Elucidating mysteries of phase-segregated membranes: Mobile-lipid recruitment facilitates pores' passage to the fluid phase

Phase segregation of multicomponent lipid bilayers leads to, under phase-coexistence conditions, domain formation, featuring delimitation by essentially one-dimensional borders. (Micro-)phase segregation of bilayers is proposed to influence the physiological behaviour of cell membranes and provides the driving force for lipid-raft formation. Experiments show a maximum in the electrical-conductivity of membranes at the phase-transition point, which has been conjectured to arise from border-nucleated transmembrane-conducting defects or pores. However, recent electroporation experiments on phase-segregated bilayers demonstrate electro-pore detection in the liquid disordered phase (Ld), wherein they diffuse over macroscopic periods without absorption into the liquid ordered phase (Lo). Here, we scrutinise transmembrane-pore formation via molecular dynamics simulations on a multicomponent phase-segregated bilayer. We find that pores created in Lo domains always migrate spontaneously to the Ld phase, via 'recruitment' of unsaturated lipids to the pore's rim to transport the pore to the fluid phase under a large stress-field driving force. Once in Ld domains, pores migrate towards their centre, never returning or pinning to Lo. These findings are explained by thermodynamics. By comparing the free-energy cost for creating pores in the bulk of Ld and Lo membranes, and in the phase-segregated system, we show that it is always more energetically tractable to create pores in Ld domains, independent of the pore size.Fil: López Martí, Jesús María. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: English, Niall J.. University College Dublin; IrlandaFil: del Popolo, Mario Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentin

Benchmark study for the application of density functional theory to the prediction of octahedral tilting in perovskites

The results of a systematic study of octahedral tilting in oxo- and fluoroperovskites by density functional theory (DFT) calculations are presented and discussed. Eleven perovskites displaying different structural, magnetic, and metallic properties have been studied by means of nine exchange-correlation functionals, ranging from the basic local density approximation to more advanced hybrid functionals, in order to determine the accuracy of these methods for the prediction of octahedral rotation angles. Octahedral tilting has attracted much attention lately due to the possibility of using them to trigger improper ferroelectricity and new families of multiferroic materials. We show that all DFT methods tend to overestimate the octahedral rotation angles by approximately 20 %, with this quantity being only slightly corrected by hybrids, including, at least, 25% of the Hartree?Fock exchange. We propose a correction to the prediction of these angles based on quantum fluctuations and the anharmonic nature of the energy surface around the minimum but find that it is only important for very small rotation angles appearing in systems like SrTiO3.We acknowledge economic support from the Spanish Ministerio de Ciencia y Tecnolog´ıa under Project No. FIS2012-30996 and the Science Foundation Ireland (SFI) Research Frontiers Programme (Reference No. 10/RFP/MTR2868

Estimation of Thermodynamic Stability of Methane and Carbon Dioxide Hydrates in the Presence of Hydrogen Sulfide

.Peer reviewedPublisher PD

Organic dyes containing coplanar dihexyl-substituted dithienosilole groups for efficient dye-sensitised solar cells

peer-reviewedA chromophore containing a coplanar dihexyl-substituted dithienosilole (CL1) synthesised for use in dye-sensitised solar cells displayed an energy conversion efficiency of 6.90% under AM 1.5 sunlight irradiation. The new sensitiser showed a similar fill factor and open-circuit voltage when compared with N719. Impedance measurements showed that, in the dark, the charge-transfer resistance of a cell using CL1 in the intermediate-frequency region was higher compared to N719 (69.8 versus 41.3 Omega). Under illumination at AM 1.5G-simulated conditions, the charge-transfer resistances were comparable, indicative of similar recombination rates by the oxidised form of the redox couple. The dye showed instability in ethanol solution, but excellent stability when attached to TiO2. Classical molecular dynamics indicated that interactions between ethanol and the dye are likely to reduce the stability of CL1 in solution form. Time-dependent density functional theory studies were performed to ascertain the absorption spectrum of the dye and assess the contribution of various transitions to optical excitation, which showed good agreement with experimental results.PUBLISHEDpeer-reviewe

Gas hydrates in sustainable chemistry

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hassanpouryouzband, A., Joonaki, E., Farahani, M. V., Takeya, S., Ruppel, C., Yang, J., English, N. J., Schicks, J. M., Edlmann, K., Mehrabian, H., Aman, Z. M., & Tohidi, B. Gas hydrates in sustainable chemistry. Chemical Society Reviews, 49(15), (2020): 5225-5309, doi:10.1039/c8cs00989a.Gas hydrates have received considerable attention due to their important role in flow assurance for the oil and gas industry, their extensive natural occurrence on Earth and extraterrestrial planets, and their significant applications in sustainable technologies including but not limited to gas and energy storage, gas separation, and water desalination. Given not only their inherent structural flexibility depending on the type of guest gas molecules and formation conditions, but also the synthetic effects of a wide range of chemical additives on their properties, these variabilities could be exploited to optimise the role of gas hydrates. This includes increasing their industrial applications, understanding and utilising their role in Nature, identifying potential methods for safely extracting natural gases stored in naturally occurring hydrates within the Earth, and for developing green technologies. This review summarizes the different properties of gas hydrates as well as their formation and dissociation kinetics and then reviews the fast-growing literature reporting their role and applications in the aforementioned fields, mainly concentrating on advances during the last decade. Challenges, limitations, and future perspectives of each field are briefly discussed. The overall objective of this review is to provide readers with an extensive overview of gas hydrates that we hope will stimulate further work on this riveting field.A. H. and K. E. were partially supported by funding from UKRI-EPSRC (grant number EP/S027815/1). C. R. was partially supported by DOE-USGS Interagency agreement DE-FE0023495. C. R. thanks L. Stern and W. Waite for insights that improved her contributions. E. J. is partially supported by Flow Programme project sponsored by Department for Business, Energy and Industrial Strategy (BEIS), UK. Any use of trade, firm or product name is for descriptive purposes only and does not imply endorsement by the U.S. Government

Ternary structure reveals mechanism of a membrane diacylglycerol kinase

Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The g-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergen

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570