Conformational control of structure and guest uptake by a tripeptide-based porous material

Chemical processes often rely on the selective sorting and transformation of molecules according to their size, shape and chemical functionality. For example, porous materials such as zeolites achieve the required selectivity through the constrained pore dimensions of a single structure.1 In contrast, proteins function by navigating between multiple metastable structures using bond rotations of the polypeptide,2,3 where each structure lies in one of the minima of a conformational energy landscape and can be selected according to the chemistry of the molecules interacting with the protein.3 Here we show that rotation about covalent bonds in a peptide linker can change a flexible metal-organic framework (MOF) to afford nine distinct crystal structures, revealing a conformational energy landscape characterised by multiple structural minima. The uptake of small molecule guests by the MOF can be chemically triggered by inducing peptide conformational change. This change transforms the material from a minimum on the landscape that is inactive for guest sorption to an active one. Chemical control of the conformation of a flexible organic linker offers a route to modify the pore geometry and internal surface chemistry and thus the function of open-framework materials

High-Throughput Discovery of Hf Promotion on the Formation of Hcp Co and Fischer-Tropsch Activity

A proxy-based high-throughput experimental approach was used to explore the stability and activity of Co-based Fischer Tropsch Synthesis catalysts with different promoters on various supports. The protocol is based on the estimation by XRD of active phase, Co, particle size and relative amounts of crystalline phases, Co to support. Sequential libraries samples enabled exploration of four Co loadings with five different promoters on six support materials. Catalysts stable to aging in syngas, displaying minimal change of particle size or relative area, were evaluated for their activity under industrial conditions. This procedure identified SiC as support for stable catalysts and a combination of Ru and Hf to promote the formation hcp Co. Unsupported bulk samples of Co with appropriate amounts of Ru and Hf revealed that the formation of hcp Co is independent of the support. The hcp Co containing catalyst presented the highest catalytic activity and C5+ selectivity amongst the samples tested in this study confirming the effectiveness of the proxy-based high-throughput method.</jats:p

Lithium Transport in Li4.4M0.4M ' S-0.6(4) (M = Al3+, Ga3+, and M ' = Ge4+, Sn4+): Combined Crystallographic, Conductivity, Solid State NMR, and Computational Studies

In order to understand the structural and compositional factors controlling lithium transport in sulfides, we explored the Li5AlS4 – Li4GeS4 phase field for new materials. Both parent compounds are defined structurally by a hexagonal close packed sulfide lattice, where distinct arrangements of tetrahedral metal sites give Li5AlS4 a layered structure and Li4GeS4 a three dimensional structure related to γ-Li3PO4. The combination of the two distinct structural motifs is expected to lead to new structural chemistry. We identified the new crystalline phase Li4.4Al0.4Ge0.6S4, and investigated the structure and Li+ ion dynamics of the family of structurally related materials Li4.4M0.4M’0.6S4 (M= Al3+, Ga3+ and M’= Ge4+, Sn4+). We used neutron diffraction to solve the full structures of the Al-homologues, which adopt a layered close-packed structure with a new arrangement of tetrahedral (M/M’) sites and a novel combination of ordered and disordered lithium vacancies. AC impedance spectroscopy revealed lithium conductivities in the range 3(2) x 10-6 to 4.3(3) x 10-5 S cm-1 at room temperature with activation energies between 0.43(1) and 0.38(1) eV. Electrochemical performance was tested in a plating and stripping experiment against Li metal electrodes and showed good stability of the Li4.4Al0.4Ge0.6S4 phase over 200 hours. A combination of variable temperature 7Li solid state nuclear magnetic resonance spectroscopy and ab initio molecular dynamics calculations on selected phases showed that two dimensional diffusion with a low energy barrier of 0.17 eV is responsible for long-range lithium transport, with diffusion pathways mediated by the disordered vacancies while the ordered vacancies do not contribute to the conductivity. This new structural family of sulfide Li+ ion conductors offers insight into the role of disordered vacancies on Li+ ion conductivity mechanisms in hexagonally close packed sulfides that can inform future materials design

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise.

BACKGROUND: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors. METHOD: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail. RESULTS: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs. CONCLUSIONS: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety

The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning.

BACKGROUND: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL). METHOD: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times. RESULTS: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content. DISCUSSION: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training

A Highly Flexible Metal-Organic Framework Constructed from Asymmetric Flexible Linkers and Heptanuclear Zinc Carboxylate Secondary Building Units and its Anisotropic Dynamic Responses Exhibited During Guest Removal and Single Crystal Coordinated Solvent Exchange

A new porous and flexible metal-organic framework (MOF) has been synthesised from the flexible asymmetric linker N-(4-Carboxyphenyl)succinamate (CSA) and heptanuclear zinc oxo-clusters of formula [Zn7O2(Carboxylate)10DMF2] involving two coordinated terminal DMF ligands. The structural response of this MOF to the removal or exchange of its guest molecules has been probed using a combination of experimental and computational approaches. The topology of the material, involving double linker connections in the a and b directions and single linker connections along the c axis, is shown to be key in the materials anisotropic response. The a and b directions remain locked during guest removal, while the c axis linker undergoes large changes significantly reducing the material’s void space. The changes to the c axis linker involve a combination of a hinge motion on the linker’s rigid side and conformational rearrangements on its flexible end, which were probed in detail during this process despite the presence of crystallographic disorder along this axis which prevented accurate characterisation by experimental methods alone. While inactive during guest removal, the flexible ends of the a and b axis linkers are observed to play a prominent role during DMF to DMSO solvent exchange, facilitating the exchange reaction arising in the cluster.</p