Maintaining Glucose Homeostasis in Response to Aging and Stress: The Role of Pcif1, Bmi1, and Pdx1

A sufficient number of functioning beta cells is necessary for maintaining glucose homeostasis. Reduction of beta cell mass or function leads to diabetes. Investigation into the maintenance of both beta cell mass and function is important for the development of therapies to prevent and/or restore functional beta cells. Here, the networks surrounding three proteins in the beta cell, Pcif1, Bmi1, and Pdx1, were studied as they relate to beta cell function and number. The Polycomb protein, Bmi1, has been shown to influence beta cell replication via epigenetic repression of the Ink4a/Arf locus, resulting in suppression of p16 protein translation. The adapter protein, Pcif1, facilitates the ubiquitination of Bmi1 and influences beta cell replication, as Pcif1 heterogyzous mice have increased rates of beta cell proliferation. I hypothesized that Pcif1 regulates beta cell proliferation through a Bmi1-dependent mechanism. Analysis of Pcif1 heterozygous islets revealed that p16 protein levels were indistinguishable from controls, thus making a p16-dependent mechanism unlikely. Further investigation of Bmi1 targets may reveal another pathway by which Pcif1 and Bmi1 influence beta cell replication. The role of Bmi1 has not been well-described in adult animals. Analysis of Bmi1 heterozygous animals revealed increased insulin sensitivity, as compared to wildtype. This was found to be due to an enhancement of Akt phosphorylation, with the upstream insulin signaling pathway unaffected. Bmi1 also appears to play a role in the development of insulin resistance, as Bmi1 levels are high in insulin-resistant animals. I also began to explore the possibility that the action of Pcif1 on Bmi1 is responsible for the role Bmi1 plays in insulin signaling. The transcription factor, Pdx1, regulates numerous processes specific to the beta cell, including multiple pathways regulating translation. Pdx1 levels have been shown to affect the ability of beta cells to respond to ER stress. A global analysis of translational efficiencies using the TRAP methodology indicated that Pdx1 activity may result in repression of translation of some transcripts. Further analysis of these transcripts will help determine how Pdx1 regulates the translatome of the beta cell and, potentially, how Pdx1 influences the beta cell stress response

Valganciclovir for suppression of human herpesvirus-8 replication: a randomized, double-blind, placebo-controlled, crossover trial.

BACKGROUND: Human herpesvirus-8 (HHV-8) replication is critical in the induction and maintenance of Kaposi sarcoma, primary effusion lymphoma, and some cases of Castleman disease. In vitro and observational studies suggest that ganciclovir inhibits HHV-8 replication, but no randomized clinical trials have been conducted. METHODS: A total of 26 men infected with HHV-8 were randomized to receive 8 weeks of valganciclovir administered orally (900 mg once per day) or 8 weeks of placebo administered orally. After a 2-week washout period, participants in each group received the study drug they had not yet taken (either valganciclovir or placebo), for 8 additional weeks. Oral swab samples were collected daily during the study, and HHV-8 and CMV DNA were quantified by real-time PCR. RESULTS: A total of 16 human immunodeficiency virus (HIV)-positive men and 10 HIV-negative men enrolled in and completed the study. Of the 3,439 swab samples that participants had been expected to provide, 3029 (88%) were available for analysis. HHV-8 was detected on 44% of swabs collected from participants who were receiving placebo, compared with 23% of swabs collected from participants who were receiving valganciclovir (relative risk [RR], 0.54 [95% confidence interval {CI}, 0.33-0.90]; P = .02). Valganciclovir reduced oropharyngeal shedding of cytomegalovirus by 80% (RR, 0.20 [95% CI, 0.08-0.48]; P < .001). Shedding of HHV-8 and shedding of cytomegalovirus were independent. Hematologic, renal, or hepatic toxicities were no more common among participants who received the active drug, compared with those who received placebo, though participants who received valganciclovir reported more days of diarrhea. CONCLUSIONS: Valganciclovir administered orally once per day is well tolerated and significantly reduces the frequency and quantity of HHV-8 replication

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.William F. Laurance, D. Carolina Useche, Julio Rendeiro, Margareta Kalka, Corey J. A. Bradshaw, Sean P. Sloan, Susan G. Laurance, Mason Campbell, Kate Abernethy, Patricia Alvarez, Victor Arroyo-Rodriguez, Peter Ashton, Julieta Benítez-Malvido, Allard Blom, Kadiri S. Bobo, Charles H. Cannon, Min Cao, Richard Carroll, Colin Chapman, Rosamond Coates, Marina Cords, Finn Danielsen, Bart De Dijn, Eric Dinerstein, Maureen A. Donnelly, David Edwards, Felicity Edwards, Nina Farwig, Peter Fashing, Pierre-Michel Forget, Mercedes Foster, George Gale, David Harris, Rhett Harrison, John Hart, Sarah Karpanty, W. John Kress, Jagdish Krishnaswamy, Willis Logsdon, Jon Lovett, William Magnusson, Fiona Maisels, Andrew R. Marshall, Deedra McClearn, Divya Mudappa, Martin R. Nielsen, Richard Pearson, Nigel Pitman, Jan van der Ploeg, Andrew Plumptre, John Poulsen, Mauricio Quesada, Hugo Rainey, Douglas Robinson, Christiane Roetgers, Francesco Rovero, Frederick Scatena, Christian Schulze, Douglas Sheil, Thomas Struhsaker, John Terborgh, Duncan Thomas, Robert Timm, J. Nicolas Urbina-Cardona, Karthikeyan Vasudevan, S. Joseph Wright, Juan Carlos Arias-G., Luzmila Arroyo, Mark Ashton, Philippe Auzel, Dennis Babaasa, Fred Babweteera, Patrick Baker, Olaf Banki, Margot Bass, Inogwabini Bila-Isia, Stephen Blake, Warren Brockelman, Nicholas Brokaw, Carsten A. Brühl, Sarayudh Bunyavejchewin, Jung-Tai Chao, Jerome Chave, Ravi Chellam, Connie J. Clark, José Clavijo, Robert Congdon, Richard Corlett, H. S. Dattaraja, Chittaranjan Dave, Glyn Davies, Beatriz de Mello Beisiegel, Rosa de Nazaré Paes da Silva, Anthony Di Fiore, Arvin Diesmos, Rodolfo Dirzo, Diane Doran-Sheehy, Mitchell Eaton, Louise Emmons, Alejandro Estrada, Corneille Ewango, Linda Fedigan, François Feer, Barbara Fruth, Jacalyn Giacalone Willis, Uromi Goodale, Steven Goodman, Juan C. Guix, Paul Guthiga, William Haber, Keith Hamer, Ilka Herbinger, Jane Hill, Zhongliang Huang, I Fang Sun, Kalan Ickes, Akira Itoh, Natália Ivanauskas, Betsy Jackes, John Janovec, Daniel Janzen, Mo Jiangming, Chen Jin, Trevor Jones, Hermes Justiniano, Elisabeth Kalko, Aventino Kasangaki, Timothy Killeen, Hen-biau King, Erik Klop, Cheryl Knott, Inza Koné, Enoka Kudavidanage, José Lahoz da Silva Ribeiro, John Lattke, Richard Laval, Robert Lawton, Miguel Leal, Mark Leighton, Miguel Lentino, Cristiane Leonel, Jeremy Lindsell, Lee Ling-Ling, K. Eduard Linsenmair, Elizabeth Losos, Ariel Lugo, Jeremiah Lwanga, Andrew L. Mack, Marlucia Martins, W. Scott McGraw, Roan McNab, Luciano Montag, Jo Myers Thompson, Jacob Nabe-Nielsen, Michiko Nakagawa, Sanjay Nepal, Marilyn Norconk, Vojtech Novotny, Sean O'Donnell, Muse Opiang, Paul Ouboter, Kenneth Parker, N. Parthasarathy, Kátia Pisciotta, Dewi Prawiradilaga, Catherine Pringle, Subaraj Rajathurai, Ulrich Reichard, Gay Reinartz, Katherine Renton, Glen Reynolds, Vernon Reynolds, Erin Riley, Mark-Oliver Rödel, Jessica Rothman, Philip Round, Shoko Sakai, Tania Sanaiotti, Tommaso Savini, Gertrud Schaab, John Seidensticker, Alhaji Siaka, Miles R. Silman, Thomas B. Smith, Samuel Soares de Almeida, Navjot Sodhi, Craig Stanford, Kristine Stewart, Emma Stokes, Kathryn E. Stoner, Raman Sukumar, Martin Surbeck, Mathias Tobler, Teja Tscharntke, Andrea Turkalo, Govindaswamy Umapathy, Merlijn van Weerd, Jorge Vega Rivera, Meena Venkataraman, Linda Venn, Carlos Verea, Carolina Volkmer de Castilho, Matthias Waltert, Benjamin Wang, David Watts, William Weber, Paige West, David Whitacre, Ken Whitney, David Wilkie, Stephen Williams, Debra D. Wright, Patricia Wright, Lu Xiankai, Pralad Yonzon & Franky Zamzan

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

International audienceSpinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signal-to-noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Open data from the first and second observing runs of Advanced LIGO and Advanced Virgo

Advanced LIGO and Advanced Virgo are monitoring the sky and collecting gravitational-wave strain data with sufficient sensitivity to detect signals routinely. In this paper we describe the data recorded by these instruments during their first and second observing runs. The main data products are gravitational-wave strain time series sampled at 16384 Hz. The datasets that include this strain measurement can be freely accessed through the Gravitational Wave Open Science Center at http://gw-openscience.org, together with data-quality information essential for the analysis of LIGO and Virgo data, documentation, tutorials, and supporting software

Search for intermediate-mass black hole binaries in the third observing run of Advanced LIGO and Advanced Virgo

International audienceIntermediate-mass black holes (IMBHs) span the approximate mass range 100−105 M⊙, between black holes (BHs) that formed by stellar collapse and the supermassive BHs at the centers of galaxies. Mergers of IMBH binaries are the most energetic gravitational-wave sources accessible by the terrestrial detector network. Searches of the first two observing runs of Advanced LIGO and Advanced Virgo did not yield any significant IMBH binary signals. In the third observing run (O3), the increased network sensitivity enabled the detection of GW190521, a signal consistent with a binary merger of mass ∼150 M⊙ providing direct evidence of IMBH formation. Here, we report on a dedicated search of O3 data for further IMBH binary mergers, combining both modeled (matched filter) and model-independent search methods. We find some marginal candidates, but none are sufficiently significant to indicate detection of further IMBH mergers. We quantify the sensitivity of the individual search methods and of the combined search using a suite of IMBH binary signals obtained via numerical relativity, including the effects of spins misaligned with the binary orbital axis, and present the resulting upper limits on astrophysical merger rates. Our most stringent limit is for equal mass and aligned spin BH binary of total mass 200 M⊙ and effective aligned spin 0.8 at 0.056 Gpc−3 yr−1 (90% confidence), a factor of 3.5 more constraining than previous LIGO-Virgo limits. We also update the estimated rate of mergers similar to GW190521 to 0.08 Gpc−3 yr−1.Key words: gravitational waves / stars: black holes / black hole physicsCorresponding author: W. Del Pozzo, e-mail: [email protected]† Deceased, August 2020