ATM localization and heterochromatin repair depend on Direct Interaction of the 53BP1-BRCT2 domain with γH2AX

53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications-H4K20me2 and H2AK13/K15ub-downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1

Pandemic Influenza and Pregnant Women

Planning for a future influenza pandemic should include considerations specific to pregnant women. First, pregnant women are at increased risk for influenza-associated illness and death. The effects on the fetus of maternal influenza infection, associated fever, and agents used for prophylaxis and treatment should be taken into account. Pregnant women might be reluctant to comply with public health recommendations during a pandemic because of concerns regarding effects of vaccines or medications on the fetus. Guidelines regarding nonpharmaceutical interventions (e.g., voluntary quarantine) also might present special challenges because of conflicting recommendations about routine prenatal care and delivery. Finally, healthcare facilities need to develop plans to minimize exposure of pregnant women to ill persons, while ensuring that women receive necessary care

Innovation and growth in the UK pharmaceuticals: the case of product and marketing introductions

New drug introductions are key to growth for pharmaceutical firms. However, not all innovations are the same and they may have differential effects that vary by firm size. We use quarterly sales data on UK pharmaceuticals in a dynamic panel model to estimate the impact of product (new drugs) and marketing (additional pack varieties) innovations within a therapeutic class on a firm’s business unit growth. We find that product innovations lead to substantial growth in both the short and long run, whereas a new pack variety only produces short-term effects. The strategies are substitutes but the marginal effects are larger for product innovations relative to additional packs, and the effects are larger for smaller business units. Nonetheless, pack introductions offer a viable short-term growth strategy, especially for small- and medium-sized businesses

The histone demethylase LSD1/KDM1A promotes the DNA damage response

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway

Factors associated with testicular self-examination among unaffected men from multiple-case testicular cancer families

<p>Abstract</p> <p>Background</p> <p>The lifetime testicular cancer (TC) risk in the general population is relatively low (~1 in 250), but men with a family history of TC are at 4 to 9 times greater risk than those without. Some health and professional organizations recommend consideration of testicular self-examination (TSE) for certain high-risk groups (e.g. men with a family history of TC). Yet little is known about factors associated with TSE behaviors in this at-risk group.</p> <p>Methods</p> <p>We collected information on this subject during an on-going NCI multidisciplinary, etiologically-focused, cross-sectional Familial Testicular Cancer (FTC) study. We present the first report specifically targeting TSE behaviors among first- and second-degree relatives (n = 99) of affected men from families with ≥ 2 TC cases. Demographic, medical, knowledge, health belief, and psychological factors consistent with the Health Belief Model (HBM) were evaluated as variables related to TSE behavior, using chi-square tests of association for categorical variables, and t-tests for continuous variables.</p> <p>Results</p> <p>For men in our sample, 46% (n = 46) reported performing TSE regularly and 51% (n = 50) reported not regularly performing TSE. Factors associated (p < .05) with regularly performing TSE in multivariate analysis were physician recommendation and testicular cancer worry. This is the first study to examine TSE in unaffected men from FTC families.</p> <p>Conclusion</p> <p>The findings suggest that, even in this high-risk setting, TSE practices are sub-optimal. Our data provide a basis for further exploring psychosocial issues that are specific to men with a family history of TC, and formulating intervention strategies aimed at improving adherence to TSE guidelines.</p

Epigenomic modifications mediating antibody maturation

Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer

The broad-band properties of the intermediate synchrotron peaked BL Lac S2 0109+22 from radio to VHE gamma-rays

The Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes observed S2 0109+22 in 2015 July during its flaring activity in high-energy gamma-rays observed by Fermi-Large Area Telescope. We analyse the MAGIC data to characterize the very high energy (VHE) gamma-ray emission of S2 0109+22, which belongs to the subclass of intermediate synchrotron peak (ISP) BL Lacertae (BL Lac) objects. We study the multifrequency emission in order to investigate the source classification. Finally, we compare the source long-term behaviour to other VHE gamma-ray emitting (TeV) blazars. We performed a temporal and spectral analysis of the data centred around the MAGIC interval of observation (MJD 57225-57231). Long-term radio and optical data have also been investigated using the discrete correlation function. The redshift of the source is estimated through optical host-galaxy imaging and also using the amount of VHE gamma-ray absorption. The quasi-simultaneous multifrequency spectral energy distribution (SED) is modelled with the conventional one-zone synchrotron self-Compton (SSC) model. MAGIC observations resulted in the detection of the source at a significance level of 5.3 sigma. The VHE gamma-ray emission of S2 0109+22 is variable on a daily time scale. VHE gamma-ray luminosity of the source is lower than the average of TeV BL Lacs. The optical polarization and long-term optical/radio behaviour of the source are different from the general population of TeV blazars. All these findings agree with the classification of the source as an ISP BL Lac object. We estimate the source redshift as z = 0.36 +/- 0.07. The SSC parameters describing the SED are rather typical for blazars

Investigating the peculiar emission from the new VHE gamma-ray source H1722+119

The Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes observed the BL Lac object H1722+119 (redshift unknown) for six consecutive nights between 2013 May 17 and 22, for a total of 12.5 h. The observations were triggered by high activity in the optical band measured by the KVA (Kungliga Vetenskapsakademien) telescope. The source was for the first time detected in the very high energy (VHE, E > 100 GeV) gamma-ray band with a statistical significance of 5.9s. The integral flux above 150 GeV is estimated to be (2.0 +/- 0.5) per cent of the Crab nebula flux. We used contemporaneous high energy (HE, 100 MeV < E < 100 GeV) gamma-ray observations from Fermi-Large Area Telescope to estimate the redshift of the source. Within the framework of the current extragalactic background light models, we estimate the redshift to be z = 0.34 +/- 0.15. Additionally, we used contemporaneous X-ray to radio data collected by the instruments on board the Swift satellite, the KVA, and the Owens Valley Radio Observatory telescope to study multifrequency characteristics of the source. We found no significant temporal variability of the flux in the HE and VHE bands. The flux in the optical and radio wavebands, on the other hand, did vary with different patterns. The spectral energy distribution of H1722+119 shows surprising behaviour in the similar to 3 x 10(14)-10(18) Hz frequency range. It can be modelled using an inhomogeneous helical jet synchrotron self-Compton model

Multi-wavelength characterization of the blazar S5 0716+714 during an unprecedented outburst phase

Context. The BL Lac object S5 0716+714, a highly variable blazar, underwent an impressive outburst in January 2015 (Phase A), followed by minor activity in February (Phase B). The MAGIC observations were triggered by the optical flux observed in Phase A, corresponding to the brightest ever reported state of the source in the R-band.Aims.The comprehensive dataset collected is investigated in order to shed light on the mechanism of the broadband emission.Methods. Multi-wavelength light curves have been studied together with the broadband spectral energy distributions (SEDs). The sample includes data from Effelsberg, OVRO, Metsahovi, VLBI, CARMA, IRAM, SMA, Swift-UVOT, KVA, Tuorla, Steward, RINGO3, KANATA, AZT-8+ST7, Perkins, LX-200, Swift-XRT, NuSTAR, Fermi-LAT and MAGIC.Results. The flaring state of Phase A was detected in all the energy bands, providing for the first time a multi-wavelength sample of simultaneous data from the radio band to the very-high-energy (VHE, E> 100 GeV). In the constructed SED, the Swift-XRT +NuSTAR data constrain the transition between the synchrotron and inverse Compton components very accurately, while the second peak is constrained from 0.1 GeV to 600 GeV by Fermi+MAGIC data. The broadband SED cannot be described with a one-zone synchrotron self-Compton model as it severely underestimates the optical flux in order to reproduce the X-ray to y-ray data. Instead we use a two-zone model. The electric vector position angle (EVPA) shows an unprecedented fast rotation. An estimation of the redshift of the source by combined high-energy (HE, 0.1 GeV < E < 100 GeV) and VHE data provides a value of ,z = 0.31 +/- 0.02(stats) +/- 0.05(sys), confirming the literature value.Conclusions. The data show the VHE emission originating in the entrance and exit of a superluminal knot in and out of a recollimation shock in the inner jet. A shock-shock interaction in the jet seems responsible for the observed flares and EVPA swing. This scenario is also consistent with the SED modeling

Multi-wavelength characterization of the blazar S5~0716+714 during an unprecedented outburst phase

The BL Lac object S5~0716+714, a highly variable blazar, underwent an impressive outburst in January 2015 (Phase A), followed by minor activity in February (Phase B). The MAGIC observations were triggered by the optical flux observed in Phase A, corresponding to the brightest ever reported state of the source in the R-band. The comprehensive dataset collected is investigated in order to shed light on the mechanism of the broadband emission. Multi-wavelength light curves have been studied together with the broadband Spectral Energy Distributions (SEDs). The data set collected spans from radio, optical photometry and polarimetry, X-ray, high-energy (HE, 0.1 GeV 100 GeV) with MAGIC. The flaring state of Phase A was detected in all the energy bands, providing for the first time a multi-wavelength sample of simultaneous data from the radio band to the VHE. In the constructed SED the \textit{Swift}-XRT+\textit{NuSTAR} data constrain the transition between the synchrotron and inverse Compton components very accurately, while the second peak is constrained from 0.1~GeV to 600~GeV by \textit{Fermi}+MAGIC data. The broadband SED cannot be described with a one-zone synchrotron self-Compton model as it severely underestimates the optical flux in order to reproduce the X-ray to $\gamma$-ray data. Instead we use a two-zone model. The EVPA shows an unprecedented fast rotation. An estimation of the redshift of the source by combined HE and VHE data provides a value of $z = 0.31 \pm 0.02_{stats} \pm 0.05_{sys}$, confirming the literature value. The data show the VHE emission originating in the entrance and exit of a superluminal knot in and out a recollimation shock in the inner jet. A shock-shock interaction in the jet seems responsible for the observed flares and EVPA swing. This scenario is also consistent with the SED modelling