Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms.
We conducted a multicenter, randomized, open-label trial, with ...blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90.
The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18).
Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).
The structure of bovine F1‐ATPase inhibited with ADP and beryllium fluoride at 2.0 Å resolution contains two ADP.BeF3− complexes mimicking ATP, bound in the catalytic sites of the βTP and βDP ...subunits. Except for a 1 Å shift in the guanidinium of αArg373, the conformations of catalytic side chains are very similar in both sites. However, the ordered water molecule that carries out nucleophilic attack on the γ‐phosphate of ATP during hydrolysis is 2.6 Å from the beryllium in the βDP subunit and 3.8 Å away in the βTP subunit, strongly indicating that the βDP subunit is the catalytically active conformation. In the structure of F1‐ATPase with five bound ADP molecules (three in α‐subunits, one each in the βTP and βDP subunits), which has also been determined, the conformation of αArg373 suggests that it senses the presence (or absence) of the γ‐phosphate of ATP. Two catalytic schemes are discussed concerning the various structures of bovine F1‐ATPase.
The β1-adrenoceptor (β1AR) is the site of action of beta blockers used in the treatment of cardiac-related illnesses. Two beta blockers, carvedilol and bucindolol, show distinctive activities ...compared to other beta blockers and have been proposed as treatments tailored to the Arg/Gly3898.56 polymorphism of the human β1AR. Both carvedilol and bucindolol are classified as biased agonists, because they stimulate G protein-independent signaling, while acting as either inverse or partial agonists of the G protein pathway. We have determined the crystal structures of a thermostabilized avian β1AR mutant bound to bucindolol and to carvedilol at 3.2 and 2.3 Å resolution, respectively. In comparison to other beta blockers, bucindolol and carvedilol interact with additional residues, in extracellular loop 2 and transmembrane helix 7, which may promote G protein-independent signaling. The structures also suggest that there may be a structural explanation for the pharmacological differences arising from the Arg/Gly3898.56 polymorphism.
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► Structures of β1AR bound to the biased agonists bucindololol and carvedilol ► The biased agonists form unique contacts with β1AR not seen with other antagonists ► The structures explain the pharmacological differences in the Arg389Gly polymorphism
The crystal structure of yeast mitochondrial F1 ATPase contains three independent copies of the complex, two of which have similar conformations while the third differs in the position of the central ...stalk relative to the α3β3 sub‐assembly. All three copies display very similar asymmetric features to those observed for the bovine enzyme, but the yeast F1 ATPase structures provide novel information. In particular, the active site that binds ADP in bovine F1 ATPase has an ATP analog bound and therefore this structure does not represent the ADP‐inhibited form. In addition, one of the complexes binds phosphate in the nucleotide‐free catalytic site, and comparison with other structures provides a picture of the movement of the phosphate group during initial binding and subsequent catalysis. The shifts in position of the central stalk between two of the three copies of yeast F1 ATPase and when these structures are compared to those of the bovine enzyme give new insight into the conformational changes that take place during rotational catalysis.
The crystal structure of the F
1
-catalytic domain of the adenosine triphosphate (ATP) synthase has been determined from the pathogenic anaerobic bacterium
Fusobacterium nucleatum
. The enzyme can ...hydrolyse ATP but is partially inhibited. The structure is similar to those of the F
1
-ATPases from
Caldalkalibacillus thermarum
, which is more strongly inhibited in ATP hydrolysis, and in
Mycobacterium smegmatis
, which has a very low ATP hydrolytic activity. The β
E
-subunits in all three enzymes are in the conventional ‘open’ state, and in the case of
C. thermarum
and
M. smegmatis
, they are occupied by an ADP and phosphate (or sulfate), but in
F. nucleatum
, the occupancy by ADP appears to be partial. It is likely that the hydrolytic activity of the
F. nucleatum
enzyme is regulated by the concentration of ADP, as in mitochondria.
IntroductionThe use of high fraction of inspired oxygen (FiO2) intraoperatively for the prevention of surgical site infection (SSI) remains controversial. Promising results of early randomised ...controlled trials (RCT) have been replicated with varying success and subsequent meta-analysis are equivocal. Recent advancements in perioperative care, including the increased use of laparoscopic surgery and pneumoperitoneum and shifts in fluid and temperature management, can affect peripheral oxygen delivery and may explain the inconsistency in reproducibility. However, the published data provides insufficient detail on the participant level to test these hypotheses. The purpose of this individual participant data meta-analysis is to assess the described benefits and harms of intraoperative high FiO2compared with regular (0.21–0.40) FiO2 and its potential effect modifiers.Methods and analysisTwo reviewers will search medical databases and online trial registries, including MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and WHO regional databases, for randomised and quasi-RCT comparing the effect of intraoperative high FiO2 (0.60–1.00) to regular FiO2 (0.21–0.40) on SSI within 90 days after surgery in adult patients. Secondary outcome will be all-cause mortality within the longest available follow-up. Investigators of the identified trials will be invited to collaborate. Data will be analysed with the one-step approach using the generalised linear mixed model framework and the statistical model appropriate for the type of outcome being analysed (logistic and cox regression, respectively), with a random treatment effect term to account for the clustering of patients within studies. The bias will be assessed using the Cochrane risk-of-bias tool for randomised trials V.2 and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. Prespecified subgroup analyses include use of mechanical ventilation, nitrous oxide, preoperative antibiotic prophylaxis, temperature (<35°C), fluid supplementation (<15 mL/kg/hour) and procedure duration (>2.5 hour).Ethics and disseminationEthics approval is not required. Investigators will deidentify individual participant data before it is shared. The results will be submitted to a peer-review journal.PROSPERO registration numberCRD42018090261.
In the crystal structure of bovine mitochondrial F1-ATPase determined at 2.8 A resolution, the three catalytic beta-subunits differ in conformation and in the bound nucleotide. The structure supports ...a catalytic mechanism in intact ATP synthase in which the three catalytic subunits are in different states of the catalytic cycle at any instant. Interconversion of the states may be achieved by rotation of the alpha 3 beta 3 subassembly relative to an alpha-helical domain of the gamma-subunit.
The serpins are a widely distributed family of proteins with diverse functions; they include the key serine protease inhibitors of human plasma as well as noninhibitory homologues such as ...hormone-binding globulins, angiotensinogen and egg-white ovalbumin. Sequence alignment based on the crystal structure. On the cleaved form of the archetypal serpin, alpha 1-antitrypsin, indicates that the serpins share a common highly ordered structure. On cleavage of the reactive centre peptide bond, they characteristically undergo a remarkable conformational change, the newly generated C terminus moving some 70 A to the opposite pole of the molecule. The structure of this post-cleavage form is known, but the conformation of the intact serpins and in particular that of their reactive centre is not. Wright et al.'s structure of plakalbumin (ovalbumin cleaved by subtilisin) has provided evidence for the conformational change that results from cleavage. We have now determined the structure of native ovalbumin to 1.95 A resolution and have found that the intact peptide loop forming the analogue to the reactive centre of the inhibitory serpins takes the unexpected form of a protruding, isolated helix. This model of the intact structures of the serpins suggests how they may interact with their target proteases.
The structures of F
1
-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined ...at 2.3-, 2.4- and 2.7-Å resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three α- and three β-subunits beneath the “crown” of β-strands in their N-terminal domains. This region of F
1
-ATPase forms a bearing to allow the rotation of the tip of the γ-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the γ-subunit and the β
TP
subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the γ-subunit and either the β
DP
or the β
E
subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the γ-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis.
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