Membrane models for molecular simulations of peripheral membrane proteins

Peripheral membrane proteins (PMPs) bind temporarily to the surface of biological membranes. They also exist in a soluble form and their tertiary structure is often known. Yet, their membrane-bound form and their interfacial-binding site with membrane lipids remain difficult to observe directly. Their binding and unbinding mechanism, the conformational changes of the PMPs and their influence on the membrane structure are notoriously challenging to study experimentally. Molecular dynamics simulations are particularly useful to fill some knowledge-gaps and provide hypothesis that can be experimentally challenged to further our understanding of PMP-membrane recognition. Because of the time-scales of PMP-membrane binding events and the computational costs associated with molecular dynamics simulations, membrane models at different levels of resolution are used and often combined in multiscale simulation strategies. We here review membrane models belonging to three classes: atomistic, coarse-grained and implicit. Differences between models are rooted in the underlying theories and the reference data they are parameterized against. The choice of membrane model should therefore not only be guided by its computational efficiency. The range of applications of each model is discussed and illustrated using examples from the literature.publishedVersio

Eliciting health state utilities for Dupuytren's contracture using a discrete choice experiment

Background and purpose An internet-based discrete choice experiment (DCE) was conducted to elicit preferences for a wide range of Dupuytren’s contracture (DC)-related health states. An algorithm was subsequently developed to convert these preferences into health state utilities that can be used to assess DC’s impact on quality of life and the value of its treatments. Methods Health state preferences for varying levels of DC hand severity were elicited via an internet survey from a sample of the UK adult population. Severity levels were deined using a combination of contractures (0, 45, or 90 degrees) in 8 proximal interphalangeal and metacarpophalangeal joints of the index, middle, ring, and little ingers. Right-handed, left-handed, and ambidextrous respondents indicated which hand was preferable in each of the 10 randomly-selected hand-pairings comparing different DC severity levels. For consistency across comparisons, anatomically precise digital hand drawings were used. To anchor preferences onto the traditional 0–1 utility scale used in health economic evaluations, unaffected hands were assigned a utility of 1.0 whereas the utility for a maximally affected hand (i.e., all 8 joints set at 90 degrees of contracture) was derived by asking respondents to indicate what combination of attributes and levels of the EQ-5D-5L proile most accurately relects the impact of living with such hand. Conditional logistic models were used to estimate indirect utilities, then rescaled to the anchor points on the EQ-5D-5L. Results Estimated utilities based on the responses of 1,745 qualiied respondents were 0.49, 0.57, and 0.63 for completely affected dominant hands, non-dominant hands, or ambidextrous hands, respectively. Utility for a dominant hand with 90-degree contracture in t h e metacarpophalangeal joints of the ring and little ingers was estimated to be 0.89. Separately, reducing the contracture of metacarpophalangeal joint for a little inger from 50 to 12 degrees would improve utility by 0.02. Interpretation DC is associated with substantial utility decrements. The algorithms presented herein provide a robust and lexible framework to assess utility for varying degrees of DC severity

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Language endangerment and language documentation in Africa

Non peer reviewe

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Les moissons du voyageur ou l'aventure scientifique des fréres d'Abbadie (1838-1848)

El vasco Antoine d'Abbadie (1810-1897) y su hermano menor Arnaud (1815-1893) viajaron mucho por Etiopía desde 1838 a 1848 con el fin de descubrir la fuente del Nilo Blanco. No tuvieron éxito, pero los dos hermanos, cuando volvieron a Francia trajeron consigo una importante colección de datos y manuscritos que ayudaron a poner en movimiento los estudios sobre Etiopía.Antoine d'Abbadie (1810-1897) euskaldunak, Arnauld (1815-1893) anaia gaztearekin batera, bidaia ugari egin zuen Etiopian zehar 1838tik 1838ra bitartean Nilo Zuriaren iturburua aurkitzeko xedearekin. Haien saioak ez zuen arrakastarik izan, baina bi anaiek Frantziara ekarri zuten gertakari eta eskuizkribu uzta esanguratsuak berriro abiarazi zituen Etiopiari buruzko ikerlanak.Le basque Antoine d'Abbadie (1810-1897) et son frère cadet Arnaud (1815-1893) voyagèrent beaucoup en Ethiopie de 1838 à 1848 dans le but de découvrir la source du Nil Blanc. Ils n'eurent pas de succès, mais les deux frères, à leur retour en France, ramenèrent une importante collection de données et manuscrits qui relancèrent les études sur l'Ethiopie.The Basque Antoine d'Abbadie (1810-1897) and his younger brother Arnauld (1815-1893) travelled extensively in Ethiopia from 1838 to 1848 with the aim of discovering the source of the White Nile. Their attempt did not succeed but the two brothers brought back to France a significant harvest of facts and manuscripts that gave impulse to studies on Ethiopia

Mission au Darfour

Tubiana Joseph, Tubiana Marie José. Mission au Darfour. In: L'Homme, 1967, tome 7 n°1. pp. 89-96

Mission au Darfour

Tubiana Joseph, Tubiana Marie José. Mission au Darfour. In: L'Homme, 1967, tome 7 n°1. pp. 89-96