Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Orientation-Specific Joining of AID-initiated DNA Breaks Promotes Antibody Class Switching

During B cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cμ constant region exons1,2. In mice, six additional sets of constant region exons (CHs) lie 100-200 kb downstream in the same transcriptional orientation as V(D)J and Cμ exons2. Long repetitive switch (S) regions precede Cμ and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cμ with a downstream CH2. Activation-Induced Cytidine Deaminase (AID) initiates CSR by promoting deamination lesions within Sμ and a downstream acceptor S region2,3; these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors3. Productive CSR must occur in a deletional orientation by joining the upstream end of an Sμ DSB to the downstream end of an acceptor S region DSB (Fig. 1a). However, the relative frequency of deletional to inversional CSR junctions had not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D)J recombination and, if so, how this is achieved was unknown. To address this question, we adapted high-throughput genome-wide translocation sequencing (HTGTS)4 into a highly sensitive DSB end-joining assay and applied it to endogenous AID-initiated S region DSBs. We find that CSR indeed is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis IgH organizational features in combination with frequent S region DSBs initiated by AID. We further implicate ATM-dependent DSB response (DSBR) factors in enforcing this mechanism and provide a solution to the enigma of why CSR is so reliant on the 53BP1 DSBR factor

The Effect of Molecular Subtype and Residual Disease on Locoregional Recurrence in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy and Postmastectomy Radiation

BACKGROUND: The relative contribution of biologic subtype to locoregional recurrence (LRR) in patients who have been treated with neoadjuvant chemotherapy (NAC), mastectomy and postmastectomy radiotherapy (PMRT) is not clearly defined. METHODS: 233 patients with Stage II-III breast cancer received NAC, mastectomy and PMRT between 2000-2009: 53% (n=123) had HR+ (ER or PR+/HER2−), 23% (n=53) had HER2+ (HER2+/HR+ or HR−), and 24% (n=57) had triple negative disease (TN: HR−/HER2−). The 5-year LRR rates were estimated by Kaplan-Meier methods. Cox regression analysis was performed to evaluate covariates associated with LRR. RESULTS: Median follow-up was 62 months. A pathologic complete response (pCR) was seen in 14% of patients. The 5-year LRR rate was 8% in the entire cohort. The LRR rate was 0% in patients with a pCR versus 9% in patients without a pCR (p=0.05). TN disease (HR=4.4, p=0.003) and pathologic node positivity (HR=9.8, p=0.03) were associated with LRR. Patients with TN disease had a higher LRR rate compared to patients with HER2+ and HR+ disease (20% versus 6% and 4%, p=0.005). In patients without a pCR, TN subtype was associated with increased LRR (26% versus 7% HER+ and 4% HR+, p<0.001). CONCLUSIONS: Patients with TN breast cancer had the highest LRR rate after NAC, mastectomy and PMRT. While no LRR was observed in TN patients with pCR, TN patients with residual disease had significantly higher LRR risk. Patients with HR+ and HER2+ breast cancer had favorable LRR rates, regardless of NAC response, likely due to receipt of adjuvant systemic targeted therapies

A Numerical Simulation of Residual Circulation in Tampa Bay. Part I: Low-frequency Temporal Variations

The residual (time-average) salinity and circulation in a numerical ocean model of the Tampa Bay estuary are shown to experience significant temporal variation under realistic forcing conditions. A version of the Estuarine Coastal Ocean Model developed for Tampa Bay with 70 by 100 horizontal grid points and 11 sigma levels is examined for the years 2001–2003. Model output variables are averaged over the entire time of the simulation to generate long-term residual fields. The residual axial current is found to be dominated by the buoyancy-driven baroclinic circulation with an outflow (southwestward) at the surface and to the sides of the shipping channel, and an inflow (northeastward) usually occurring subsurface within or above the shipping channel. Averages over 30 d are used to examine variations in the residual fields. During the simulation the average surface salinity near the head of Tampa Bay varies with the freshwater inflow, from 12‰ to 33%. At the bay mouth salinity varies from 30%. to 36%.. A localized measure of the baroclinic circulation in the shipping channel indicates the residual circulation can vary strongly, attaining a magnitude triple the long-term mean value. The baroclinic circulation can be disrupted, going to near zero or even reversing, when the buoyancy-driven flow is weak and the surface winds are to the northeast. Three time periods, representing different environmental conditions, are chosen to examine these results in detail. A scaling argument indicates the relative strength of buoyancy versus wind as ΔρgH2(LC Dω2)−1, where δρ is head-to-mouth density difference across the bay,g is gravitational acceleration,H is depth,L is bay length,C D is the surface wind drag coefficient, andw is wind speed. Tampa Bay is usually in the buoyancy dominated regime. The importance of winds in the weak-buoyancy case is demonstrated in an additional simulation without wind stress

P2X7-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy

RationaleThe function of the P2X(7) nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.ObjectivesTo evaluate the association between P2X(7), asthma exacerbations, and incomplete symptom control in a more diverse population.MethodsA matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X(7) pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently.Measurements and main resultsA total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β(2)-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV(1) reversal (P &lt; 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase.ConclusionsP2X(7) pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy