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Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side. The resulting cascade of structural changes throughout the protein shows how motions are choreographed as bR transports protons uphill against a transmembrane concentration gradient.

Gestational diabetes mellitus (GDM) is a growing concern, affecting an increasing number of pregnant women worldwide. By predisposing both the affected mothers and children to future disease, GDM contributes to an intergenerational cycle of obesity and diabetes. In order to stop this cycle, safe and effective treatments for GDM are required. This study sought to determine the treatment effects of dietary supplementation with myo-inositol (MI) and vitamins B2, B6, B12, and D in a mouse model of GDM (pregnant db/+ dams). In addition, the individual effects of vitamin B2 were examined. Suboptimal B2 increased body weight and fat deposition, decreased GLUT4 adipose tissue expression, and increased expression of inflammatory markers. MI supplementation reduced weight and fat deposition, and reduced expression of inflammatory markers in adipose tissue of mice on suboptimal B2. MI also significantly reduced the hyperleptinemia observed in db/+ mice, when combined with supplemented B2. MI was generally associated with adipose tissue markers of improved insulin sensitivity and glucose uptake, while the combination of vitamins B2, B6, B12, and D was associated with a reduction in adipose inflammatory marker expression. These results suggest that supplementation with MI and vitamin B2 could be beneficial for the treatment/prevention of GDM.

Many pathogenic bacteria utilise sialic acids as an energy source or use them as an external coating to evade immune detection. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acids. Here, we report a substrate-bound 1.95 Å resolution structure and subsequent characterisation of SiaT, a sialic acid transporter from Proteus mirabilis . SiaT is a secondary active transporter of the sodium solute symporter (SSS) family, which use Na + gradients to drive the uptake of extracellular substrates. SiaT adopts the LeuT-fold and is in an outward-open conformation in complex with the sialic acid N -acetylneuraminic acid and two Na + ions. One Na + binds to the conserved Na2 site, while the second Na + binds to a new position, termed Na3, which is conserved in many SSS family members. Functional and molecular dynamics studies validate the substrate-binding site and demonstrate that both Na + sites regulate N -acetylneuraminic acid transport. Sialic acid transporters (SiaT) are required for sialic acid uptake in a number of human pathogens and are of interest as targets for antimicrobial drug development. Here the authors present the substrate bound SiaT structure from the uropathogen Proteus mirabilis and provide insights into the mechanism of sialic acid transport.

Cytochrome c oxidase catalyses the reduction of molecular oxygen to water while the energy released in this process is used to pump protons across a biological membrane. Although an extremely well-studied biological system, the molecular mechanism of proton pumping by cytochrome c oxidase is still not understood. Here we report a method to produce large quantities of highly diffracting microcrystals of ba 3 -type cytochrome c oxidase from Thermus thermophilus suitable for serial femtosecond crystallography. The room-temperature structure of cytochrome c oxidase is solved to 2.3 Å resolution from data collected at an X-ray Free Electron Laser. We find overall agreement with earlier X-ray structures solved from diffraction data collected at cryogenic temperature. Previous structures solved from synchrotron radiation data, however, have shown conflicting results regarding the identity of the active-site ligand. Our room-temperature structure, which is free from the effects of radiation damage, reveals that a single-oxygen species in the form of a water molecule or hydroxide ion is bound in the active site. Structural differences between the ba 3 -type and aa 3 -type cytochrome c oxidases around the proton-loading site are also described.

Photosynthetic reaction centres harvest the energy content of sunlight by transporting electrons across an energy-transducing biological membrane. Here we use time-resolved serial femtosecond crystallography 1 using an X-ray free-electron laser 2 to observe light-induced structural changes in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds. Structural perturbations first occur at the special pair of chlorophyll molecules of the photosynthetic reaction centre that are photo-oxidized by light. Electron transfer to the menaquinone acceptor on the opposite side of the membrane induces a movement of this cofactor together with lower amplitude protein rearrangements. These observations reveal how proteins use conformational dynamics to stabilize the charge-separation steps of electron-transfer reactions. Time-resolved serial femtosecond crystallography is used to reveal the structural changes that stabilize the charge-separation steps of electron-transfer reactions in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds.

Photosynthetic reaction centres harvest the energy content of sunlight by transporting electrons across an energy-transducing biological membrane. In this study we use time-resolved serial femtosecond crystallography using an X-ray free-electron laser to observe light-induced structural changes in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds. Structural perturbations first occur at the special pair of chlorophyll molecules of the photosynthetic reaction centre that are photo-oxidized by light. Electron transfer to the menaquinone acceptor on the opposite side of the membrane induces a movement of this cofactor together with lower amplitude protein rearrangements. These observations reveal how proteins use conformational dynamics to stabilize the charge-separation steps of electron-transfer reactions.

Hypertension care requires considerable resources from primary healthcare, and efficient work models are desirable both to improve treatment outcome and to ease staff workload. This study's objective was to describe how healthcare staff experienced the implementation of a new nurse-led work model for hypertension care. Qualitative content analysis was used for data analysis. Digitally conducted interviews with 14 physicians, nurses and managers from six of the eleven primary healthcare centres participating in an intervention to improve hypertension care in the Västra Götaland region. The intervention included training of healthcare professionals in a new nurse-led team work model using standardized protocols for treatment and follow-up. The intervention was appreciated, even requested, by both nurses, physicians and managers. The clearly defined division of tasks in the team provided structure, safety, and eased the workload. Treatment was streamlined and the work was perceived as more professional and stimulating. However, implementation of the new work model, including task shift, required close cooperation between nurses and physicians, trust and dedication. Implementation failed if the staff turnover was high, or if management support lacked. Personal qualities, judgement, experience and learning by cooperating with each other, were highlighted as important additional factors for competence and professionally performed hypertension care. Healthcare can benefit from this intervention, but manager support and involvement of both nurses and physicians are crucial factors for successful implementation. Structured protocols cannot replace experience and personal qualities but provide appreciated support and increased safety.

Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro. We used an in vivo orthotopic xenograft mouse model with metastatic luciferase-labeled WNT5A-low DU145 cells and metastatic luciferase-labeled WNT5A-high PC3prostate cancer cells. We provide here the first evidence that Foxy-5 significantly inhibits the initial metastatic dissemination of tumor cells to regional and distal lymph nodes by 90% and 75%, respectively. Importantly, this effect was seen only with the WNT5A-low DU145 cells and not with the WNT5A-high PC3 cells. The inhibiting effect in the DU145-based model occurred despite the fact that no effects were observed on primary tumor growth, apoptosis or proliferation. These findings are consistent with and supported by the in vitro data, where Foxy-5 specifically targets invasion without affecting apoptosis or viability of WNT5A-low prostate cancer cells. To conclude, our data indicate that the WNT5A-mimicking peptide Foxy-5, which has been recently used in a phase 1 clinical trial, is an attractive candidate for complimentary anti-metastatic treatment of prostate cancer patients with tumors exhibiting absent or low WNT5A expression.

A pilot study to evaluate a staff training intervention implementing a nurse-led hypertension care model. Clinical and laboratory data from all primary care centres (PCCs) in the Swedish region Västra Götaland (VGR), retrieved from regional registers. Intervention started 2018 in 11 PCCs. A total of 190 PCCs served as controls. Change from baseline was assessed 2 years after start of intervention. Training of selected personnel, primarily in drug choice, team-based care, measurement techniques, and use of standardized medical treatment protocols. Hypertensive patients without diabetes or ischemic heart disease were included. The intervention and control groups contained approximately 10,000 and 145,000 individuals, respectively. Blood pressure (BP) <140/90 mmHg, LDL-cholesterol (LDL-C) <3.0 mmol/L, BP ending on -0 mmHg (digit preference, an indirect sign of manual measuring technique), choice of antihypertensive drugs, cholesterol lowering therapy and attendance patterns were measured. In the intervention group, the percentage of patients reaching the BP target did not change significantly, 56%-61% (control 50%-52%), non-significant. However, the percentage of patients with LDL-  < 3.0 mmol/L increased from 34%-40% (control 36%-36%), .043, and digit preference decreased, 39%-27% (control 41%-35%),  = 0.000. The number of antihypertensive drugs was constant, 1.63 - 1.64 (control 1.62 - 1.62), non-significant, but drug choice changed in line with recommendations. Although this primary care intervention based on staff training failed to improve BP control, it resulted in improved cardiovascular control by improved cholesterol lowering treatment.

In a population-based cohort of ruptured abdominal aortic aneurysms (rAAAs), our aim was to investigate clinical, morphological and biomechanical features in patients with small rAAAs. All patients admitted to an emergency department in Stockholm and Gotland, a region with a population of 2.1 million, between 2009-2013 with a CT-verified rupture (n = 192) were included, and morphological measurements were performed. Patients with small rAAAs, maximal diameter (Dmax) ≤ 60 mm were selected (n = 27), and matched 2:1 by Dmax, sex and age to intact AAA (iAAAs). For these patients, morphology including volume and finite element analysis-derived biomechanics were assessed. The mean Dmax for all rAAAs was 80.8 mm (SD = 18.9 mm), women had smaller Dmax at rupture (73.4 ± 18.4 mm vs 83.1 ± 18.5 mm, p = 0.003), and smaller neck and iliac diameters compared to men. Aortic size index (ASI) was similar between men and women (4.1 ± 3.1 cm/m2 vs 3.8 ± 1.0 cm/m2). Fourteen percent of all patients ruptured at Dmax ≤ 60 mm, and a higher proportion of women compared to men ruptured at Dmax ≤ 60 mm: 27% (12/45) vs. 10% (15/147), p = 0.005. Also, a higher proportion of patients with a chronic obstructive pulmonary disease ruptured at Dmax ≤ 60 mm (34.6% vs 14.6%, p = 0.026). Supra-renal aortic size index (14.0, IQR 13.3-15.3 vs 12.8, IQR = 11.4-14.0) and peak wall rupture index (PWRI, 0.35 ± 0.08 vs 0.43 ± 0.11, p = 0.016) were higher for small rAAAs compared to matched iAAAs. Aortic size index, peak wall stress and aneurysm volume did not differ. More than one tenth of ruptures occur at smaller diameters, women continuously suffer an even higher risk of presenting with smaller diameters, and this must be considered in surveillance programs. The increased supra-renal aortic size index and PWRI are potential markers for rupture risk, and patients under surveillance with these markers may benefit from increased attention, and potentially from timely repair.