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I review the current status of X-ray reflection (a.k.a. broad iron line) based black hole spin measurements. This is a powerful technique that allows us to measure robust black hole spins across the mass range, from the stellar-mass black holes in X-ray binaries to the supermassive black holes in active galactic nuclei. After describing the basic assumptions of this approach, I lay out the detailed methodology focusing on “best practices” that have been found necessary to obtain robust results. Reflecting my own biases, this review is slanted towards a discussion of supermassive black hole (SMBH) spin in active galactic nuclei (AGN). Pulling together all of the available XMM-Newton and Suzaku results from the literature that satisfy objective quality control criteria, it is clear that a large fraction of SMBHs are rapidly-spinning, although there are tentative hints of a more slowly spinning population at high ( M >5×10 7   M ⊙ ) and low ( M <2×10 6   M ⊙ ) mass. I also engage in a brief review of the spins of stellar-mass black holes in X-ray binaries. In general, reflection-based and continuum-fitting based spin measures are in agreement, although there remain two objects (GRO J1655–40 and 4U 1543–475) for which that is not true. I end this review by discussing the exciting frontier of relativistic reverberation, particularly the discovery of broad iron line reverberation in XMM-Newton data for the Seyfert galaxies NGC 4151, NGC 7314 and MCG–5-23-16. As well as confirming the basic paradigm of relativistic disk reflection, this detection of reverberation demonstrates that future large-area X-ray observatories such as LOFT will make tremendous progress in studies of strong gravity using relativistic reverberation in AGN.

The spin of a black hole retains the memory of how the black hole grew, and can be a potent source of energy for powering relativistic jets. To understand the diagnostic power and astrophysical significance of black hole spin, however, we must first devise observational methods for measuring spin. Here, I describe the current state of black hole spin measurements, highlighting the progress made by X-ray astronomers, as well as the current excitement of gravitational wave- and radio astronomy-based techniques. Today’s spin measurements are already constraining models for the growth of supermassive black holes and giving new insights into the dynamics of stellar core collapse, as well as hinting at the physics of relativistic jet production. Future X-ray, radio and gravitational wave observatories will transform black hole spin into a precision tool for astrophysics and test fundamental theories of gravity.Current black hole spin measurements, in X-rays, radio and gravitational waves, are already constraining models for the growth of black holes, the dynamics of stellar core-collapse and the physics of relativistic jet production.

To meet the 1.5 °C target, methane (CH4) from ruminants must be reduced by 11 to 30% by 2030 and 24 to 47% by 2050 compared to 2010 levels. A meta-analysis identified strategies to decrease product-based (PB; CH₄ per unit meat or milk) and absolute (ABS) enteric CH₄ emissions while maintaining or increasing animal productivity (AP; weight gain or milk yield). Next, the potential of different adoption rates of one PB or one ABS strategy to contribute to the 1.5 °C target was estimated. The database included findings from 430 peer-reviewed studies, which reported 98 mitigation strategies that can be classified into three categories: animal and feed management, diet formulation, and rumen manipulation. A random-effects meta-analysis weighted by inverse variance was carried out. Three PB strategies—namely, increasing feeding level, decreasing grass maturity, and decreasing dietary forage-to-concentrate ratio—decreased CH₄ per unit meat or milk by on average 12% and increased AP by a median of 17%. Five ABS strategies—namely CH₄ inhibitors, tanniferous forages, electron sinks, oils and fats, and oilseeds—decreased daily methane by on average 21%. Globally, only 100% adoption of the most effective PB and ABS strategies can meet the 1.5 °C target by 2030 but not 2050, because mitigation effects are offset by projected increases in CH₄ due to increasing milk and meat demand. Notably, by 2030 and 2050, low- and middle-income countries may not meet their contribution to the 1.5 °C target for this same reason, whereas high-income countries could meet their contributions due to only a minor projected increase in enteric CH₄ emissions.

Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant. In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 × 103 cells per mm3 or higher, and a platelet count of 80 000/mm3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1·3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1–14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1–21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one-sided stratified log rank test at a significance level of 0·02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228. Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0·712, 96% CI 0·56–0·906; one-sided p value 0·0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0·709, 95% CI 0·524–0·959; two-sided p value 0·025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group. In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile. NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.

Outflows from active galactic nuclei (AGNs) are one of the fundamental mechanisms by which the central supermassive black hole interacts with its host galaxy. Detected in ≥50% of nearby AGNs, these outflows have been found to carry kinetic energy that is a large fraction of the AGN power, and thereby give ‘negative’ feedback to their host galaxies. To understand the physical processes that regulate them, it is important to have a robust estimate of their physical and dynamical parameters. In this Review Article, we summarize our current understanding of the physics of the ionized outflows detected via absorption in the ultraviolet and X-ray wavelength bands. We discuss the most relevant observations and our current knowledge and uncertainties in the measurements of the outflow parameters, as well as their origin and acceleration mechanisms. The commissioning and concept studies of large telescope missions with high-resolution spectrographs in ultraviolet/optical and X-rays along with rapid advancements in simulations offer great promise for discoveries in this field over the next decade. This Review Article summarizes our current understanding of ionized outflows in active galactic nuclei, observed in absorption in the ultraviolet and X-ray wavelengths, including the most relevant observations as well as their origin and acceleration mechanisms.

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the G s -protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function. The structure of a complex containing calcitonin gene-related peptide, the human calcitonin gene-related peptide receptor and the G s heterotrimer, determined using Volta phase-plate cryo-electron microscopy, provides structural insight into the regulation of G-protein-coupled receptors by receptor activity modifying protein 1.

[...]one community health centre instituted policies requiring proof of citizenship to receive medical care, an unlawful requirement for publicly funded health centres. 16 Third, health systems should increase pathways to reach patients afraid to leave their homes, including telehealth, community health worker programmes, home visits, and other forms of proactive outreach. [...]a flurry of actions by the US Government, many being challenged in court, 19 have undermined provision of governmental public health information, blocked funds for biomedical research and global humanitarian assistance, and sought to withhold funding from health systems that provide gender-affirming care. 20–22 The abrogation of immigrants' rights must not be lost amid these other assaults. KRP is a medical adviser for Physicians for Human Rights and reports consulting fees from the Florence Immigrant and Refugee Rights Project, honoraria for teaching at Fordham University for an HIV research ethics course and at a University of California San Francisco carceral ethics conference, travel support from Immigration and Customs Enforcement (ICE) for previous teaching at an Executive Office for Immigration Review attorney training, unrelated travel support from the American Academy of Pediatrics, and unrelated funding from the MIT Lincoln Lab.

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity 1 . Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation 2 – 6 . Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors. The structure of GLP-1R and its G protein in complex with the small molecule TT-OAD2 sheds light on how the TT-OAD2 agonist can activate the receptor and provides insights into the development of therapeutic agents for metabolic disorders.

Mitigating environmental phosphorus loading (EPL) from dairy farms reduces water pollution and improves the sustainability of production. Studies generally simulate EPL from dairy farms using a representative farm type from existing databases. However, housed and pasture-based dairy farming systems might contribute to eutrophication differently and have a varied feasibility of implementing mitigation. This study is the first that quantified EPL from dairy farms using data for FARMSCOPER collected from farmers and comparing EPL and identifying a least-cost suite of mitigation methods. Structural characteristics of 27 dairy farms in Great Britain (GB) were collected. Annual EPL from each farm was simulated in FARMSCOPER under three scenarios. Mean EPL of the production systems was compared to investigate any relationship between EPL and average 305 day adjusted milk yield of cows on each farm. A least-cost suite of mitigation methods was optimised for two model farms to represent either a housed or pasture-based system. Across both systems, ‘current’ implementation of mitigation methods was simulated to have reduced EPL from 0.63 to 0.56 kg P/ha (11%). The ‘current’ EPL positively correlated with milk production on a kg and kg/ha basis ( P ≤ 0.001 and P = 0.033, respectively). Farms operating a housed system had a mean ‘current’ EPL that was 59% greater than the pasture-based system though not significant ( P = 0.316). This was partly due to a small sample size and because FARMSCOPER’s estimates exclude variations in farm practices (i.e., feeding). EPL was reduced by ~ 50% and ~ 60% without incurring annual financial losses by implementing existing mitigation methods for pasture-based and housed systems, respectively. This study highlights the importance of mitigating EPL from GB dairy farming, especially considering the increasing number of higher yielding herds and housed production systems. Furthermore, emphasis should be on increasing implementation of system-specific mitigating methods; efforts to include more recent and specific farm data to improve the FARMSCOPER tool will benefit this.