An approach for verifying biogenic greenhouse gas emissions inventories with atmospheric CO₂ concentration data

Verifying national greenhouse gas (GHG) emissions inventories is a critical step to ensure that reported emissions data to the United Nations Framework Convention on Climate Change (UNFCCC) are accurate and representative of a country\u27s contribution to GHG concentrations in the atmosphere. Furthermore, verifying biogenic fluxes provides a check on estimated emissions associated with managing lands for carbon sequestration and other activities, which often have large uncertainties. We report here on the challenges and results associated with a case study using atmospheric measurements of CO₂ concentrations and inverse modeling to verify nationally-reported biogenic CO₂ emissions. The biogenic CO₂ emissions inventory was compiled for the Mid-Continent region of United States based on methods and data used by the US government for reporting to the UNFCCC, along with additional sources and sinks to produce a full carbon balance. The biogenic emissions inventory produced an estimated flux of −408 ± 136 Tg CO₂ for the entire study region, which was not statistically different from the biogenic flux of −478 ± 146 Tg CO₂ that was estimated using the atmospheric CO₂concentration data. At sub-regional scales, the spatial density of atmospheric observations did not appear sufficient to verify emissions in general. However, a difference between the inventory and inversion results was found in one isolated area of West-central Wisconsin. This part of the region is dominated by forestlands, suggesting that further investigation may be warranted into the forest C stock or harvested wood product data from this portion of the study area. The results suggest that observations of atmospheric CO₂ concentration data and inverse modeling could be used to verify biogenic emissions, and provide more confidence in biogenic GHG emissions reporting to the UNFCCC

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial

Background: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. Methods: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2–6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1–5, cyclophosphamide 150 mg/m2 per day orally on days 1–5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. Findings: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56–67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41–61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63–NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32–0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. Interpretation: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. Funding: Cancer Research UK and Janssen

BCAR3 Regulates Src/p130Cas Association, Src Kinase Activity, and Breast Cancer Adhesion Signaling*

The nonreceptor protein-tyrosine kinase c-Src is frequently overexpressed and/or activated in a variety of cancers, including those of the breast. Several heterologous binding partners of c-Src have been shown to regulate its catalytic activity by relieving intramolecular autoinhibitory interactions. One such protein, p130Cas (Cas), is expressed at high levels in both breast cancer cell lines and breast tumors, providing a potential mechanism for c-Src activation in breast cancers. The Cas-binding protein BCAR3 (breast cancer antiestrogen resistance-3) is expressed at high levels in invasive breast cancer cell lines, and this molecule has previously been shown to coordinate with Cas to increase c-Src activity in COS-1 cells. In this study, we show for the first time using gain- and loss-of-function approaches that BCAR3 regulates c-Src activity in the endogenous setting of breast cancer cells. We further show that BCAR3 regulates the interaction between Cas and c-Src, both qualitatively as well as quantitatively. Finally, we present evidence that the coordinated activity of these proteins contributes to breast cancer cell adhesion signaling and spreading. Based on these data, we propose that the c-Src/Cas/BCAR3 signaling axis is a prominent regulator of c-Src activity, which in turn controls cell behaviors that lead to aggressive and invasive breast tumor phenotypes

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges

Measurements of ttˉt\bar{t} differential cross-sections of highly boosted top quarks decaying to all-hadronic final states in pppp collisions at s=13 \sqrt{s}=13\, TeV using the ATLAS detector

Measurements are made of differential cross-sections of highly boosted pair-produced top quarks as a function of top-quark and $t\bar{t}$ system kinematic observables using proton--proton collisions at a center-of-mass energy of $\sqrt{s} = 13$ TeV. The data set corresponds to an integrated luminosity of $36.1$ fb$^{-1}$, recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Events with two large-radius jets in the final state, one with transverse momentum $p_{\rm T} > 500$ GeV and a second with $p_{\rm T}>350$ GeV, are used for the measurement. The top-quark candidates are separated from the multijet background using jet substructure information and association with a $b$-tagged jet. The measured spectra are corrected for detector effects to a particle-level fiducial phase space and a parton-level limited phase space, and are compared to several Monte Carlo simulations by means of calculated $\chi^2$ values. The cross-section for $t\bar{t}$ production in the fiducial phase-space region is $292 \pm 7 \ \rm{(stat)} \pm 76 \rm{(syst)}$ fb, to be compared to the theoretical prediction of $384 \pm 36$ fb

Measurements of ttˉt\bar{t} differential cross-sections of highly boosted top quarks decaying to all-hadronic final states in pppp collisions at s=13 \sqrt{s}=13\, TeV using the ATLAS detector

Measurements are made of differential cross-sections of highly boosted pair-produced top quarks as a function of top-quark and $t\bar{t}$ system kinematic observables using proton--proton collisions at a center-of-mass energy of $\sqrt{s} = 13$ TeV. The data set corresponds to an integrated luminosity of $36.1$ fb$^{-1}$, recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Events with two large-radius jets in the final state, one with transverse momentum $p_{\rm T} > 500$ GeV and a second with $p_{\rm T}>350$ GeV, are used for the measurement. The top-quark candidates are separated from the multijet background using jet substructure information and association with a $b$-tagged jet. The measured spectra are corrected for detector effects to a particle-level fiducial phase space and a parton-level limited phase space, and are compared to several Monte Carlo simulations by means of calculated $\chi^2$ values. The cross-section for $t\bar{t}$ production in the fiducial phase-space region is $292 \pm 7 \ \rm{(stat)} \pm 76 \rm{(syst)}$ fb, to be compared to the theoretical prediction of $384 \pm 36$ fb