Evolution of the TGF-β Signaling Pathway and Its Potential Role in the Ctenophore, Mnemiopsis leidyi

The TGF-β signaling pathway is a metazoan-specific intercellular signaling pathway known to be important in many developmental and cellular processes in a wide variety of animals. We investigated the complexity and possible functions of this pathway in a member of one of the earliest branching metazoan phyla, the ctenophore Mnemiopsis leidyi. A search of the recently sequenced Mnemiopsis genome revealed an inventory of genes encoding ligands and the rest of the components of the TGF-β superfamily signaling pathway. The Mnemiopsis genome contains nine TGF-β ligands, two TGF-β-like family members, two BMP-like family members, and five gene products that were unable to be classified with certainty. We also identified four TGF-β receptors: three Type I and a single Type II receptor. There are five genes encoding Smad proteins (Smad2, Smad4, Smad6, and two Smad1s). While we have identified many of the other components of this pathway, including Tolloid, SMURF, and Nomo, notably absent are SARA and all of the known antagonists belonging to the Chordin, Follistatin, Noggin, and CAN families. This pathway likely evolved early in metazoan evolution as nearly all components of this pathway have yet to be identified in any non-metazoan. The complement of TGF-β signaling pathway components of ctenophores is more similar to that of the sponge, Amphimedon, than to cnidarians, Trichoplax, or bilaterians. The mRNA expression patterns of key genes revealed by in situ hybridization suggests that TGF-β signaling is not involved in ctenophore early axis specification. Four ligands are expressed during gastrulation in ectodermal micromeres along all three body axes, suggesting a role in transducing earlier maternal signals. Later expression patterns and experiments with the TGF-β inhibitor SB432542 suggest roles in pharyngeal morphogenesis and comb row organization

Impact and Process Evaluation of Integrated Community and Clinic-Based HIV-1 Control: A Cluster-Randomised Trial in Eastern Zimbabwe

BACKGROUND: HIV-1 control in sub-Saharan Africa requires cost-effective and sustainable programmes that promote behaviour change and reduce cofactor sexually transmitted infections (STIs) at the population and individual levels. METHODS AND FINDINGS: We measured the feasibility of community-based peer education, free condom distribution, income-generating projects, and clinic-based STI treatment and counselling services and evaluated their impact on the incidence of HIV-1 measured over a 3-y period in a cluster-randomised controlled trial in eastern Zimbabwe. Analysis of primary outcomes was on an intention-to-treat basis. The income-generating projects proved impossible to implement in the prevailing economic climate. Despite greater programme activity and knowledge in the intervention communities, the incidence rate ratio of HIV-1 was 1.27 (95% confidence interval [CI] 0.92–1.75) compared to the control communities. No evidence was found for reduced incidence of self-reported STI symptoms or high-risk sexual behaviour in the intervention communities. Males who attended programme meetings had lower HIV-1 incidence (incidence rate ratio 0.48, 95% CI 0.24–0.98), and fewer men who attended programme meetings reported unprotected sex with casual partners (odds ratio 0.45, 95% CI 0.28–0.75). More male STI patients in the intervention communities reported cessation of symptoms (odds ratio 2.49, 95% CI 1.21–5.12). CONCLUSIONS: Integrated peer education, condom distribution, and syndromic STI management did not reduce population-level HIV-1 incidence in a declining epidemic, despite reducing HIV-1 incidence in the immediate male target group. Our results highlight the need to assess the community-level impact of interventions that are effective amongst targeted population sub-groups

Identification and In Vivo Characterization of NvFP-7R, a Developmentally Regulated Red Fluorescent Protein of Nematostella vectensis

In recent years, the sea anemone Nematostella vectensis has emerged as a critical model organism for comparative genomics and developmental biology. Although Nematostella is a member of the anthozoan cnidarians (known for producing an abundance of diverse fluorescent proteins (FPs)), endogenous patterns of Nematostella fluorescence have not been described and putative FPs encoded by the genome have not been characterized.We described the spatiotemporal expression of endogenous red fluorescence during Nematostella development. Spatially, there are two patterns of red fluorescence, both restricted to the oral endoderm in developing polyps. One pattern is found in long fluorescent domains associated with the eight mesenteries and the other is found in short fluorescent domains situated between tentacles. Temporally, the long domains appear simultaneously at the 12-tentacle stage. In contrast, the short domains arise progressively between the 12- and 16-tentacle stage. To determine the source of the red fluorescence, we used bioinformatic approaches to identify all possible putative Nematostella FPs and a Drosophila S2 cell culture assay to validate NvFP-7R, a novel red fluorescent protein. We report that both the mRNA expression pattern and spectral signature of purified NvFP-7R closely match that of the endogenous red fluorescence. Strikingly, the red fluorescent pattern of NvFP-7R exhibits asymmetric expression along the directive axis, indicating that the nvfp-7r locus senses the positional information of the body plan. At the tissue level, NvFP-7R exhibits an unexpected subcellular localization and a complex complementary expression pattern in apposed epithelia sheets comprising each endodermal mesentery.These experiments not only identify NvFP-7R as a novel red fluorescent protein that could be employed as a research tool; they also uncover an unexpected spatio-temporal complexity of gene expression in an adult cnidarian. Perhaps most importantly, our results define Nematostella as a new model organism for understanding the biological function of fluorescent proteins in vivo

Lower prevalence of Entamoeba species in children with vertically transmitted HIV infection in Western Kenya

A cross-sectional molecular epidemiological study of Entamoeba species was conducted among asymptomatic Kenyan children with (n=123) and without (n=111) HIV infection. The prevalence of E. histolytica was low (0.4%). Entamoeba species infection was inversely related with HIV infection [HIV(+): 29.3% vs. HIV(-): 55.0%, P<0.001]: multiple-species infection was related to higher CD4+ T-cell counts. Thus, HIV infection is not a risk factor for amebic infection, and multiple-species infection can be an indicator of better immune status. © 2016 Wolters Kluwer Health, Inc

Searches for neutrinos in the direction of radio-bright blazars with the ANTARES telescope

Active galaxies, especially blazars, are among the most promising neutrino source candidates. To date, ANTARES searches for these objects considered GeV-TeV $\gamma$-ray bright blazars. Here, a statistically complete radio-bright blazar sample is used as the target for searches of origins of neutrinos collected by the ANTARES neutrino telescope over 13 years of operation. The hypothesis of a neutrino-blazar directional correlation is tested by pair counting and by a complementary likelihood-based approach. The resulting post-trial $p$-value is $3.0\%$ ($2.2\sigma$ in the two-sided convention), possibly indicating a correlation. Additionally, a time-dependent analysis is performed to search for temporal clustering of neutrino candidates as a mean of detecting neutrino flares in blazars. None of the investigated sources alone reaches a significant flare detection level. However, the presence of 18 sources with a pre-trial significance above $3\sigma$ indicates a $p=1.4\%$ ($2.5\sigma$ in the two-sided convention) detection of a time-variable neutrino flux. An \textit{a posteriori} investigation reveals an intriguing temporal coincidence of neutrino, radio, and $\gamma$-ray flares of the J0242+1101 blazar at a $p=0.5\%$ ($2.9\sigma$ in the two-sided convention) level. Altogether, the results presented here suggest a possible connection of neutrino candidates detected by the ANTARES telescope with radio-bright blazars

Review of the online analyses of multi-messenger alerts and electromagnetic transient events with the ANTARES neutrino telescope

By constantly monitoring at least one complete hemisphere of the sky, neutrino telescopes are well designed to detect neutrinos emitted by transient astrophysical events. Real-time searches with the ANTARES telescope have been performed to look for neutrino candidates coincident with gamma-ray bursts detected by the Swift and Fermi satellites, highenergy neutrino events registered by IceCube, transient events from blazars monitored by HAWC, photon-neutrino coincidences by AMON notices and gravitational wave candidates observed by LIGO/Virgo. By requiring temporal coincidence, this approach increases the sensitivity and the significance of a potential discovery. Thanks to the good angular accuracy of neutrino candidates reconstructed with the ANTARES telescope, a coincident detection can also improve the positioning area of non-well localised triggers such as those detected by gravitational wave interferometers. This paper summarises the results of the follow-up performed by the ANTARES telescope between 01/2014 and 02/2022, which corresponds to the end of the data taking period.Comment: 21 pages, 10 figures, JCAP08 (2023) 072 (19 p

Caffeine Reduces 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor

Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development