Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses

Clusters of Sexual Behavior in Human Immunodeficiency Virus-positive Men Who Have Sex With Men Reveal Highly Dissimilar Time Trends.

Separately addressing specific groups of people who share patterns of behavioral change might increase the impact of behavioral interventions to prevent transmission of sexually transmitted infections. We propose a method based on machine learning to assist the identification of such groups among men who have sex with men (MSM). By means of unsupervised learning, we inferred "behavioral clusters" based on the recognition of similarities and differences in longitudinal patterns of condomless anal intercourse with nonsteady partners (nsCAI) in the HIV Cohort Study over the last 18 years. We then used supervised learning to investigate whether sociodemographic variables could predict cluster membership. We identified 4 behavioral clusters. The largest behavioral cluster (cluster 1) contained 53% of the study population and displayed the most stable behavior. Cluster 3 (17% of the study population) displayed consistently increasing nsCAI. Sociodemographic variables were predictive for both of these clusters. The other 2 clusters displayed more drastic changes: nsCAI frequency in cluster 2 (20% of the study population) was initially similar to that in cluster 3 but accelerated in 2010. Cluster 4 (10% of the study population) had significantly lower estimates of nsCAI than all other clusters until 2017, when it increased drastically, reaching 85% by the end of the study period. We identified highly dissimilar behavioral patterns across behavioral clusters, including drastic, atypical changes. The patterns suggest that the overall increase in the frequency of nsCAI is largely attributable to 2 clusters, accounting for a third of the population

Motion of influential players can support cooperation in Prisoner's Dilemma

We study a spatial Prisoner's dilemma game with two types (A and B) of players located on a square lattice. Players following either cooperator or defector strategies play Prisoner's Dilemma games with their 24 nearest neighbors. The players are allowed to adopt one of their neighbor's strategy with a probability dependent on the payoff difference and type of the given neighbor. Players A and B have different efficiency in the transfer of their own strategy therefore the strategy adoption probability is reduced by a multiplicative factor (w < 1) from the players of type B. We report that the motion of the influential payers (type A) can improve remarkably the maintenance of cooperation even for their low densities.Comment: 7 pages, 7 figure

Design of a bed load and driftwood filtering dam, analysis of the phenomena and hydraulic design

Flood protection often calls on to the realization of retention works for bed load as well as wood and debris flow. Certain relatively recent arrangements did not perform according to their intended function, what shows the complexity of the design and the implementation of such works. Adaptations were necessary to reach the security objectives. The design of a retention dam for solid materials and floating driftwood requires the consideration of numerous hydraulic and material transport processes. The analyses and design validation can be made with two approaches: physical modelling by the construction of a reduced scale model and the test realization or numerical simulation, by means of software packages such as GESMAT (1D) or TOPOFLOW (2D). The present work consists in implementing both approaches, in estimating and in comparing the answers which could be given for a bed load and debris flow filtering dam on a river with a slope of the order of 10%. Thanks to water level gauges and visual observations during tests on the physical model, the progression of the obstructions by driftwood and bed load is well understood, and the effectiveness of these obstructions proven. The tested work plays at first a role of filtering and retention and secondly a role of side overflow towards a zone with low damage potential, when the capacity of the in-stream retention space is reached. The performed numerical simulations, essentially in 1D, reproduce well the phenomena of bed load aggradation. Moreover, the potential obstruction by floating wood is considered and influences the behavior of the structure. By putting in parallel physical and numerical models, it was possible thanks to the results from the physical scale model to refine the numerical simulation tools taking into consideration additional components and behavior-type rules. These further established rules can now be used for other cases where physical modelling is not foreseen

Acoustic and optical variations during rapid downward motion episodes in the deep north-western Mediterranean Sea

An Acoustic Doppler Current Profiler (ADCP) was moored at the deep-sea site of the ANTARES neutrino telescope near Toulon, France, thus providing a unique opportunity to compare high-resolution acoustic and optical observations between 70 and 170 m above the sea bed at 2475 m. The ADCP measured downward vertical currents of magnitudes up to 0.03 m s-1 in late winter and early spring 2006. In the same period, observations were made of enhanced levels of acoustic reflection, interpreted as suspended particles including zooplankton, by a factor of about 10 and of horizontal currents reaching 0.35 m s-1. These observations coincided with high light levels detected by the telescope, interpreted as increased bioluminescence. During winter 2006 deep dense-water formation occurred in the Ligurian subbasin, thus providing a possible explanation for these observations. However, the 10-20 days quasi-periodic episodes of high levels of acoustic reflection, light and large vertical currents continuing into the summer are not direct evidence of this process. It is hypothesized that the main process allowing for suspended material to be moved vertically later in the year is local advection, linked with topographic boundary current instabilities along the rim of the 'Northern Current'.Comment: 30 pages, 7 figure

Time calibration of the ANTARES neutrino telescope

The ANTARES deep-sea neutrino telescope comprises a three-dimensional array of photomultipliers to detect the Cherenkov light induced by upgoing relativistic charged particles originating from neutrino interactions in the vicinity of the detector. The large scattering length of light in the deep sea facilitates an angular resolution of a few tenths of a degree for neutrino energies exceeding 10 TeV. In order to achieve this optimal performance, the time calibration procedures should ensure a relative time calibration between the photomultipliers at the level of similar to 1 ns. The methods developed to attain this level of precision are described

Performance of the front-end electronics of the ANTARES neutrino telescope

ANTARES is a high-energy neutrino telescope installed in the Mediterranean Sea at a depth of 2475 m. It consists of a three-dimensional array of optical modules, each containing a large photomultiplier tube. A total of 2700 front-end ASICs named Analogue Ring Samplers (ARS) process the phototube signals, measure their arrival time, amplitude and shape as well as perform monitoring and calibration tasks. The ARS chip processes the analogue signals from the optical modules and converts information into digital data. All the information is transmitted to shore through further multiplexing electronics and an optical link. This paper describes the performance of the ARS chip; results from the functionality and characterization tests in the laboratory are summarized and the long-term performance in the apparatus is illustrated.Comment: 20 pages, 22 figures, published in Nuclear Instruments and Methods

Search for a diffuse flux of high-energy νμ\nu_\mu with the ANTARES neutrino telescope

A search for a diffuse flux of astrophysical muon neutrinos, using data collected by the ANTARES neutrino telescope is presented. A $(0.83\times 2\pi)$ sr sky was monitored for a total of 334 days of equivalent live time. The searched signal corresponds to an excess of events, produced by astrophysical sources, over the expected atmospheric neutrino background. The observed number of events is found compatible with the background expectation. Assuming an $E^{-2}$ flux spectrum, a 90% c.l. upper limit on the diffuse $\nu_\mu$ flux of E^2\Phi_{90%} = 5.3 \times 10^{-8} \ \mathrm{GeV\ cm^{-2}\ s^{-1}\ sr^{-1}} in the energy range 20 TeV - 2.5 PeV is obtained. Other signal models with different energy spectra are also tested and some rejected.Comment: 14 pages, 6 figure