Novel insights into host-fungal pathogen interactions derived from live-cell imaging

Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007–2013 grant agreement HEALTH-F2-2010-260338–ALLFUN to NARG.Peer reviewedPublisher PD

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

Abstract Although Candida glabrata is an important human pathogenic yeast, its pathogenicity mechanisms are largely unknown. Immune evasion strategies seem to play key roles during infection, since very little inflammation is observed in mouse models. Furthermore, C. glabrata multiplies intracellularly after engulfment by macrophages. In this study, we sought to identify the strategies that enable C. glabrata to survive phagosome biogenesis and antimicrobial activities within human monocyte-derived macrophages. We show that, despite significant intracellular proliferation, macrophage damage or apoptosis was not apparent, and production of reactive oxygen species was inhibited. Additionally, with the exception of GM-CSF, levels of pro- and anti-inflammatory cytokines were only marginally increased. We demonstrate that adhesion to and internalization by macrophages occur within minutes, and recruitment of endosomal early endosomal Ag 1 and lysosomal-associated membrane protein 1 indicates phagosome maturation. However, phagosomes containing viable C. glabrata, but not heat-killed yeasts, failed to recruit cathepsin D and were only weakly acidified. This inhibition of acidification did not require fungal viability, but it had a heat-sensitive surface attribute. Therefore, C. glabrata modifies the phagosome into a nonacidified environment and multiplies until the host cells finally lyse and release the fungi. Our results suggest persistence of C. glabrata within macrophages as a possible immune evasion strategy.</jats:p

Candida glabrata : a review of its features and resistance

Candida species belong to the normal microbiota of the oral cavity and gastrointestinal and vaginal tracts, and are responsible for several clinical manifestations, from mucocutaneous overgrowth to bloodstream infections. Once believed to be non-pathogenic, Candida glabrata was rapidly blamable for many human diseases. Year after year, these pathological circumstances are more recurrent and problematic to treat, especially when patients reveal any level of immunosuppression. These difficulties arise from the capacity of C. glabrata to form biofilms and also from its high resistance to traditional antifungal therapies. Thus, this review intends to present an excerpt of the biology, epidemiology, and pathology of C. glabrata, and detail an approach to its resistance mechanisms based on studies carried out up to the present.The authors are grateful to strategic project PTDC/SAU-MIC/119069/2010 for the financial support to the research center and for Celia F. Rodrigues' grant

Using synthetic MR images for distortion correction

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information

Parallel hippocampal-parietal circuits for self- and goal-oriented processing

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing

Accuracy and reliability of diffusion imaging models

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain\u27s white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL\u27s BedpostX [BPX], DSI Studio\u27s Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3\u27s Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI

A somato-cognitive action network alternates with effector regions in motor cortex

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representation