baseline examination, the subjects were followed clinically for an average of two years. 17 subjects progressed to Alzheimer's disease (PMCI) and 37 subjects remained stable (SMCI). The baseline SPECT ratio values were compared between PMCI and SMCI. Receiver operating characteristic (ROC) analysis was applied for the discrimination of the two subgroups at baseline. RESULTS: The conversion rate of MCI to AD was 13.7% per year. PMCI had a significantly decreased rCBF in the left posterior cingulate cortex, as compared to SMCI. Left posterior cingulate rCBF ratios were entered into a logistic regression model for ROC curve calculation. The area under the ROC curve was 74%–76%, which indicates an acceptable discrimination between PMCI and SMCI at baseline. CONCLUSION: A reduced relative blood flow of the posterior cingulate gyrus could be found at least two years before the patients met the clinical diagnostic criteria of AD

Aspects of the planetary Birkhoff normal form

The discovery in [G. Pinzari. PhD thesis. Univ. Roma Tre. 2009], [L. Chierchia and G. Pinzari, Invent. Math. 2011] of the Birkhoff normal form for the planetary many--body problem opened new insights and hopes for the comprehension of the dynamics of this problem. Remarkably, it allowed to give a {\sl direct} proof of the celebrated Arnold's Theorem [V. I. Arnold. Uspehi Math. Nauk. 1963] on the stability of planetary motions. In this paper, using a "ad hoc" set of symplectic variables, we develop an asymptotic formula for this normal form that may turn to be useful in applications. As an example, we provide two very simple applications to the three-body problem: we prove a conjecture by [V. I. Arnold. cit] on the "Kolmogorov set"of this problem and, using Nehoro{\v{s}}ev Theory [Nehoro{\v{s}}ev. Uspehi Math. Nauk. 1977], we prove, in the planar case, stability of all planetary actions over exponentially-long times, provided mean--motion resonances are excluded. We also briefly discuss perspectives and problems for full generalization of the results in the paper.Comment: 44 pages. Keywords: Averaging Theory, Birkhoff normal form, Nehoro{\v{s}}ev Theory, Planetary many--body problem, Arnold's Theorem on the stability of planetary motions, Properly--degenerate kam Theory, steepness. Revised version, including Reviewer's comments. Typos correcte

News, intelligence and 'little lies' : rumours between the Cherokees and the British 1740-1785

Rumour and information are one of the most fundamental ways in which people engage with one another. Rumours can change the way that individuals and groups see each other and the actions that they take. Sociologists and anthropologists have long used rumour as a way to explore the experiences of their subjects. Historians of early America have, in recent years, begun to make use of rumour as a way of examining the, often hidden, world of interactions between American Indians and white Europeans. This thesis will expand upon this work by exploring the changing role of rumour within an intercultural relationship over several decades. This thesis will focus on rumour in the relationship between the Cherokee Nation and the colonists of the British Empire. It will explore the ways that rumour influenced these interactions and the impact of the rapidly changing backcountry environment of the latter eighteenth century, both on rumour and on the wider Cherokee- British relationship. This thesis will argue that rumour shifted in the course of the eighteenth century from being a diplomatic tool which could be used- either to create further panic and confusion or to calm and smooth over problems- to an uncontrollable force which would deepen and exacerbate the divisions between Cherokees and the British. Rumour played an important role in politics and society in the eighteenth century backcountry and its changing function offers a way to better understand the shifting currents of life in early America

Evaluation of current algorithms for segmentation of scar tissue from late Gadolinium enhancement cardiovascular magnetic resonance of the left atrium: an open-access grand challenge

Background: Late Gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging can be used to visualise regions of fibrosis and scarring in the left atrium (LA) myocardium. This can be important for treatment stratification of patients with atrial fibrillation (AF) and for assessment of treatment after radio frequency catheter ablation (RFCA). In this paper we present a standardised evaluation benchmarking framework for algorithms segmenting fibrosis and scar from LGE CMR images. The algorithms reported are the response to an open challenge that was put to the medical imaging community through an ISBI (IEEE International Symposium on Biomedical Imaging) workshop. Methods: The image database consisted of 60 multicenter, multivendor LGE CMR image datasets from patients with AF, with 30 images taken before and 30 after RFCA for the treatment of AF. A reference standard for scar and fibrosis was established by merging manual segmentations from three observers. Furthermore, scar was also quantified using 2, 3 and 4 standard deviations (SD) and full-width-at-half-maximum (FWHM) methods. Seven institutions responded to the challenge: Imperial College (IC), Mevis Fraunhofer (MV), Sunnybrook Health Sciences (SY), Harvard/Boston University (HB), Yale School of Medicine (YL), King’s College London (KCL) and Utah CARMA (UTA, UTB). There were 8 different algorithms evaluated in this study. Results: Some algorithms were able to perform significantly better than SD and FWHM methods in both pre- and post-ablation imaging. Segmentation in pre-ablation images was challenging and good correlation with the reference standard was found in post-ablation images. Overlap scores (out of 100) with the reference standard were as follows: Pre: IC = 37, MV = 22, SY = 17, YL = 48, KCL = 30, UTA = 42, UTB = 45; Post: IC = 76, MV = 85, SY = 73, HB = 76, YL = 84, KCL = 78, UTA = 78, UTB = 72. Conclusions: The study concludes that currently no algorithm is deemed clearly better than others. There is scope for further algorithmic developments in LA fibrosis and scar quantification from LGE CMR images. Benchmarking of future scar segmentation algorithms is thus important. The proposed benchmarking framework is made available as open-source and new participants can evaluate their algorithms via a web-based interface

Granulation in Red Giants: observations by the Kepler mission and 3D convection simulations

The granulation pattern that we observe on the surface of the Sun is due to hot plasma from the interior rising to the photosphere where it cools down, and descends back into the interior at the edges of granules. This is the visible manifestation of convection taking place in the outer part of the solar convection zone. Because red giants have deeper convection zones and more extended atmospheres than the Sun, we cannot a priori assume that granulation in red giants is a scaled version of solar granulation. Until now, neither observations nor 1D analytical convection models could put constraints on granulation in red giants. However, thanks to asteroseismology, this study can now be performed. The resulting parameters yield physical information about the granulation. We analyze \sim1000 red giants that have been observed by Kepler during 13 months. We fit the power spectra with Harvey-like profiles to retrieve the characteristics of the granulation (time scale tau_gran and power P_gran). We also introduce a new time scale, tau_eff, which takes into account that different slopes are used in the Harvey functions. We search for a correlation between these parameters and the global acoustic-mode parameter (the position of maximum power, nu_max) as well as with stellar parameters (mass, radius, surface gravity (log g) and effective temperature (T_eff)). We show that tau_eff nu_max^{-0.89} and P_gran nu_max^{-1.90}, which is consistent with the theoretical predictions. We find that the granulation time scales of stars that belong to the red clump have similar values while the time scales of stars in the red-giant branch are spread in a wider range. Finally, we show that realistic 3D simulations of the surface convection in stars, spanning the (T_eff, log g)-range of our sample of red giants, match the Kepler observations well in terms of trends.Comment: 43 pages, 13 figures. Accepted for publication in Ap