Genome Integrity And Cell Division: Next-Generation Answers To Enduring Questions

Studies of genome integrity have been historically limited to low-resolution tools that afford little-to-no information on precise genomic locations of DNA damage. Because many sources of genomic instability begin with endogenous DNA breaks at specific genetic sequences, it is possible to develop new, next-generation sequencing approaches to understand classic cytological observations in the field of DNA repair. I have employed here protocols to map DNA breaks (END-seq) and nascent DNA synthesis (EdU-seq) to address mechanisms of genomic instability during both meiosis and mitosis. Cell division presents unique challenges to genome integrity. During meiosis, the enzyme SPO11 generates intentional, requisite DNA breaks to initiate meiotic recombination and homologous chromosome synapsis. In contrast, DNA damage during mitosis is primarily used to prevent deleterious outcomes that have been implicated in cancer and age-related pathologies. I have utilized and modified next-gen technologies to address numerous unanswered mechanisms of fragility and repair during both meiosis and mitosis. While it is common to think of DNA repair as evolved processes that combat environment-derived damage, these studies in cell division, a process that relies on inducing and repairing damage, illustrate a different evolutionary perspective in which damage and repair are also controlled pathways to maintain and adapt genomes across the tree of life

Searching for VHE gamma-ray emission associated with IceCube neutrino alerts using FACT, H.E.S.S., MAGIC, and VERITAS

The realtime follow-up of neutrino events is a promising approach to searchfor astrophysical neutrino sources. It has so far provided compelling evidencefor a neutrino point source: the flaring gamma-ray blazar TXS 0506+056 observedin coincidence with the high-energy neutrino IceCube-170922A detected byIceCube. The detection of very-high-energy gamma rays (VHE, $\mathrm{E} >100\,\mathrm{GeV}$) from this source helped establish the coincidence andconstrained the modeling of the blazar emission at the time of the IceCubeevent. The four major imaging atmospheric Cherenkov telescope arrays (IACTs) -FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program oftarget-of-opportunity observations of neutrino alerts sent by IceCube. Thisprogram has two main components. One are the observations of known gamma-raysources around which a cluster of candidate neutrino events has been identifiedby IceCube (Gamma-ray Follow-Up, GFU). Second one is the follow-up of singlehigh-energy neutrino candidate events of potential astrophysical origin such asIceCube-170922A. GFU has been recently upgraded by IceCube in collaborationwith the IACT groups. We present here recent results from the IACT follow-upprograms of IceCube neutrino alerts and a description of the upgraded IceCubeGFU system.<br

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

Genome Integrity and Cell Division: Next-Generation Answers to Enduring Questions

Studies of genome integrity have been historically limited to low-resolution tools that afford little-to-no information on precise genomic locations of DNA damage. Because many sources of genomic instability begin with endogenous DNA breaks at specific genetic sequences, it is possible to develop new, next-generation sequencing approaches to understand classic cytological observations in the field of DNA repair. I have employed here protocols to map DNA breaks (END-seq) and nascent DNA synthesis (EdU-seq) to address mechanisms of genomic instability during both meiosis and mitosis. Cell division presents unique challenges to genome integrity. During meiosis, the enzyme SPO11 generates intentional, requisite DNA breaks to initiate meiotic recombination and homologous chromosome synapsis. In contrast, DNA damage during mitosis is primarily used to prevent deleterious outcomes that have been implicated in cancer and age-related pathologies. I have utilized and modified next-gen technologies to address numerous unanswered mechanisms of fragility and repair during both meiosis and mitosis. While it is common to think of DNA repair as evolved processes that combat environment-derived damage, these studies in cell division, a process that relies on inducing and repairing damage, illustrate a different evolutionary perspective in which damage and repair are also controlled pathways to maintain and adapt genomes across the tree of life

ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis

Meiotic recombination is initiated by SPO11-induced double-strand breaks (DSBs). In most mammals, the methyltransferase PRDM9 guides SPO11 targeting, and the ATM kinase controls meiotic DSB numbers. Following MRE11 nuclease removal of SPO11, the DSB is resected and loaded with DMC1 filaments for homolog invasion. Here, we demonstrate the direct detection of meiotic DSBs and resection using END-seq on mouse spermatocytes with low sample input. We find that DMC1 limits both minimum and maximum resection lengths, whereas 53BP1, BRCA1 and EXO1 play surprisingly minimal roles. Through enzymatic modifications to END-seq, we identify a SPO11-bound meiotic recombination intermediate (SPO11-RI) present at all hotspots. We propose that SPO11-RI forms because chromatin-bound PRDM9 asymmetrically blocks MRE11 from releasing SPO11. In Atm–/– spermatocytes, trapped SPO11 cleavage complexes accumulate due to defective MRE11 initiation of resection. Thus, in addition to governing SPO11 breakage, ATM and PRDM9 are critical local regulators of mammalian SPO11 processing

Constraints on particle acceleration in SS433/W50 from MAGIC and H.E.S.S. observations

Context. The large jet kinetic power and non-thermal processes occurring in the microquasar SS 433 make this source a good candidate for a very high-energy (VHE) gamma-ray emitter. Gamma-ray fluxes above the sensitivity limits of current Cherenkov telescopes have been predicted for both the central X-ray binary system and the interaction regions of SS 433 jets with the surrounding W50 nebula. Non-thermal emission at lower energies has been previously reported, indicating that efficient particle acceleration is taking place in the system.Aim. We explore the capability of SS 433 to emit VHE gamma rays during periods in which the expected flux attenuation due to periodic eclipses (Porb~ 13.1 days) and precession of the circumstellar disk (Ppre ~ 162 days) periodically covering the central binary system is expected to be at its minimum. The eastern and western SS 433/W50 interaction regions are also examined using the whole data set available. We aim to constrain some theoretical models previously developed for this system with our observations.Methods. We made use of dedicated observations from the Major Atmospheric Gamma Imaging Cherenkov telescopes (MAGIC) and High Energy Spectroscopic System (H.E.S.S.) of SS 433 taken from 2006 to 2011. These observation were combined for the first time and accounted for a total effective observation time of 16.5 h, which were scheduled considering the expected phases of minimum absorption of the putative VHE emission. Gamma-ray attenuation does not affect the jet/medium interaction regions. In this case, the analysis of a larger data set amounting to ~40–80 h, depending on the region, was employed.Results. No evidence of VHE gamma-ray emission either from the central binary system or from the eastern/western interaction regions was found. Upper limits were computed for the combined data set. Differential fluxes from the central system are found to be ≲ 10−12–10−13 TeV−1 cm−2 s−1 in an energy interval ranging from ~few × 100 GeV to ~few TeV. Integral flux limits down to ~ 10−12–10−13 ph cm−2 s−1 and ~ 10−13–10−14 ph cm−2 s−1 are obtainedat 300 and 800 GeV, respectively. Our results are used to place constraints on the particle acceleration fraction at the inner jetregions and on the physics of the jet/medium interactions.Conclusions. Our findings suggest that the fraction of the jet kinetic power that is transferred to relativistic protons must be relatively small in SS 433, qp ≤ 2.5 × 10−5, to explain the lack of TeV and neutrino emission from the central system. At the SS 433/W50 interface, the presence of magnetic fields ≳10 μG is derived assuming a synchrotron origin for the observed X-ray emission. This also implies the presence of high-energy electrons with Ee− up to 50 TeV, preventing an efficient production of gamma-ray fluxes in these interaction regions.Key words: gamma rays: general / stars: black holes / X-rays: binaries / ISM: jets and outflow

Combined dark matter searches towards dwarf spheroidal galaxies with Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS

Cosmological and astrophysical observations suggest that 85% of the total matter of the Universe is made of Dark Matter (DM). However, its nature remains one of the most challenging and fundamental open questions of particle physics. Assuming particle DM, this exotic form of matter cannot consist of Standard Model (SM) particles. Many models have been developed to attempt unraveling the nature of DM such as Weakly Interacting Massive Particles (WIMPs), the most favored particle candidates. WIMP annihilations and decay could produce SM particles which in turn hadronize and decay to give SM secondaries such as high energy γ rays. In the framework of indirect DM search, observations of promising targets are used to search for signatures of DM annihilation. Among these, the dwarf spheroidal galaxies (dSphs) are commonly favored owing to their expected high DM content and negligible astrophysical background. In this work, we present the very first combination of 20 dSph observations, performed by the Fermi-LAT, HAWC, H.E.S.S., MAGIC, and VERITAS collaborations in order to maximize the sensitivity of DM searches and improve the current results. We use a joint maximum likelihood approach combining each experiment’s individual analysis to derive more constraining upper limits on the WIMP DM self-annihilation cross-section as a function of DM particle mass. We present new DM constraints over the widest mass range ever reported, extending from 5 GeV to 100 TeV thanks to the combination of these five different γ-ray instruments