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Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Janssen Australia and New Zealand (Janssen-Cilag Pty Ltd) Pulmonary Arterial Hypertension (PAH) management strategies focus on lowering mortality risk, extending the patient’s life span through the control and alleviation of disease symptoms, improving Quality of Life (QoL) and decreasing the burden of illness. This paper describes preliminary results of an Investigator Initiated pilot study exploring the relationship between PRO measures (PAH-SYMPACT, EQ5D5L); Burden of Illness assessment; and the ESC/ERS Risk Stratification. Findings Measures of PAH risk and QoL were assessed in 42 patients presenting to the IPAH clinic for management; mean age 69.2 [range 39, 84]; females 35 (83.3%), males 7 (16.7%). Tools analysed and compared included: PAH-SYMPACT and EQ-5D-5L as PRO and QoL measures; and ESC-ERS PAH risk stratification criteria to assess mortality risk. Health utility scores were derived from existing value sets: there was a 20% median reduction in QALYs for our patient population, with detrimental effects being more marked in those patients with greater impairment of EQ-5D-5L physical and cognitive-emotional domains (respectively: r = -0.92, p Conclusions The fact that PRO indices showed little correlation with established risk stratification markers implies that the information provided by PROs is not redundant, and it is yet be assessed whether the incorporation of PRO’s may add further to the precision of risk assessment, a little-studied area which this group is further exploring. There should be more widespread and uniform use of PRO measures as part of standard PAH management.

International audience; We demonstrated that the chemical intercalation of Zn$^{2+}$ ions within the interlayer space of the structure of a disordered layered titanate results in a drastic increase of the room temperature bulk proton conductivity from 8.11 x 10$^{-5}$ S.m$^{-1}$ for the pristine to 3.7 x10$^{-2}$ S.m-1 for Zn-titanate. Because of the crystallographic disordered nature of these compounds, we combined different techniques to establish the structural-transport relationships. Pair distribution function revealed that upon chemical insertion of Zn$^{2+}$ , the local lepidocrocite arrangement is maintained, providing a suited model to investigate the effect of chemically intercalated ions on the transport properties and dynamics within the interlayer space. Broadband dielectric spectroscopy (50 to 10$^{10}$ Hz) enabled to establish that Zn$^{2+}$ inclusion promotes proton-hopping by self-dissociation of H$_2$O molecules yielding high proton mobility. Using Zn-K edge EXAFS and chemical analyses (EDX, TGA, $^1$H NMR), Zn$^{2+}$ ions were shown to be stabilized by ZnCl$_2$ (H$_2$O) complex within the interlayer space. Such complexes induce an increase of the H-bonding strength as evidenced by $^1$H NMR, yielding a fast proton motion. Molecular dynamic simulations highlighted proton transfer between water molecules from structural interlayer and bonded to Zn 2+ ions. The increasing interactions between these water molecules favors proton transfer at the origin of the fast bulk proton conductivity, which was assigned to a Grotthuss-type mechanism taking place at long-range order. This work provides a better understanding of how ion-water interactions mediated ionic transport and opens perspectives into the design of ionic conductors that can be used in energy storage applications.

Dropout events are dramatic decreases in radiation belt electron populations that can occur in as little as 30 minutes. Loss to magnetopause due to a combination of magnetopause shadowing and outward radial transport plays a significant role in these events. We examine the dropout of relativistic electron populations during the October 2012 geomagnetic storm using simulated electron phase space density, evaluating the contribution of different processes to losses across the magnetopause. We compare loss contribution from outward transport calculated using a standard empirical radial diffusion model that assumes a dipolar geomagnetic field to an event-specific radial diffusion model evaluated with a non-dipolar geomagnetic field. We additionally evaluate the contribution of Shabansky type 1 particles, which bounce along magnetic field lines with local equatorial maxima, to the loss calculated during this event. We find that the empirical radial diffusion model with a dipolar background field underestimates the contribution of radial diffusion to this dropout event by up to 10% when compared to the event-specific, non-dipolar radial diffusion model. We additionally find that including Shabansky type 1 particles in the initial electron phase space density, that is, allowing some magnetic field lines distorted from the typical single-minima configuration in drift shell construction, increases the calculated loss by an average of 0.75%. This shows that the treatment of the geomagnetic field significantly impacts the calculation of electron losses to the magnetopause during dropout events, with the non-dipolar treatment of radial diffusion being essential to accurately quantify the loss of outer radiation belt populations.

Proanthocyanidins (condensed tannins) are important in food chemistry, agriculture, and health, driving demand for improvements in structure determination. We used ultrahigh resolution Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) methods to determine the exact composition of individual species in heterogeneous mixtures of proanthocyanidin polymers from Sorghum bicolor grain and Neptunia lutea leaves. Fragmentation patterns obtained with FT-ICR ESI MS-MS (electrospray ionization) confirmed structural details from thiolysis-high-performance liquid chromatography (HPLC)-diode array detection (DAD) and 1H-13C heteronuclear single quantum coherence (HSQC) NMR. We found that A-type linkages were characteristic of shorter polymers in predominantly B-linked proanthocyanidin. We suggest that supramolecular complex formation between proanthocyanidins and matrix components such as 2,5-dihydroxybenzoic acid was responsible for anomalous 152 dalton peaks, incorrectly assigned as 3-O-galloylation, when using FT-ICR matrix-assisted laser desorption ionization (MALDI-MS). Our data illustrate the power of the ultrahigh resolution FT-ICR methods but include the caveat that MALDI-MS must be paired with complementary analytical tools to avoid artifacts.

The development of practical multivalent-ion batteries critically depends on the identification of suitable positive electrode materials. To gain a better understanding of the intercalation chemistry of multivalent ions, model frameworks can be used to study the distinct specificities of possible multivalent ions, thus expanding our knowledge on the emerging “beyond Li battery” technology. Here, we compare the intercalation chemistry of Mg2+, Zn2+, and Ca2+ ions in a disordered layered-type structure featuring water interlayers and cationic vacancies as possible host sites. The thermodynamics of cation-inserted reactions performed on the model structure indicated that these reactions are thermodynamically favorable with Zn2+ being the least stable ion. Galvanostatic measurements confirmed that the structure is inactive toward Zn2+ intercalation, while Mg2+ can be reversibly inserted (0.37 Mg2+ per formula unit) with minor changes in the atomic arrangement, as demonstrated by pair distribution function analysis. Moreover, we demonstrate that nonsolvated Mg2+ was intercalated in the structure. Finally, the intercalation of Ca2+ performed at 100 °C with Ca(BF4)2 in propylene carbonate induced the collapse of the layered structure releasing water molecules that contribute to the degradation of the electrolyte, as revealed by the presence of CaF2 at the electrode level. The decomposition of the structure led to the formation of an electrochemically active phase featuring a strong long-range disorder, yet a short-range order close to that found in perovskite structures, particularly with corner-shared TiO6 octahedra. We, hence, hypothesize that defective CaTiO3-based perovskite could be explored as viable cathode materials for rechargeable Ca-based batteries., The research leading to these results received funding from the French National Research Agency under Idex@Sorbonne University for the Future Investments Program (no. ANR-11-IDEX-0004-02). Funding from the European Union’s Horizon 2020 research is acknowledged: European Research Council (ERC-2016-STG, CAMBAT grant agreement no. 715087). The work done at the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. A.P. is grateful to the Spanish Ministry for Economy, Industry and Competitiveness Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2015-0496). We thank IMPC FR2482 for SEM-FEG and TEM instrumentation funded by CNRS, Sorbonne Université and C’Nano projets of Region Ile-de-France.

A program is described that enables the energetics of crystal packing to be analysed quickly and easily through a user interface, using Pixel, Python scripts and the widely known visualizer Mercury., The interpretation of crystal structures in terms of intermolecular interaction energies enables phase stability and polymorphism to be rationalized in terms of quantitative thermodynamic models, while also providing insight into the origin of physical and chemical properties including solubility, compressibility and host–guest formation. The Pixel method is a semi-empirical procedure for the calculation of intermolecular interactions and lattice energies based only on crystal structure information. Molecules are represented as blocks of undistorted ab initio molecular electron and nuclear densities subdivided into small volume elements called pixels. Electrostatic, polarization, dispersion and Pauli repulsion terms are calculated between pairs of pixels and nuclei in different molecules, with the accumulated sum equating to the intermolecular interaction energy, which is broken down into physically meaningful component terms. The MrPIXEL procedure enables Pixel calculations to be carried out with minimal user intervention from the graphical interface of Mercury, which is part of the software distributed with the Cambridge Structural Database (CSD). Following initial setup of a crystallographic model, one module assigns atom types and writes necessary input files. A second module then submits the required electron-density calculation either locally or to a remote server, downloads the results, and submits the Pixel calculation itself. Full lattice energy calculations can be performed for structures with up to two molecules in the crystallographic asymmetric unit. For more complex cases, only molecule–molecule energies are calculated. The program makes use of the CSD Python API, which is also distributed with the CSD.

There is limited information regarding the use of risk assessment tools with aging offender populations. It is known that the likelihood of offending behaviour decreases with age, a small group of men either continue or begin to offend sexually in the later decades of life. The current study investigated the predictive validity of the Static-99 and the Static-99R, in a sample of convicted Australian sex offenders aged 50 and older. A sample of 118 participants was identified, of which 17 (14.4%) re-offended within a follow-up period ranging from four months to 20 years (M = 9.07 years). There were seven recidivists (13.46%) above the age of 60 years (n = 52) and 10 aged 40 to 59.9 years (n = 66). Both the Static-99 and Static-99R demonstrated moderate predictive validity with both age groups. The limitations of this study are discussed as well as recommendations for future research.

Background Higher adult body mass index (BMI) increases diabetes risk, whereas, paradoxically, lower birthweight is associated with higher risks of adult-onset diabetes. Increased diabetes risks associated with low birthweight might be due to increased risks among those who become overweight or obese as adults but evidence on risks among those of normal BMI is limited. Methods In the Million Women Study, 413,516 women without prior diabetes, at mean age 60(SD5) years, reported their birthweight, and current height and weight. Birthweight and BMI at age 60 years were validated against recorded values at similar ages. Participants were followed for diabetes by electronic linkage to national hospital admissions records. Cox regression yielded multivariable-adjusted relative risks (RRs) for diabetes, overall and subdivided simultaneously by categories of birthweight and adult BMI. Results During 15(SD3) years follow-up, 24,528 women had hospital admissions with diabetes, first recorded at average age 70(SD6) years. Adult-onset diabetes risks increased strongly with increasing adult BMI (RR per 5 kg/m2 increase: 2.03, 95% CI 2.01-2.06). Compared to those with birthweight 3.0-3.4 kg, RRs of diabetes for birthweight Conclusions At every level of adult adiposity, there were strong inverse associations between birthweight and adult-onset diabetes risk. Key messages While adult adiposity increases diabetes risk, there is a strong and independent increase in diabetes risk with decreasing birthweight.

The Cambridge Structural Database (CSD) currently contains over 400 000 transition-metal-containing entries, however many entries still lack curated oxidation-state assignments. Surveying and editing the remaining entries would be far too resource- and time-intensive to be carried out manually. Here, a highly reliable automated workflow for oxidation-state assignment in transition-metal coordination complexes via CSD Python API (application programming interface) scripts is presented. The strengths and limitations of the bond-valence sum (BVS) method are discussed and the use of complementary methods for improved assignment confidence is explored. In total, four complementary techniques have been implemented in this study. The resulting workflow overcomes the limitations of the BVS approach, widening the applicability of an automated procedure to more CSD entries. Assignments are successful for 99% of the cases where a high consensus between different methodologies is observed. Out of a total number of 54 999 unique metal atoms in a test dataset, the procedure yielded the correct oxidation state in 47 072 (86%) of cases.

Redox active molecules are of interest in many fields such as medicine, catalysis or energy storage. In particular, in supercapacitor applications, they can be grafted to ionic liquids to form so-called biredox ionic liquids. To completely understand the structural and transport properties of such systems, an insight at the molecular scale is often required but few force fields are developed ad hoc for these molecules. Moreover, they do not include polarization effects, which can lead to inaccurate solvation and dynamical properties. In this work, we developed polarizable force fields for redox-active species anthraquinone (AQ) and 2,2,6,6-tetra-methylpiperidinyl-1-oxyl (TEMPO) in their oxidized and reduced states, as well as for acetonitrile. We validate structural properties of AQ, AQ$^{\bullet-}$, AQ$^{2-}$, TEMPO$^{\bullet}$ and TEMPO$^{+}$ in acetonitrile against density functional theory-based molecular dynamics simulations and we study the solvation of these redox molecules in acetonitrile. This work is a first step toward the characterization of the role played by AQ and TEMPO in electrochemical and catalytic devices.

Crystal packing energy calculations are applied to the [Fe(PM-L)2(NCS)2] family of spin crossover (SCO) complexes (PM-L = 4-substituted derivatives of the N-(2-pyridylmethylene)-4-aminobiphenyl ligand) with the aim of relating quantitatively the cooperativity of observed SCO transitions to intermolecular interactions in the crystal structures. This approach reveals a linear variation of the transition abruptness with the sum of the magnitudes of the interaction energy changes within the first molecular coordination sphere in the crystal structure. Abrupt transitions are associated with the presence of significant stabilising and destabilising changes in intermolecular interaction energies. While the numerical trend established for the PM-L family does not directly extend to other classes of SCO complex in which the intermolecular interactions may be very different, a plot of transition abruptness against the range of interaction energy changes normalised by the largest change shows a clustering of complexes with similar transition abruptness. The changes in intermolecular interactions are conveniently visualised using energy difference frameworks, which illustrate the cooperativity pathways of an SCO transition., The abruptness of spin crossover (SCO) is related to intermolecular energy changes occurring over the course of an SCO transition. Crossover is abrupt when SCO-induced strain is accommodated synergistically in a few key interactions.

Spurred by the increasing needs in electrochemical energy storage devices, the electrode/electrolyte interface has received a lot of interest in recent years. Molecular dynamics simulations play a proeminent role in this field since they provide a microscopic picture of the mechanisms involved. The current state-of-the-art consists in treating the electrode as a perfect conductor, precluding the possibility to analyze the effect of its metallicity on the interfacial properties. Here we show that the Thomas-Fermi model provides a very convenient framework to account for the screening of the electric field at the interface and differenciating good metals such as gold from imperfect conductors such as graphite. All the interfacial properties are modified by screening within the metal: the capacitance decreases significantly and both the structure and dynamics of the adsorbed electrolyte are affected. The proposed model opens the door for quantitative predictions of the capacitive properties of materials for energy storage., 10 pages, 10 figures (contains the SI)

Background Hypertension has been associated with an increased risk of kidney cancer, but evidence of association with cancers elsewhere in the urinary tract is mixed. We examined the association between hypertension and the incidence of cancers of the kidney (by histotype), and urinary tract, in a large cohort of UK women. Methods Participants were recruited in 1996–2001 from 66 NHS breast-screening centres, and completed a questionnaire on anthropometric, reproductive and lifestyle factors, and medical history, including self-reported hypertension requiring treatment. They were followed for cancer and death via record linkage to national registries. We used Cox regression models to estimate relative risks (RRs) of cancers of the kidney and urinary tract, associated with self-reported hypertension requiring treatment at recruitment, adjusted for potential confounders. Analyses were conducted in Stata 15. Results In 1,319,718 women without previous cancer, 211,663 (16%) reported at recruitment that they were currently being treated for hypertension. After 16.9 years’ (SD 4.6) mean follow-up, 5391 kidney cancers, including 4248 renal cell carcinomas and 442 urothelial carcinomas, accrued. Hypertension requiring treatment at recruitment was associated with a significantly greater increase in the risk of renal cell carcinomas (RR=1.69, 95% CI: 1.57–1.82) than urothelial carcinomas of the kidney (RR=1.27, 95% CI: 1.00–1.62); heterogeneity by histotype, p=0.02. There were no clear associations between hypertension at recruitment and the risk of urothelial carcinomas elsewhere in the urinary tract (ureter: n=249, RR=0.82, 95% CI: 0.57–1.17; bladder: n=2929, RR=1.00, 95% CI: 0.91–1.11). The association seen with renal cell carcinomas persisted even after exclusion of the first 10 years of follow-up (RR=1.69, 95% CI: 1.54–1.85), suggesting it was not an artefact of reverse causation. Conclusion Hypertension is strongly associated with an increased risk of kidney cancer, with significant heterogeneity by histotype. The risk of renal cell carcinoma is substantially increased in those with a history of hypertension, but there is little or no association with urothelial carcinomas, either in the kidney or the rest of the urinary tract.

Azanone (HNO) is a reactive nitrogen species with pronounced biological activity and high therapeutic potential for cardiovascular dysfunction. A critical barrier to understanding the biology of HNO and furthering clinical development is quantification and real-time monitoring of delivery in living systems. Here, we describe the design and synthesis of the first chemiluminescent probe for HNO, HNOCL-1, which can detect HNO generated from as low as 138 nM Angeli’s salt with high selectivity based on reaction with a phosphine group to form a self-cleavable azaylide intermediate. We have capitalized on this high sensitivity to develop a generalizable kinetics-based approach, which provides real-time quantitative estimates of HNO concentration that show good agreement with computational simulations. This method can be used to quantify picomolar HNO concentrations generated from hydrogen sulfide (H(2)S) and nitric oxide (NO). HNOCL-1 can monitor dynamics of HNO delivery in living cells and tissues, demonstrating the versatility of this method for tracking HNO in living systems.

International audience; A lamellar lepidocrocite-type titanate structure with ∼25% Ti4+ vacancies was recently synthesized, and it showed potential for use as an electrode in rechargeable lithium-ion batteries. In addition to lithium, we explore this material’s ability to accommodate other monovalent ions with greater natural abundance (e.g., sodium and potassium) in order to develop lower-cost alternatives to lithium-ion batteries constructed from more widely available elements. Galvanostatic discharge/charge curves for the lepidocrocite material indicate that increasing the ionic radius of the monovalent ion results in a deteriorating performance of the electrode. Using first-principles electronic structure calculations, we identify the relaxed geometries of the structure while varying the placement of the ion in the structure. We then use these geometries to compute the energy of formations. Additionally, we determine that all ions are favorable in the structure, but interlayer positions are preferred compared to vacancy positions. We also conclude that the exchange between the interlayer and vacancy positions is a process that involves the interaction between interlayer water and surface hydroxyl groups next to the titanate layer. We observe a cooperative effect between structural water and OH groups to assist alkali ions to move from the interlayer to the vacancy site. Thus, the as-synthesized lepidocrocite serves as a prototypical structure to investigate the migration mechanism of ions within a confined space along with the interaction between water molecules and the titanate framework.

Peroxynitrite (ONOO-) is a highly reactive oxygen species which has been recognized as an endogenous mediator of physiological activities like the immune response as well as a damaging agent of oxidative stress under pathological conditions. While its biological importance is becoming clearer, many of the details of its production and mechanism of action remain elusive due to the lack of available selective and sensitive detection methods. Herein, we report the development, characterization, and biological applications of a reaction-based chemiluminescent probe for ONOO- detection, termed as PNCL. PNCL reacts with ONOO-via an isatin moiety through an oxidative decarbonylation reaction to initiate light emission that can be observed instantly with high selectivity against other reactive sulphur, oxygen, and nitrogen species. Detailed studies were performed to study the reaction between isatin and ONOO-, which confirm selectivity for ONOO- over NO2˙. PNCL has been applied for ONOO- detection in aqueous solution and live cells. Moreover, PNCL can be employed to detect cellular ONOO- generated in macrophages stimulated to mount an immune response with lipopolysaccharide (LPS). The sensitivity granted by chemiluminescent detection together with the specificity of the oxidative decarbonylation reaction provides a useful tool to explore ONOO- chemistry and biology.

Biredox ionic liquids are a new class of functionalized electrolytes that may play an important role in future capacitive energy storage devices. By allowing additional storage of electrons inside the liquids, they can improve device performance significantly. However current devices employ nanoporous carbons in which the diffusion of the liquid and the adsorption of the ions could be affected by the occurrence of electron-transfer reactions. It is therefore necessary to understand better the thermodynamics and the kinetics of such reactions in biredox ionic liquids. Here we perform ab initio molecular dynamics simulations of both the oxidized and reduced species of several redox-active ionic molecules (used in biredox ionic liquids) dissolved in acetonitrile solvent and compare them with the bare redox molecules. We show that in all the cases, it is necessary to introduce a two Gaussian state model to calculate the reaction free energies accurately. These reaction free energies are only slightly affected by the presence of the IL group on the molecule. We characterize the structure of the solvation shell around the redox active part of the molecules and show that in the case of TEMPO-based molecules strong reorientation effects occur during the oxidation reaction., 11 pages, 12 figures

International audience; Proton chemistry is a fascinating field with both fundamental and applied aspects. The development of solid-state proton conductors relying on abundant elements could help bring these two aspects. In this scope, we synthesized a disordered structure which, as revealed by the real-space refinement of the pair distribution function, has been identified to be the trititanate arrangement. The layered structure is stabilized by the presence of hydronium ions and water molecules located in the interlayer space. This compound displays a high ionic conductivity of 4·10–2 S/m with an activation energy of 0.24 eV, assigned to H+ mobility as shown by broadband dielectric spectroscopy. Proton mobility was further evidenced by solid-state proton nuclear magnetic resonance. Density functional theory calculations revealed that proton transfer occurs both within the interlayer space and with terminal oxide of the titanate framework through a Grotthuss-based mechanism rationalizing the high conductivity measured experimentally. Finally, we investigated the electrochemical properties with respect to the proton as a charge carrier using proton-free (KCl) and proton-donor (buffer acetic acid) electrolytes. The results showed that the structure can reversibly intercalate protons at a very high rate opening existing perspectives in the development of negative electrode materials for aqueous proton batteries. Overall, this study helps better understand the proton transfer mechanism occurring in a confined layered-type structure.

Chemical doping and other surface modifications have been used to engineer the bulk properties of materials, but their influence on the surface structure and consequently the surface chemistry are often unknown. Previous work has been successful in fluorinating anatase TiO

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users. Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

International audience; The Na-ion battery is recognized as a possible alternative to Li-ion battery for applications where power and cost override energy density performances. However, the increasing instability of their electrolyte with temperature is still problematic. Thus, a central question remains how to design Na-based electrolytes. Here, we report discovery of a Na-based electrolyte formulation which enlists four additives (vinylene carbonate (VC), succinonitrile (SN), 1, 3-propane sultone (PS) and sodium difluoro(oxalate)borate (NaODFB) in proper quantities that synergistically combined their positive attributes to lead a stable solid electrolyte interphase (SEI) at both negative and positive electrodes surface at 55 °C. Moreover, we rationalized the role of each additive that consists in producing specific NaF coatings, thin elastomers, sulfate-based deposits and so on via combined impedance (EIS) and X-ray photoelectron spectroscopy (XPS). We demonstrated that empirical electrolyte design rules previously established for Li-ion technology together with theoretical guidance is a vital strategy in the quest for better Na-based electrolytes that can be extended to other chemistries. Overall, this finding, which we implement to practical 18650 cells, widens the route to the rapid development of the Na-ion technology based on the Na 3 V 2 (PO 4) 2 F 3 /C chemistry.

Background The use of hormone therapy for the menopause (HT) has been shown to affect the sensitivity and specificity of mammographic screening. However there is little evidence on how the association between HT use and risk of screen detected breast cancer compares with that of interval breast cancer. We examined these associations in a large UK prospective study. Methods We used Cox proportional hazard models to estimate the relative risk (RR) of screen detected and of interval cancer in relation to HT use among post-menopausal women who attended for routine mammographic screening. Analyses were stratified by year of birth and year of recruitment and adjusted for relevant confounders including socio-economic status, reproductive history, anthropometric and other lifestyle factors. Results Of the 1,076,203 eligible women in the cohort, 14,730 were diagnosed with a screen-detected cancer and 8,659 with an interval breast cancer. When compared to non-users of HT, current-or-recent users were at a much higher risk of an interval cancer (RR=2.18, 95%CI 2.07–2.30) than of a screen detected cancer (RR=1.44, 95%CI 1.38–1.51). For oestrogen only HT, the corresponding RRs and 95% CI for interval and screen-detected cancers were 1.60(1.48–1.73) and 1.11(1.05–1.19); and for oestrogen and progestogen HT, the corresponding values were 2.75(2.58–2.92) and 1.79(1.70–1.88). Conclusion In this large cohort of UK women, current-or-recent users of HT were at a substantially higher risk of being diagnosed with an interval cancer than with a screen detected cancer. The difference in risk between screen-detected and interval cancer was apparent for HT preparations containing oestrogen only and combinations of oestrogen and progestogen.

The capital market is one indicator of a country's economic progress, which contributes to the economic development of a country. Which can be described as a country's wheels, the source of funds for companies that are the support of a country. This research was conducted with the goals of studying accuracy support resistance by using Fibonacci retracement indicators based on candlestick stock price movements. The type of research used consists of a type of quantitative research using secondary data that contains a graph of the stock price of the LQ45 index mining sector which then carried out a different sample dependent test.The results of this study indicate that the support and resistance on the Fibonacci Retracement indicator has a difference with the selection price so that it can complete estimates of inaccurate support resistance.