Description: Haploinsufficiency of Progranulin ( PGRN ), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD. Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway. Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN. These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations.

Description: Hormone replacement therapy (HRT) and epidermal growth factor receptor ( EGFR ) single nucleotide polymorphisms (SNPs) have been reported as risk factors for lung cancer in never smokers. We investigate the interaction of EGFR SNPs and HRT for lung adenocarcinoma risk in never-smoking women. This study included 532 never-smoking female lung adenocarcinoma patients and 532 controls, with EGFR SNPs retrieved from a genome-wide association study. The associations of EGFR SNPs with the lung adenocarcinoma risk were estimated by multivariate-adjusted logistic regression. The Haploview program was used to select tagged EGFR SNPs interacted with HRT and construct haplotype blocks. The Benjamini and Hochberg method was used to reduce the multiple testing effects. Among 84 EGFR SNPs retrieved, 11 tagging EGFR SNPs showed an interaction with HRT and lung adenocarcinoma risk, which were mostly located near the tyrosine kinase domain. Eight of the tagged SNPs were in two haplotype blocks. The interactions between HRT and numbers of protective EGFR SNP genotypes are significant in both blocks ( P for interaction = 0.0004 and 0.0032, respectively). A trend of decrease in lung adenocarcinoma risk was found in subjects with HRT harboring an increasing number of protective EGFR SNP genotypes in both blocks ( P = 0.0032 and 0.0046, respectively). In conclusion, HRT use may modify the association of EGFR SNPs with lung adenocarcinoma risk. The EGFR SNPs have a cumulative effect on decreasing lung adenocarcinoma risk in never-smoking women with HRT use.

Description: Molecular understanding of placental functions and pregnancy disorders is limited by the absence of methods for placenta-specific gene manipulation. Although persistent placenta-specific gene expression has been achieved by lentivirus-based gene delivery methods, developmentally and physiologically important placental genes have highly stage-specific functions, requiring controllable, transient expression systems for functional analysis. Here, we describe an inducible, placenta-specific gene expression system that enables high-level, transient transgene expression and monitoring of gene expression by live bioluminescence imaging in mouse placenta at different stages of pregnancy. We used the third generation tetracycline-responsive tranactivator protein Tet-On 3G, with 10- to 100-fold increased sensitivity to doxycycline (Dox) compared with previous versions, enabling unusually sensitive on-off control of gene expression in vivo . Transgenic mice expressing Tet-On 3G were created using a new integrase-based, site-specific approach, yielding high-level transgene expression driven by a ubiquitous promoter. Blastocysts from these mice were transduced with the Tet-On 3G-response element promoter-driving firefly luciferase using lentivirus-mediated placenta-specific gene delivery and transferred into wild-type pseudopregnant recipients for placenta-specific, Dox-inducible gene expression. Systemic Dox administration at various time points during pregnancy led to transient, placenta-specific firefly luciferase expression as early as d 5 of pregnancy in a Dox dose-dependent manner. This system enables, for the first time, reliable pregnancy stage-specific induction of gene expression in the placenta and live monitoring of gene expression during pregnancy. It will be widely applicable to studies of both placental development and pregnancy, and the site-specific Tet-On G3 mouse will be valuable for studies in a broad range of tissues.

Description: Metastasis often occurs in colorectal cancer (CRC) patients and is the main difficulty in cancer treatment. The upregulation of poly- N -acetyllactosamine-related glycosylation is found in CRC patients and is associated with progression and metastasis in cancer. β-1,4-Galactosyltransferase III (B4GALT3) is an enzyme responsible for poly- N -acetyllactosamine synthesis, and therefore, we investigated its expression in CRC patients. We found that B4GALT3 negatively correlated with poorly differentiated histology ( P 〈 0.001), advanced stages ( P = 0.0052), regional lymph node metastasis ( P = 0.0018) and distant metastasis ( P = 0.0463) in CRC patients. B4GALT3 overexpression in CRC cells suppressed cell migration, invasion and adhesion, whereas B4GALT3 knockdown enhanced malignant cell phenotypes. The β1 integrin-blocking antibody reversed the B4GALT3-mediated increase in cell invasion. B4GALT3 expression altered glycosylation on the N-glycan of β1 integrin probably through changes in poly- N -acetyllactosamine expression. Furthermore, more activated β1 integrin along with the activation of its downstream signaling transduction were found in B4GALT3 knockdown cells, whereas overexpression of B4GALT3 suppressed the expression of active β1 integrin and inhibited its downstream signaling. Our results suggest that B4GALT3 is negatively associated with CRC metastasis and suppresses cell invasiveness through inhibiting activation of β1 integrin.

Description: Human immunodeficiency virus (HIV)-infected and viremic individuals exhibit elevated levels of plasma cytokines. Here we show that most cytokines are not in free form but appear associated with exosomes that are distinct from virions. Purified exosomes were analyzed to determine the levels of 21 cytokines and chemokines and compared with exosome-depleted plasma. Most cytokines were markedly enriched in exosomes from HIV-positive individuals relative to negative controls and to plasma. Moreover, exposure of naive peripheral blood mononuclear cells to exosomes purified from HIV-positive patients induced CD38 expression on naive and central memory CD4 + and CD8 + T cells, probably contributing to inflammation and viral propagation via bystander cell activation.

Description: We use a data set of nearby galaxies drawn from the HERA CO-Line Extragalactic Survey, ATLAS 3D , and COLD GASS surveys to study variations in molecular gas depletion time ( t dep ) in galaxy structures such as bulges, grand-design spiral arms, bars and rings. Molecular gas is traced by CO line emission and star formation rate (SFR) is derived using the combination of far-ultraviolet and mid-infrared (MIR) data. The contribution of old stars to MIR emission for the ATLAS 3D sample is corrected using 2MASS K -band images. We apply a two-dimensional image decomposition algorithm to decompose galaxies into bulges and discs. Spiral arms, bars and rings are identified in the residual maps, and molecular gas depletion times are derived on a square grid of 1 kpc 2 size. In previous work, we showed that t dep correlates strongly with specific star formation rate (sSFR). We now find that at a given sSFR, the bulge has shorter t dep than the disc. The shift to shorter depletion times is most pronounced in the inner bulge ( R 〈 0.1 R e ). Grids from galaxies with bars and rings are similar to those from galactic bulges in that they have reduced t dep at a given sSFR. In contrast, the t dep versus sSFR relation in the discs of galaxies with spiral arms is displaced to longer t dep at fixed sSFR. We then show that the differences in the t dep –sSFR relation for bulges, discs, arms, bars and rings can be linked to variations in stellar , rather than gas surface density between different structures. Our best current predictor for t dep , both globally and for 1 kpc grids, is given by t dep  = –0.36 log ( SFR ) – 0.50 log ( * ) + 5.87.

Description: We study the Kennicutt–Schmidt relation between average star formation rate (SFR) and average cold gas surface density in the H  i -dominated ISM of nearby spiral and dwarf irregular galaxies. We divide galaxies into grid cells varying from sub-kpc to tens of kpc in size. Grid-cell measurements of low SFRs using Hα emission can be biased and scatter may be introduced because of non-uniform sampling of the IMF or because of stochastically varying star formation. In order to alleviate these issues, we use far-ultraviolet emission to trace SFR, and we sum up the fluxes from different bins with the same gas surface density to calculate the average SFR at a given value of gas . We study the resulting Kennicutt–Schmidt relation in 400 pc, 1 kpc and 10 kpc scale grids in nearby massive spirals and in 400 pc scale grids in nearby faint dwarf irregulars. We find a relation with a power-law slope of 1.5 in the H  i -dominated regions for both kinds of galaxies. The relation is offset towards longer gas consumption time-scales compared to the molecular-hydrogen-dominated centres of spirals, but the offset is an order of magnitude less than that quoted by earlier studies. Our results lead to the surprising conclusion that conversion of gas to stars is independent of metallicity in the H  i -dominated regions of star-forming galaxies. Our observed relations are better fit by a model of star formation based on thermal and hydrostatic equilibrium in the ISM, in which stellar heating and supernova feedback set the thermal and turbulent pressure.

Description: Retinitis pigmentosa (RP) affects about 1.8 million individuals worldwide. X-linked retinitis pigmentosa (XLRP) is one of the most severe forms of RP. Nearly 85% of XLRP cases are caused by mutations in the X-linked retinitis pigmentosa 2 ( RP2 ) and RPGR . RP2 has been considered to be a GTPase activator protein for ARL3 and to play a role in the traffic of ciliary proteins. The mechanism of how RP2 mutations cause RP is still unclear. In this study, we generated an RP2 knockout zebrafish line using transcription activator-like effector nuclease technology. Progressive retinal degeneration could be observed in the mutant zebrafish. The degeneration of rods' outer segments (OSs) is predominant, followed by the degeneration of cones' OS. These phenotypes are similar to the characteristics of RP2 patients, and also partly consistent with the phenotypes of RP2 knockout mice and morpholino-mediated RP2 knockdown zebrafish. For the first time, we found RP2 deletion leads to decreased protein levels and abnormal retinal localizations of GRK1 and rod transducin subunits (GNAT1 and GNB1) in zebrafish. Furthermore, the distribution of the total farnesylated proteins in zebrafish retina is also affected by RP2 ablation. These molecular alterations observed in the RP2 knockout zebrafish might probably be responsible for the gradual loss of the photoreceptors' OSs. Our work identified the progression of retinal degeneration in RP2 knockout zebrafish, provided a foundation for revealing the pathogenesis of RP caused by RP2 mutations, and would help to develop potential therapeutics against RP in further studies.

Description: Background Risk prediction models for hepatocellular carcinoma are available for individuals with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections who are at high risk but not for the general population with average or unknown risk. We developed five simple risk prediction models based on clinically available data from the general population. Methods A prospective cohort of 428 584 subjects from a private health screening firm in Taiwan was divided into two subgroups—one with known HCV test results (n = 130 533 subjects) and the other without (n = 298 051 subjects). A total of 1668 incident hepatocellular carcinomas occurred during an average follow-up of 8.5 years. Model inputs included age, sex, health history–related variables; HBV or HCV infection–related variables; serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alfa-fetoprotein (AFP), as well as other variables of routine blood panels for liver function. Cox proportional hazards regression method was used to identify risk predictors of hepatocellular carcinoma. Receiver operating characteristic curves were used to assess discriminatory accuracy of the models. Models were internally validated. All statistical tests were two-sided. Results Age, sex, health history, HBV and HCV status, and serum ALT, AST, AFP levels were statistically significant independent predictors of hepatocellular carcinoma risk (all P 〈 .05). Use of serum transaminases only in a model showed a higher discrimination compared with HBV or HCV only (for transaminases, area under the curve [AUC] = 0.912, 95% confidence interval [CI] = 0.909 to 0.915; for HBV, AUC = 0.840, 95% CI = 0.833 to 0.848; and for HCV, AUC = 0.841, 95% CI = 0.834 to 0.847). Adding HBV and HCV data to the transaminase-only model improved the discrimination (AUC = 0.933, 95% CI = 0.929 to 0.949). Internal validation showed high discriminatory accuracy and calibration of these models. Conclusion Models with transaminase data were best able to predict hepatocellular carcinoma risk even among subjects with unknown or HBV- or HCV-negative infection status.

Description: We have updated our radially resolved semi-analytic models (SAMs) of galaxy formation, which track both the atomic and molecular gas phases of the interstellar medium. The models are adapted from those of Guo et al. using similar methodology as by Fu et al. and are run on halo merger trees from the Millennium and Millennium-II simulations with the following main changes. (1) We adopt a simple star formation law SFR H 2 . (2) We inject the heavy elements produced by supernovae directly into the halo hot gas, instead of first mixing them with the cold gas in the disc. (3) We include radial gas inflows in discs using a model of the form v inflow  = α r . The models are used to study the radial profiles of star formation rate and gas-phase metallicity in present-day galaxies. The surface density profiles of molecular gas in L * galaxies place strong constraints on inflow velocities, favouring models where v inflow  ~ 7 km s –1 at a galactocentric radius of 10 kpc. Radial gas inflow has little influence on gas-phase and stellar metallicity gradients, which are affected much more strongly by the fraction of metals that are directly injected into the halo gas, rather than mixed with the cold gas. Metals ejected out of the galaxy in early epochs result in late infall of pre-enriched gas and flatter present-day gas-phase metallicity gradients. A prescription in which 80 per cent of the metals are injected into the halo gas results in good fits to the flat observed metallicity gradients in galaxies with stellar masses greater than 10 10 M , as well as the relations between gas-phase metallicity and specific star formation rate in the outer parts of galactic discs. We examine the correlation between the gas-phase metallicity gradient and global galaxy properties, finding that it is most strongly correlated with the bulge-to-total ratio of the galaxy. This is because gas is consumed when the bulge forms during galaxy mergers, and the gas-phase metallicity gradient is then set by newly accreted gas.