Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis

Priorities for synthesis research in ecology and environmental science

ACKNOWLEDGMENTS We thank the National Science Foundation grant #1940692 for financial support for this workshop, and the National Center for Ecological Analysis and Synthesis (NCEAS) and its staff for logistical support.Peer reviewedPublisher PD

Priorities for synthesis research in ecology and environmental science

ACKNOWLEDGMENTS We thank the National Science Foundation grant #1940692 for financial support for this workshop, and the National Center for Ecological Analysis and Synthesis (NCEAS) and its staff for logistical support.Peer reviewedPublisher PD

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Gender differences in the management and experience of Chronic Obstructive Pulmonary Disease

AbstractWhether women receive the same medical care for COPD as men and if they are at risk of different outcomes as a result, is not known. The Confronting COPD International Survey was performed in the USA, Canada, France, Italy, Germany, The Netherlands, Spain and the UK in 2000 with 3265 COPD participants. Forty-one per cent were women; mean age in women and men was 61.2 (sd 10.5) and 64.4 (11.0) years, mean pack-years of smoking 36 (29) and 46 (35) years, respectively. After adjusting for age, pack-years, country and severe dyspnea (MRC scores 5 and 4), women were less likely to have had spirometry (OR 0.84, 95% C.I. 0.72–0.98) but more likely to get smoking cessation advice (OR 1.57, 1.33–1.86). Despite significantly lower pack-years of smoking, women were more likely to report severe dyspnea than men (OR 1.30, 1.10–1.54), with similar cough (OR 1.08, 0.92–1.27) and less sputum (OR 0.84, 0.72–0.98). There were no differences in the risk of hospitalisation or emergency room visit. This study indicates that gender differences in COPD care and outcomes exist