First described in 2009 in Japan, the emerging multidrug-resistant fungal pathogen Candida auris is becoming a worldwide public health threat that has been attracting considerable attention due to its rapid and widespread emergence over the past decade. The reasons behind the recent emergence of this fungus remain a mystery to date. Genetic analyses indicate that this fungal pathogen emerged simultaneously in several different continents, where 5 genetically distinct clades of C . auris were isolated from distinct geographical locations. Although C . auris belongs to the CTG clade (its constituent species translate the CTG codon as serine instead of leucine, as in the standard code), C . auris is a haploid fungal species that is more closely related to the haploid and often multidrug-resistant species Candida haemulonii and Candida lusitaniae and is distantly related to the diploid and clinically common fungal pathogens Candida albicans and Candida tropicalis . Infections and outbreaks caused by C . auris in hospitals settings have been rising over the past several years. Difficulty in its identification, multidrug resistance properties, evolution of virulence factors, associated high mortality rates in patients, and long-term survival on surfaces in the environment make C . auris particularly problematic in clinical settings. Here, we review progress made over the past decade on the biological and clinical aspects of C . auris . Future efforts should be directed toward understanding the mechanistic details of its biology, epidemiology, antifungal resistance, and pathogenesis with a goal of developing novel tools and methods for the prevention, diagnosis, and treatment of C . auris infections.

Lager-brewing arose in 15th century Bavaria [1] and is nowadays the most popular technique for alcoholic beverage production in the world. The technique is characterized by low temperature fermentation using the domesticated yeast Saccharomyces pastorianus (synonym S. carlsbergensis). It has been clear that the lager yeast is a hybrid with one portion of its genome having originated from S. cerevisiae ale yeast [2]. However, the source of the non-ale subgenome, which endows lager yeast with cold tolerance, had been a matter of debate [3]. Recently, a Patagonian origin hypothesis of lager yeast has been proposed based on the discovery of a new cryotolerant Saccharomyces species from Patagonian native forests of Argentina [4]. This yeast, named S. eubayanus, exhibited the closest known match (99.56%) to the non-ale portion of lager yeast and, thus, was believed to be its progenitor. However, we now show that this yeast species is likely native to the Tibetan Plateau. One of the Tibetan populations of the species exhibits closer affinity with lager yeast than the Patagonian population as inferred from population genetics and genome sequence analyses. We thus provide strong evidence for a Far East Asian origin hypothesis of lager yeast, which apparently corresponds better with geography and world trade history.

Diffusion MRI is a non-invasive imaging technique that allows the measurement of water molecule diffusion through tissue in vivo. The directional features of water diffusion allow one to infer the connectivity patterns prevalent in tissue and possibly track changes in this connectivity over time for various clinical applications. In this paper, we present a novel statistical model for diffusion-weighted MR signal attenuation which postulates that the water molecule diffusion can be characterized by a continuous mixture of diffusion tensors. An interesting observation is that this continuous mixture and the MR signal attenuation are related through the Laplace transform of a probability distribution over symmetric positive definite matrices. We then show that when the mixing distribution is a Wishart distribution, the resulting closed form of the Laplace transform leads to a Rigaut-type asymptotic fractal expression, which has been phenomenologically used in the past to explain the MR signal decay but never with a rigorous mathematical justification until now. Our model not only includes the traditional diffusion tensor model as a special instance in the limiting case, but also can be adjusted to describe complex tissue structure involving multiple fiber populations. Using this new model in conjunction with a spherical deconvolution approach, we present an efficient scheme for estimating the water molecule displacement probability functions on a voxel-by-voxel basis. Experimental results on both simulations and real data are presented to demonstrate the robustness and accuracy of the proposed algorithms.

Diffusion magnetic resonance imaging (MRI) is a relatively new imaging modality which is capable of measuring the diffusion of water molecules in biological systems noninvasively. The measurements from diffusion MRI provide unique clues for extracting orientation information of brain white matter fibers and can be potentially used to infer the brain connectivity in vivo using tractography techniques. Diffusion tensor imaging (DTI), currently the most widely used technique, fails to extract multiple fiber orientations in regions with complex microstructure. In order to overcome this limitation of DTI, a variety of reconstruction algorithms have been introduced in the recent past. One of the key ingredients in several model-based approaches is deconvolution operation which is presented in a unified deconvolution framework in this paper. Additionally, some important computational issues in solving the deconvolution problem that are not addressed adequately in previous studies are described in detail here. Further, we investigate several deconvolution schemes towards achieving stable, sparse, and accurate solutions. Experimental results on both simulations and real data are presented. The comparisons empirically suggest that nonnegative least squares method is the technique of choice for the multifiber reconstruction problem in the presence of intravoxel orientational heterogeneity.

The emerging human fungal pathogen Candida auris has been recognized as a multidrug resistant species and is associated with high mortality. This fungus was first described in Japan in 2009 and has been reported in at least 18 countries on five continents. In this study, we report the first isolate of C. auris from the bronchoalveolar lavage fluid (BALF) of a hospitalized woman in China. Interestingly, this isolate is susceptible to all tested antifungals including amphotericin B, fluconazole, and caspofungin. Copper sulfate (CuSO4) also has a potent inhibitory effect on the growth of this fungus. Under different culture conditions, C. auris exhibits multiple morphological phenotypes including round-to-ovoid, elongated, and pseudohyphal-like forms. High concentrations of sodium chloride induce the formation of a pseudohyphal-like form. We further demonstrate that C. auris is much less virulent than Candida albicans in both mouse systemic and invertebrate Galleria mellonella models.

In this paper, we present a unified framework for the rigid and nonrigid point set registration problem in the presence of significant amounts of noise and outliers. The key idea of this registration framework is to represent the input point sets using Gaussian mixture models. Then, the problem of point set registration is reformulated as the problem of aligning two Gaussian mixtures such that a statistical discrepancy measure between the two corresponding mixtures is minimized. We show that the popular iterative closest point (ICP) method [1] and several existing point set registration methods [2], [3], [4], [5], [6], [7] in the field are closely related and can be reinterpreted meaningfully in our general framework. Our instantiation of this general framework is based on the the L2 distance between two Gaussian mixtures, which has the closed-form expression and in turn leads to a computationally efficient registration algorithm. The resulting registration algorithm exhibits inherent statistical robustness, has an intuitive interpretation, and is simple to implement. We also provide theoretical and experimental comparisons with other robust methods for point set registration.

Morphological plasticity has historically been an indicator of increased virulence among fungal pathogens, allowing rapid adaptation to changing environments. Candida auris has been identified as an emerging multidrug-resistant human pathogen of global importance. Since the discovery of this species, it has been thought that C. auris is incapable of filamentous growth. Here, we report the discovery of filamentation and three distinct cell types in C. auris: typical yeast, filamentation-competent (FC) yeast, and filamentous cells. These cell types form a novel phenotypic switching system that contains a heritable (typical yeast-filament) and a nonheritable (FC-filament) switch. Intriguingly, the heritable switch between the typical yeast and the FC/filamentous phenotype is triggered by passage through a mammalian body, whereas the switch between the FC and filamentous phenotype is nonheritable and temperature-dependent. Low temperatures favor the filamentous phenotype, whereas high temperatures promote the FC yeast phenotype. Systemic in vivo and in vitro investigations were used to characterize phenotype-specific variations in global gene expression, secreted aspartyl proteinase (SAP) activity, and changes in virulence, indicating potential for niche-specific adaptations. Taken together, our study not only sheds light on the pathogenesis and biology of C. auris but also provides a novel example of morphological and epigenetic switching in fungi.

The conserved cAMP-dependent protein kinase (PKA) plays critical roles in the regulation of morphological transitions and virulence in the human fungal pathogen Candida albicans. It has long been thought that the PKA catalytic subunit is essential for cell viability in this fungus. Paradoxically, the single adenylyl cyclase-encoding gene, CYR1, which is required for the production of cAMP in C. albicans, is not essential for cell growth. Here, a double mutant of TPK1 and TPK2 (tpk2/tpk2 tpk1/tpk1, t2t1), which encode two isoforms of the PKA catalytic subunit was successfully generated, suggesting that this subunit is not essential for cell viability. Inactivation of the PKA catalytic subunit blocked filamentation and dramatically attenuated white-to-opaque switching, but promoted sexual mating. Comparative transcriptomic analyses demonstrated that the t2t1 and cyr1/cyr1 mutants exhibited similar global gene expression profiles. Compared with the WT strain, the general transcriptional activity and metabolism were significantly decreased in both the t2t1 and cyr1/cyr1 mutants. Using combined phosphoproteomic and bioinformatic analyses, we identified 181 potential PKA phosphorylation targets, which represent 148 unique proteins involved in a wide spectrum of biological processes. The study sheds new insights into the global regulatory features of the cAMP/PKA pathway in C. albicans.