Structure determination of GPCRs: cryo-EM compared with X-ray crystallography

G protein-coupled receptors (GPCRs) are the largest single family of cell surface receptors encoded by the human genome and they play pivotal roles in co-ordinating cellular systems throughout the human body, making them ideal drug targets. Structural biology has played a key role in defining how receptors are activated and signal through G proteins and beta-arrestins. The application of structure-based drug design (SBDD) is now yielding novel compounds targeting GPCRs. There is thus significant interest from both academia and the pharmaceutical industry in the structural biology of GPCRs as currently only about one quarter of human non-odorant receptors have had their structure determined. Initially, all the structures were determined by X-ray crystallography, but recent advances in electron cryo-microscopy (cryo-EM) now make GPCRs tractable targets for single-particle cryo-EM with comparable resolution to X-ray crystallography. So far this year, 78% of the 99 GPCR structures deposited in the PDB (Jan-Jul 2021) were determined by cryo-EM. Cryo-EM has also opened up new possibilities in GPCR structural biology, such as determining structures of GPCRs embedded in a lipid nanodisc and multiple GPCR conformations from a single preparation. However, X-ray crystallography still has a number of advantages, particularly in the speed of determining many structures of the same receptor bound to different ligands, an essential prerequisite for effective SBDD. We will discuss the relative merits of cryo-EM and X-ray crystallography for the structure determination of GPCRs and the future potential of both techniques

The CLIMPACTS synthesis report: An assessment of the effects of climate change and variation in New Zealand using the CLIMPACTS system

In the late 1980s, New Zealand undertook the first national assessment of climate change and its possible impacts on the country.The landmark report, reflecting the judgement of scores of national experts, called for greater efforts in building the national research capacity in order to better quantify the range of impacts that could occur in New Zealand from climate change and variability. In response, the collaborative CLIMPACTS Programme was established to provide this capacity. Ten years on from the first national assessment, the present synthesis offers some results from, as well as a demonstration of, the capacity developed by the CLIMPACTS Programme. The purpose of the present document is to provide a summary report from the CLIMPACTS Programme on climate change and its effects on New Zealand.The chapters and their contents are not comprehensive. Rather, they are focused on a specific set of questions, which conform to the particular expertise of the CLIMPACTS Programme members and which employ a limited set of the wide range of tools available within the CLIMPACTS Model. Other important areas such as forests, indigenous ecosystems and pests and diseases are not yet covered

Measurement of the total cross section and ρ -parameter from elastic scattering in pp collisions at √s=13 TeV with the ATLAS detector

In a special run of the LHC with β⋆=2.5 km, proton–proton elastic-scattering events were recorded at s√=13 TeV with an integrated luminosity of 340 μb−1 using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from −t=2.5⋅10−4 GeV2 to −t=0.46 GeV2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σtot, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t→0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σtot and ρ are σtot(pp→X)=104.7±1.1 mb ,ρ=0.098±0.011. The uncertainty in σtot is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude.publishedVersio

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.New methods for child psychiatric diagnosis and treatment outcome evaluatio

Precision measurement of the B0 meson lifetime using B0 → J/ψ K∗0 decays with the ATLAS detector

Abstract A measurement of the $$B^{0}$$ B 0 meson lifetime using $$B^{0} \rightarrow J/\psi K^{*0}$$ B 0 → J / ψ K ∗ 0 decays in data from 13  $$\text {TeV}$$ TeV proton–proton collisions with an integrated luminosity of $$140~\mathrm {fb^{-1}}$$ 140 fb - 1 recorded by the ATLAS detector at the LHC is presented. The measured effective lifetime is $$\tau = 1.5053\pm 0.0012~\mathrm {(stat.)} \pm 0.0035~\mathrm {(syst.)~ps}.$$ τ = 1.5053 ± 0.0012 ( stat . ) ± 0.0035 ( syst . ) ps . The average decay width extracted from the effective lifetime, using parameters from external sources, is $$\begin{aligned} \Gamma _d = 0.6639\pm 0.0005~\mathrm {(stat.)} \pm 0.0016~\mathrm {(syst.)}\\ \pm 0.0038~\text {(ext.)} \text {~ps}^{-1}, \end{aligned}$$ Γ d = 0.6639 ± 0.0005 ( stat . ) ± 0.0016 ( syst . ) ± 0.0038 (ext.) ps - 1 , where the uncertainties are statistical, systematic and from external sources. The earlier ATLAS measurement of $$\Gamma _s$$ Γ s in the $$B^{0}_{s} \rightarrow J/\psi \phi$$ B s 0 → J / ψ ϕ decay was used to derive a value for the ratio of the average decay widths $$\Gamma _d$$ Γ d and $$\Gamma _s$$ Γ s for $$B^{0}$$ B 0 and $$B^{0}_{s}$$ B s 0 mesons respectively, of $$\frac{\Gamma _d }{\Gamma _s } = 0.9905\pm 0.0022~\text {(stat.)} \pm 0.0036~\text {(syst.)} \pm 0.0057~\text {(ext.)}.$$ Γ d Γ s = 0.9905 ± 0.0022 (stat.) ± 0.0036 (syst.) ± 0.0057 (ext.) . The measured lifetime, average decay width and decay width ratio are in agreement with theoretical predictions and with measurements by other experiments. This measurement provides the most precise result of the effective lifetime of the $$B^{0}$$ B 0 meson to date. </jats:p

Observation of quantum entanglement with top quarks at the ATLAS detector

Entanglement is a key feature of quantum mechanics with applications in fields such as metrology, cryptography, quantum information and quantum computation. It has been observed in a wide variety of systems and length scales, ranging from the microscopic to the macroscopic. However, entanglement remains largely unexplored at the highest accessible energy scales. Here we report the highest-energy observation of entanglement, in top–antitop quark events produced at the Large Hadron Collider, using a proton–proton collision dataset with a centre-of-mass energy of √s = 13 TeV and an integrated luminosity of 140 inverse femtobarns (fb)−1 recorded with the ATLAS experiment. Spin entanglement is detected from the measurement of a single observable D, inferred from the angle between the charged leptons in their parent top- and antitop-quark rest frames. The observable is measured in a narrow interval around the top–antitop quark production threshold, at which the entanglement detection is expected to be significant. It is reported in a fiducial phase space defined with stable particles to minimize the uncertainties that stem from the limitations of the Monte Carlo event generators and the parton shower model in modelling top-quark pair production. The entanglement marker is measured to be D = −0.537 ± 0.002 (stat.) ± 0.019 (syst.) for 340 GeV < mtt < 380 GeV. The observed result is more than five standard deviations from a scenario without entanglement and hence constitutes the first observation of entanglement in a pair of quarks and the highest-energy observation of entanglement so far

Search for charged Higgs bosons produced in top-quark decays or in association with top quarks and decaying via H±→τ±ντ in 13 TeV pp collisions with the ATLAS detector

Charged Higgs bosons produced either in top-quark decays or in association with a top quark, subsequently decaying via H±→τ±ντ, are searched for in 140  fb−1 of proton-proton collision data at s=13  TeV recorded with the ATLAS detector. Depending on whether the top quark is produced together with the H± decays hadronically or semileptonically, the search targets τ+jets or τ+lepton final states, in both cases with a τ-lepton decaying into a neutrino and hadrons. No significant excess over the Standard Model background expectation is observed. For the mass range of 80≤mH±≤3000  GeV, upper limits at 95% confidence level are set on the production cross section of the charged Higgs boson times the branching fraction B(H±→τ±ντ) in the range 4.5 pb–0.4 fb. In the mass range 80–160 GeV, assuming the Standard Model cross section for tt¯ production, this corresponds to upper limits between 0.27% and 0.02% on B(t→bH±)×B(H±→τ±ντ).</jats:p

The performance of missing transverse momentum reconstruction and its significance with the ATLAS detector using 140 fb-1 of √s = 13 TeV TeV pp collisions

Abstract This paper presents the reconstruction of missing transverse momentum ( $$p_{\text {T}}^{\text {miss}}$$ p T miss ) in proton–proton collisions, at a center-of-mass energy of 13 TeV. This is a challenging task involving many detector inputs, combining fully calibrated electrons, muons, photons, hadronically decaying $$\tau$$ τ -leptons, hadronic jets, and soft activity from remaining tracks. Possible double counting of momentum is avoided by applying a signal ambiguity resolution procedure which rejects detector inputs that have already been used. Several $$p_{\text {T}}^{\text {miss}}$$ p T miss ‘working points’ are defined with varying stringency of selections, the tightest improving the resolution at high pile-up by up to 39% compared to the loosest. The $$p_{\text {T}}^{\text {miss}}$$ p T miss performance is evaluated using data and Monte Carlo simulation, with an emphasis on understanding the impact of pile-up, primarily using events consistent with leptonic Z decays. The studies use $$140~\text {fb}^{-1}$$ 140 fb - 1 of data, collected by the ATLAS experiment at the Large Hadron Collider between 2015 and 2018. The results demonstrate that $$p_{\text {T}}^{\text {miss}}$$ p T miss reconstruction, and its associated significance, are well understood and reliably modelled by simulation. Finally, the systematic uncertainties on the soft $$p_{\text {T}}^{\text {miss}}$$ p T miss component are calculated. After various improvements the scale and resolution uncertainties are reduced by up to $$76\%$$ 76 % and $$51\%$$ 51 % , respectively, compared to the previous calculation at a lower luminosity

Search for heavy Majorana or Dirac neutrinos and right-handed W gauge bosons in final states with charged leptons and jets in pp collisions at √s = 13 TeV with the ATLAS detector

A search for heavy right-handed Majorana or Dirac neutrinos NR and heavy right-handed gauge bosons WR is performed in events with energetic electrons or muons, with the same or opposite electric charge, and energetic jets. The search is carried out separately for topologies of clearly separated final-state products (“resolved” channel) and topologies with boosted final states with hadronic and/or leptonic products partially overlapping and reconstructed as a large-radius jet (“boosted” channel). The events are selected from pp collision data at the LHC with an integrated luminosity of 139 fb−1 collected by the ATLAS detector at √s = 13 TeV. No significant deviations from the Standard Model predictions are observed. The results are interpreted within the theoretical framework of a left-right symmetric model, and lower limits are set on masses in the heavy righthanded WR boson and NR plane. The excluded region extends to about m(WR) = 6.4 TeV for both Majorana and Dirac NR neutrinos at m(NR) < 1 TeV. NR with masses of less than 3.5 (3.6) TeV are excluded in the electron (muon) channel at m(WR) = 4.8 TeV for the Majorana neutrinos, and limits of m(NR) up to 3.6 TeV for m(WR) = 5.2 (5.0) TeV in the electron (muon) channel are set for the Dirac neutrinos. These constitute the most stringent exclusion limits to date for the model considered