Glycan Precursor Transport in Cryptococcus neoformans

Glycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions. For pathogens, they are also often required for virulence and survival in the host. Our interest in glycoconjugates stems from their role in the fungal pathogen Cryptococcus neoformans. This yeast colonizes the lungs and disseminates to the brain of immunocompromised individuals, where it causes a meningoencephalitis that is frequently lethal, killing almost 200,000 people each year. The major virulence factor of this yeast is a polysaccharide capsule that enables it to manipulate the host immune response and resist host antimicrobial defenses. Synthesis of the capsular glycans and other critical glycoconjugates occurs primarily in the secretory compartment, although almost all activated precursors are made in cytosol. This topological problem is resolved by nucleotide sugar transporters (NSTs), which are thus required for such glycosylation. The identity and regulation of the complete set of cryptococcal NSTs, however, remain elusive. This major gap in our knowledge severely limits our understanding of and ability to manipulate critical biosynthetic processes in this important pathogen. Here, we identified three novel NSTs and determined their kinetic profiles and roles in cryptococcal biology. Uut1 is a high-affinity ER-localized UDP-glucuronic acid (UDP-GlcA) transporter, and Uxt1 and Uxt2 are dual UDP-xylose (UDP-Xyl) transporters found in the Golgi apparatus and endoplasmic reticulum, respectively. Mutants lacking these proteins exhibited compositional changes in their glycoconjugates, including the capsule, increased sensitivity to stress, and altered interactions with phagocytes. UDP-GlcA and UDP-Xyl transport activities were also required for full virulence. Interestingly, UDP-Xyl transport was not required for persistence within the host, as the double uxt1Δ uxt2Δ mutant established a chronic infection of the lung and induced delayed formation of tertiary lymphoid tissue. Collectively, this work advanced our understanding of the localization and sequence of glycan biosynthetic events, and their relationship to virulence. It also set the stage for further studies of fundamental glycobiology, cryptococcal biology and pathogenesis, and potential antifungal agents

Modeling the Dust Properties of z ~ 6 Quasars with ART^2 -- All-wavelength Radiative Transfer with Adaptive Refinement Tree

The detection of large quantities of dust in z ~ 6 quasars by infrared and radio surveys presents puzzles for the formation and evolution of dust in these early systems. Previously (Li et al. 2007), we showed that luminous quasars at z > 6 can form through hierarchical mergers of gas-rich galaxies. Here, we calculate the dust properties of simulated quasars and their progenitors using a three-dimensional Monte Carlo radiative transfer code, ART^2 -- All-wavelength Radiative Transfer with Adaptive Refinement Tree. ART^2 incorporates a radiative equilibrium algorithm for dust emission, an adaptive grid for inhomogeneous density, a multiphase model for the ISM, and a supernova-origin dust model. We reproduce the SED and dust properties of SDSS J1148+5251, and find that the infrared emission are closely associated with the formation and evolution of the quasar host. The system evolves from a cold to a warm ULIRG owing to heating and feedback from stars and AGN. Furthermore, the AGN has significant implications for the interpretation of observation of the hosts. Our results suggest that vigorous star formation in merging progenitors is necessary to reproduce the observed dust properties of z~6 quasars, supporting a merger-driven origin for luminous quasars at high redshifts and the starburst-to-quasar evolutionary hypothesis. (Abridged)Comment: 26 pages, 22 figures, accepted by ApJ. Version with full resolution images is available at http://www.cfa.harvard.edu/~yxli/ARTDUST/astroph0706.3706.pd

Genome-wide identification of potato long intergenic noncoding RNAs responsive to <i>Pectobacterium carotovorum</i> subspecies <i>brasiliense</i> infection

BACKGROUND: Long noncoding RNAs (lncRNAs) represent a class of RNA molecules that are implicated in regulation of gene expression in both mammals and plants. While much progress has been made in determining the biological functions of lncRNAs in mammals, the functional roles of lncRNAs in plants are still poorly understood. Specifically, the roles of long intergenic nocoding RNAs (lincRNAs) in plant defence responses are yet to be fully explored. RESULTS: In this study, we used strand-specific RNA sequencing to identify 1113 lincRNAs in potato (Solanum tuberosum) from stem tissues. The lincRNAs are expressed from all 12 potato chromosomes and generally smaller in size compared to protein-coding genes. Like in other plants, most potato lincRNAs possess single exons. A time-course RNA-seq analysis between a tolerant and a susceptible potato cultivar showed that 559 lincRNAs are responsive to Pectobacterium carotovorum subsp. brasiliense challenge compared to mock-inoculated controls. Moreover, coexpression analysis revealed that 17 of these lincRNAs are highly associated with 12 potato defence-related genes. CONCLUSIONS: Together, these results suggest that lincRNAs have potential functional roles in potato defence responses. Furthermore, this work provides the first library of potato lincRNAs and a set of novel lincRNAs implicated in potato defences against P. carotovorum subsp. brasiliense, a member of the soft rot Enterobacteriaceae phytopathogens. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-2967-9) contains supplementary material, which is available to authorized users

Adiposity in early, middle and later adult life and cardiometabolic risk markers in later life; findings from the British regional heart study.

OBJECTIVES: This research investigates the associations between body mass index (BMI) at 21, 40-59, 60-79 years of age on cardiometabolic risk markers at 60-79 years. METHODS: A prospective study of 3464 British men with BMI measured at 40-59 and 60-79 years, when cardiometabolic risk was assessed. BMI at 21 years was ascertained from military records, or recalled from middle-age (adjusted for reporting bias); associations between BMI at different ages and later cardiometabolic risk markers were examined using linear regression. Sensitive period, accumulation and mobility life course models were devised for high BMI (defined as BMI≥75th centile) and compared with a saturated BMI trajectory model. RESULTS: At ages 21, 40-59 and 60-79 years, prevalences of overweight (BMI≥25 kg/m2) were 12%, 53%, 70%, and obesity (≥30 kg/m2) 1.6%, 6.6%, and 17.6%, respectively. BMI at 21 years was positively associated with serum insulin, blood glucose, and HbA1c at 60-79 years, with increases of 1.5% (95%CI 0.8,2.3%), 0.4% (0.1,0.6%), 0.3% (0.1,0.4%) per 1 kg/m2, respectively, but showed no associations with blood pressure or blood cholesterol. However, these associations were modest compared to those between BMI at 60-79 years and serum insulin, blood glucose and HbA1c at 60-79 years, with increases of 8.6% (8.0,9.2%), 0.7% (0.5,0.9%), and 0.5% (0.4,0.7%) per 1 kg/m2, respectively. BMI at 60-79 years was also associated with total cholesterol and blood pressure. Associations for BMI at 40-59 years were mainly consistent with those of BMI at 60-79 years. None of the life course models fitted the data as well as the saturated model for serum insulin. A sensitive period at 50 years for glucose and HbA1c and sensitive period at 70 years for blood pressure were identified. CONCLUSIONS: In this cohort of men who were thin compared to more contemporary cohorts, BMI in later life was the dominant influence on cardiovascular and diabetes risk. BMI in early adult life may have a small long-term effect on diabetes risk

Biomarker Discovery in Subclinical Mycobacterial Infections of Cattle

BACKGROUND: Bovine tuberculosis is a highly prevalent infectious disease of cattle worldwide; however, infection in the United States is limited to 0.01% of dairy herds. Thus detection of bovine TB is confounded by high background infection with M. avium subsp. paratuberculosis. The present study addresses variations in the circulating peptidome based on the pathogenesis of two biologically similar mycobacterial diseases of cattle. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that serum proteomes of animals in response to either M. bovis or M. paratuberculosis infection will display several commonalities and differences. Sera prospectively collected from animals experimentally infected with either M. bovis or M. paratuberculosis were analyzed using high-resolution proteomics approaches. iTRAQ, a liquid chromatography and tandem mass spectrometry approach, was used to simultaneously identify and quantify peptides from multiple infections and contemporaneous uninfected control groups. Four comparisons were performed: 1) M. bovis infection versus uninfected controls, 2) M. bovis versus M. paratuberculosis infection, 3) early, and 4) advanced M. paratuberculosis infection versus uninfected controls. One hundred and ten differentially elevated proteins (P < or = 0.05) were identified. Vitamin D binding protein precursor (DBP), alpha-1 acid glycoprotein, alpha-1B glycoprotein, fetuin, and serine proteinase inhibitor were identified in both infections. Transthyretin, retinol binding proteins, and cathelicidin were identified exclusively in M. paratuberculosis infection, while the serum levels of alpha-1-microglobulin/bikunin precursor (AMBP) protein, alpha-1 acid glycoprotein, fetuin, and alpha-1B glycoprotein were elevated exclusively in M. bovis infected animals. CONCLUSIONS/SIGNIFICANCE: The discovery of these biomarkers has significant impact on the elucidation of pathogenesis of two mycobacterial diseases at the cellular and the molecular level and can be applied in the development of mycobacterium-specific diagnostic tools for the monitoring progression of disease, response to therapy, and/or vaccine based interventions