Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Reduced growth and proliferation dynamics of nasal epithelial stem/progenitor cells in nasal polyps in vitro

10.1038/srep04619Scientific Reports4

On the role of alternatives in the acquisition of simple and complex disjunctions in French and Japanese

International audienc

HIV infection and sexual risk among men who have sex with men and women (MSMW): A systematic review and meta-analysis

Objectives: To estimate the number of men who have sex with men and women who are HIV-positive in the United States, and to compare HIV prevalence rates between men who have sex with men and women, men who have sex with men only, and men who have sex with women exclusively. Methods: Following PRISMA guidelines, we conducted a systematic review and meta-analysis of reports referencing HIV prevalence and men who have sex with men and women. We searched PubMed and Ovid PsycINFO for peer-reviewed, U.S.-based articles reporting on HIV prevalence among men who have sex with men and women. We conducted event rate, effect size, moderation and sensitivity analyses. Results: We estimate that 1.0% of U.S. males are bisexually-behaving, and that 121,800 bisexually-behaving men are HIV-positive. Men who have sex with men and women are less than half as likely to be HIV-positive as men who have sex with men only (16.9% vs. 33.3%; OR = 0.41, 95% CI: 0.31, 0.54), but more than five times as likely to be HIV-positive as men who have sex with women exclusively (18.3% vs. 3.5%; OR = 5.71, 95% CI: 3.47, 9.39). They are less likely to engage in unprotected receptive anal intercourse than men who have sex with men only (15.9% vs. 35.0%; OR = 0.36, 95% CI: 0.28, 0.46). Men who have sex with men and women in samples with high racial/ethnic minority proportions had significantly higher HIV prevalence than their counterparts in low racial/ethnic minority samples. Conclusions: This represents the first meta-analysis of HIV prevalence in the U.S. between men who have sex with men and women and men who have sex with men only. Data collection, research, and HIV prevention and care delivery specifically tailored to men who have sex with men and women are necessary to better quantify and ameliorate this population's HIV burden. © 2014 Friedman et al

Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases. © 2013 Ziraldo et al

Galactic Dynamics via General Relativity: A Compilation and New Developments

We consider the consequences of applying general relativity to the description of the dynamics of a galaxy, given the observed flattened rotation curves. The galaxy is modeled as a stationary axially symmetric pressure-free fluid. In spite of the weak gravitational field and the non-relativistic source velocities, the mathematical system is still seen to be non-linear. It is shown that the rotation curves for various galaxies as examples are consistent with the mass density distributions of the visible matter within essentially flattened disks. This obviates the need for a massive halo of exotic dark matter. We determine that the mass density for the luminous threshold as tracked in the radial direction is $10^{-21.75}$ kg$\cdot$m$^{-3}$ for these galaxies and conjecture that this will be the case for other galaxies yet to be analyzed. We present a velocity dispersion test to determine the extent, if of any significance, of matter that may lie beyond the visible/HI region. Various comments and criticisms from colleagues are addressed.Comment: 35 pages, 13 figure

Testing theories of temporal inferences: Evidence from child language

Sentences involving past tense verbs, such as “My dogs were on the carpet”, tend to give rise to the inference that the corresponding present tense version, “My dogs are on the carpet”, is false. This inference is often referred to as a cessation or temporal inference, and is generally analyzed as a type of implicature. There are two main proposals for capturing this asymmetry: one assumes a difference in informativity between the past and present counterparts (Altshuler & Schwarzschild 2013), while the other proposes a structural difference between the two (Thomas 2012). The two approaches are similar in terms of empirical coverage, but differ in their predictions for language acquisition. Using a novel animated picture selection paradigm, we investigated these predictions. Specifically, we compared the performance of a group of 4–6-year-old children and a group of adults on temporal inferences, scalar implicatures arising from “some”, and inferences of adverbial modifiers under negation. The results revealed that overall, children computed all three inferences at a lower rate than adult controls; however they were more adult-like on temporal inferences and inferences of adverbial modifiers than on scalar implicatures. We discuss the implications of the findings, both for a developmental alternatives-based hypothesis (e.g., Barner et al. 2011; Singh et al. 2016; Tieu et al. 2016; 2018), as well as theories of temporal inferences, arguing that the finding that children were more (and equally) adult-like on temporal inferences and adverbial modifiers supports a structural theory of temporal inferences along the lines of Thomas (2012)

Detection and Classification of Bacterial Cells After Centrifugation and Filtration of Liquid Specimens Using Laser-Induced Breakdown Spectroscopy

Five species of bacteria including Escherichia coli, Mycobacterium smegmatis, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Enterobacter cloacae were deposited from suspensions of various titers onto disposable nitrocellulose filter media for analysis by laser-induced breakdown spectroscopy (LIBS). Bacteria were concentrated and isolated in the center of the filter media during centrifugation using a simple and convenient sample preparation step. Summing all the single-shot LIBS spectra acquired from a given bacterial deposition provided perfectly sensitive and specific discrimination from sterile water control specimens in a partial least squares discriminant analysis (PLS-DA). Use of the single-shot spectra provided only a 0.87 and 0.72 sensitivity and specificity, respectively. To increase the statistical validity of chemometric analyses, a library of pseudodata was created by adding Gaussian noise to the measured intensity of every emission line in an averaged spectrum of each bacterium. The normally distributed pseudodata, consisting of 4995 spectra, were used to compare the performance of the PLS-DA with a discriminant function analysis (DFA) and an artificial neural network (ANN). For the highly similar bacterial data, no algorithm showed significantly superior performance, although the PLS-DA performed least accurately with a classification error of 0.21 compared to 0.16 and 0.17 for ANN and DFA, respectively. Single-shot LIBS spectra from all of the bacterial species were classified in a DFA model tested with a tenfold cross-validation. Classification errors ranging from 20% to 31% were measured due to repeatability limitations in the single-shot data