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The structures of three intermediate states of photosystem II, which is crucial for photosynthesis, have been solved at room temperature, shedding new light on this process. Room temperature structures of photosystem II During the conversion of light into energy in plants, photosystem II oxidizes water within a Mn 4 CaO 5 cluster in the oxygen evolving complex (OEC). This process involves five intermediate states that have eluded structural determination until now. Junko Yano and colleagues use a femtosecond X-ray free electron laser (XFEL) to capture three of these states at room temperature. As the structure was solved in the presence of ammonia, a water analogue, the authors are able to conclude that the ammonia-binding Mn site is not a substrate water site. Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the Mn 4 CaO 5 cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S 0 to S 4 ) 1 , in which S 1 is the dark-stable state and S 3 is the last semi-stable state before O–O bond formation and O 2 evolution 2 , 3 . A detailed understanding of the O–O bond formation mechanism remains a challenge, and will require elucidation of both the structures of the OEC in the different S-states and the binding of the two substrate waters to the catalytic site 4 , 5 , 6 . Here we report the use of femtosecond pulses from an X-ray free electron laser (XFEL) to obtain damage-free, room temperature structures of dark-adapted (S 1 ), two-flash illuminated (2F; S 3 -enriched), and ammonia-bound two-flash illuminated (2F-NH 3 ; S 3 -enriched) PS II. Although the recent 1.95 Å resolution structure of PS II at cryogenic temperature using an XFEL 7 provided a damage-free view of the S 1 state, measurements at room temperature are required to study the structural landscape of proteins under functional conditions 8 , 9 , and also for in situ advancement of the S-states. To investigate the water-binding site(s), ammonia, a water analogue, has been used as a marker, as it binds to the Mn 4 CaO 5 cluster in the S 2 and S 3 states 10 . Since the ammonia-bound OEC is active, the ammonia-binding Mn site is not a substrate water site 10 , 11 , 12 , 13 . This approach, together with a comparison of the native dark and 2F states, is used to discriminate between proposed O–O bond formation mechanisms.

Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the Mn4CaO5 cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S0 to S4), in which S1 is the dark-stable state and S3 is the last semi-stable state before O-O bond formation and O2 evolution. A detailed understanding of the O-O bond formation mechanism remains a challenge, and will require elucidation of both the structures of the OEC in the different S-states and the binding of the two substrate waters to the catalytic site. Here we report the use of femtosecond pulses from an X-ray free electron laser (XFEL) to obtain damage-free, room temperature structures of dark-adapted (S1), two-flash illuminated (2F; S3-enriched), and ammonia-bound two-flash illuminated (2F-NH3; S3-enriched) PS II. Although the recent 1.95 A resolution structure of PS II at cryogenic temperature using an XFEL provided a damage-free view of the S1 state, measurements at room temperature are required to study the structural landscape of proteins under functional conditions, and also for in situ advancement of the S-states. To investigate the water-binding site(s), ammonia, a water analogue, has been used as a marker, as it binds to the Mn4CaO5 cluster in the S2 and S3 states. Since the ammonia-bound OEC is active, the ammonia-binding Mn site is not a substrate water site. This approach, together with a comparison of the native dark and 2F states, is used to discriminate between proposed O-O bond formation mechanisms.

The Association of American Medical Colleges' (AAMC) initiative for Core Entrustable Professional Activities for Entering Residency includes as an element of Entrustable Professional Activity 13 to \"identify system failures and contribute to a culture of safety and improvement.\" We set out to determine the feasibility of using medical students' action learning projects (ALPs) to expedite implementation of evidence-based pathways for three common patient diagnoses in the emergency department (ED) setting (Atrial fibrillation, congestive heart failure, and pulmonary embolism). These prospective quality improvement (QI) initiatives were performed over six months in three Northeastern PA hospitals. Emergency physician mentors were recruited to facilitate a QI experience for third-year medical students for each project. Six students were assigned to each mentor and given class time and network infrastructure support (information technology, consultant experts in lean management) to work on their projects. Students had access to background network data that revealed potential for improvement in disposition (home) for patients. Under the leadership of their mentors, students accomplished standard QI processes such as performing the background literature search and assessing key stakeholders' positions that were involved in the respective patient's care. Students effectively developed flow diagrams, computer aids for clinicians and educational programs, and participated in recruiting champions for the new practice standard. They met with other departmental clinicians to determine barriers to implementation and used this feedback to help set specific parameters to make clinicians more comfortable with the changes in practice that were recommended. All three clinical practice guidelines were initiated at consummation of the students' projects. After implementation, 86% (38/44) of queried ED providers felt comfortable with medical students being a part of future ED QI initiatives, and 84% (26/31) of the providers who recalled communicating with students on these projects felt they were effective. Using this novel technique of aligning small groups of medical students with seasoned mentors, it is feasible for medical students to learn important aspects of QI implementation and allows for their engagement to more efficiently move evidence-based medicine from the literature to the bedside.

IntroductionPatients with heart failure (HF) are classically categorised by left ventricular ejection fraction (LVEF). Efforts to predict outcomes and response to specific therapy among LVEF-based groups may be suboptimal, in part due to the underlying heterogeneity within clinical HF phenotypes. A multidimensional characterisation of ambulatory patients with and without HF across LVEF groups is needed to better understand and manage patients with HF in a more precise manner.Methods and analysisTo date, the first cohort of 1313 out of total planned 3000 patients with and without HF has been enroled in this single-centre, longitudinal observational cohort study. Baseline and 1-year follow-up blood samples and clinical characteristics, the presence and duration of comorbidities, serial laboratory, echocardiographic data and images and therapy information will be obtained. HF diagnosis, aetiology of disease, symptom onset and clinical outcomes at 1 and 5 years will be adjudicated by a team of clinicians. Clinical outcomes of interest include all-cause mortality, cardiovascular mortality, all-cause hospitalisation, cardiovascular hospitalisation, HF hospitalisation, right-sided HF and acute kidney injury. Results from the Preserved versus Reduced Ejection Fraction Biomarker Registry and Precision Medicine Database for Ambulatory Patients with Heart Failure (PREFER-HF) trial will examine longitudinal clinical characteristics, proteomic, metabolomic, genomic and imaging data to better understand HF phenotypes, with the ultimate goal of improving precision medicine and clinical outcomes for patients with HF.Ethics and disseminationInformation gathered in this research will be published in peer-reviewed journals. Written informed consent for PREFER-HF was obtained from all participants. All study procedures were approved by the Mass General Brigham Institutional Review Board in Boston, Massachusetts and performed in accordance with the Declaration of Helsinki (Protocol Number: 2016P000339).Trial registration numberPREFER-HF ClinicalTrials.gov identifier: NCT03480633.