This article provides a step‐by‐step guide to the use of the CrystFEL software for processing serial crystallography data from an X‐ray free‐electron laser or a synchrotron light source. Whereas ...previous papers have described the theory and algorithms and their rationale, this paper describes the steps to be performed from a user perspective, including command‐line examples.
A step‐by‐step guide to processing serial crystallography data from X‐ray free‐electron lasers and synchrotron sources using CrystFEL is provided.
A post-refinement procedure has been devised for ‘snapshot’ diffraction data consisting entirely of partially recorded reflections, each diffraction pattern from a crystal in an orientation unrelated ...to the others. Initial estimates of the diffraction geometry are used to calculate initial partialities, which are then used to scale the entire dataset together to produce initial estimates of the fully integrated intensities. The geometrical parameters for each pattern are then refined to maximize the agreement between these estimates and the calculated intensities in each pattern, and the procedure repeated iteratively. The performance of the procedure was investigated using simulated data and found to yield a significant improvement in the data quality.
Underground hydrogen storage is a long‐duration energy storage option for a low‐carbon economy. Although research into the technical feasibility of underground hydrogen storage is ongoing, existing ...underground gas storage (UGS) facilities are appealing candidates for the technology because of their ability to store and deliver natural gas. We estimate that UGS facilities in the United States (U.S.) can store 327 TWh (9.8 MMT) of pure hydrogen. A complete transition to hydrogen storage would reduce the collective working‐gas energy of UGS facilities by ∼75%; however, most (73.2%) UGS facilities could maintain current energy demand using a 20% hydrogen‐natural gas blend. U.S. UGS facilities can buffer 23.9%–44.6% of the high and low hydrogen demand projected for 2050, respectively, which exceeds the current percentage of natural gas demand buffered by storage. Thus, transitioning UGS infrastructure to hydrogen could substantially reduce the number of new hydrogen storage facilities needed to support a hydrogen economy.
Plain Language Summary
Hydrogen is a high energy content fuel that can be produced with low or zero greenhouse gas emissions from water and other chemicals. Creating hydrogen during periods of energy surplus and storing it underground is one long‐duration, low‐emission, energy storage option that can balance supply and demand for an entire electric grid. In the United States (U.S.), existing underground gas storage (UGS) facilities are a logical first place to consider subsurface hydrogen storage, because their geology has proven favorable for storing natural gas. We estimated that existing UGS facilities can store 327 TW‐h (9.8 million metric tons) of pure hydrogen. Transitioning from natural gas to pure hydrogen storage would reduce the total energy stored in existing UGS facilities by ∼75%. Storing hydrogen‐natural gas mixtures also reduces energy storage potential, but most (73.2%) UGS facilities can meet current energy demands with a 20% hydrogen blend. U.S. UGS facilities can store 23.9%–44.6% of the projected high and low hydrogen demand for 2050, respectively, suggesting that a partial transition of UGS infrastructure could reduce the need for new hydrogen storage facilities. These findings motivate research that explores the technical feasibility of underground hydrogen storage in natural gas storage reservoirs.
Key Points
The total hydrogen working‐gas energy of underground gas storage facilities in the United States is estimated to be 327 TW‐hours
Most (73.2%) underground gas storage facilities can store hydrogen blends up to 20% and continue to meet their current energy demand
Hydrogen storage in existing underground gas storage facilities can sufficiently buffer the hydrogen demand projected for 2050
Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed ...as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.
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•Crystal structure of the human Angiotensin II type 1 receptor at 2.9-Å resolution•Structure is solved by X-ray laser serial femtosecond crystallography•Antagonist ZD7155 forms critical interactions with Tyr35, Trp84 and Arg167•Docking reveals binding modes of common angiotensin receptor blockers
Structure determination of human Angiotensin II type 1 receptor bound to an antagonist using serial femtosecond crystallography with X-ray free-electron laser and docking studies of other common anti-hypertensive drugs into the structure offer insights into design of blood pressure modulators.
A growing number of bacteria are recognized to conduct electrons across their cell envelope, and yet molecular details of the mechanisms supporting this process remain unknown. Here, we report the ...atomic structure of an outer membrane spanning protein complex, MtrAB, that is representative of a protein family known to transport electrons between the interior and exterior environments of phylogenetically and metabolically diverse microorganisms. The structure is revealed as a naturally insulated biomolecular wire possessing a 10-heme cytochrome, MtrA, insulated from the membrane lipidic environment by embedding within a 26 strand β-barrel formed by MtrB. MtrAB forms an intimate connection with an extracellular 10-heme cytochrome, MtrC, which presents its hemes across a large surface area for electrical contact with extracellular redox partners, including transition metals and electrodes.
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•The 20 hemes of a 3-component complex are arranged to move electrons across 185 Å•A β-barrel and 10-heme cytochrome form an insulated transmembrane nanowire•An extracellular 10-heme cytochrome has a large surface area for electron exchange•The hemes of both cytochromes are packed with a maximum inter-heme distance of 8 Å
Structural analysis shows how a naturally insulated molecular “wire” conducts electrons across lipid membranes in bacteria while protecting the membrane from redox damage and facilitating extracellular electron exchange
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms by synchronization to environmental cues and is involved in diverse physiological processes such as the ...regulation of blood pressure and core body temperature, oncogenesis, and immune function. Melatonin is formed in the pineal gland in a light-regulated manner by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness by activating two high-affinity G-proteincoupled receptors, type 1A (MT1) and type 1B (MT2). Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids, and is one of the most popular supplements in the United States. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine. The structure of MT2 is described in an accompanying paper. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung ...tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.
Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and ...extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
The progressive loss of skeletal muscle mass, strength and/or function with advancing age, termed sarcopenia, poses a major threat to independence and quality of life. Therefore, there is significant ...merit in better understanding the biology of sarcopenia and developing therapeutic interventions to prevent, slow or reverse its progression. Since the discovery of myostatin, a potent negative regulator of growth that is highly enriched in skeletal muscle, there has been great interest in it as a potential mediator of sarcopenia as well as a therapeutic target. The complex biology of myostatin, the promise of myostatin inhibition as an effective means to counter sarcopenia, and the challenges facing its clinical translation are reviewed herein.
Team SA involves a common perspective between two or more individuals regarding current environmental events, their meaning, and projected future status. Team SA has been theorized to be important ...for resuscitation team effectiveness. Accordingly, multidimensional frameworks of observable behaviors relevant to resuscitation teams are needed to understand more deeply the nature of team SA, its implications for team effectiveness, and whether it can be trained. A seven-dimension team resuscitation SA framework was developed following a literature review and consensus process using a modified Delphi approach with a group of content experts. We applied a pre-post design within a day-long team training program involving four video-recorded simulated resuscitation events and 42 teams across Canada. The first and fourth events represented "pre" and "post" training events, respectively. Teams were scored on SA five times within each 15-minute event. Distractions were introduced to investigate whether SA scores would be affected. The current study provides initial construct validity evidence for a new measure of SA and explicates SA's role in resuscitation teams.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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