'Ma maman va-t-elle mourir?' : comment répondre aux questions des enfants lorsqu'un membre de la famille a le cancer.

'Conférence Schering 2000.

Multivariate proteomic profiling identifies novel accessory proteins of coated vesicles.

Despite recent advances in mass spectrometry, proteomic characterization of transport vesicles remains challenging. Here, we describe a multivariate proteomics approach to analyzing clathrin-coated vesicles (CCVs) from HeLa cells. siRNA knockdown of coat components and different fractionation protocols were used to obtain modified coated vesicle-enriched fractions, which were compared by stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative mass spectrometry. 10 datasets were combined through principal component analysis into a "profiling" cluster analysis. Overall, 136 CCV-associated proteins were predicted, including 36 new proteins. The method identified >93% of established CCV coat proteins and assigned >91% correctly to intracellular or endocytic CCVs. Furthermore, the profiling analysis extends to less well characterized types of coated vesicles, and we identify and characterize the first AP-4 accessory protein, which we have named tepsin. Finally, our data explain how sequestration of TACC3 in cytosolic clathrin cages causes the severe mitotic defects observed in auxilin-depleted cells. The profiling approach can be adapted to address related cell and systems biological questions

Sustainable futures over the next decade are rooted in soil science

Funding information: Dutch Knowledge Base Program; European Commission, Grant/Award Number: NEW 810; Horizon 2020 Framework Programme, Grant/Award Numbers: 774378, 869625; Korea Environmental Industry and Technology Institute, Grant/Award Number: 2019002820004; Natural Environment Research Council, Grant/Award Number: NE/R016429/1; Svenska Forskningsrådet Formas, Grant/Award Number: 2017-00608; UK Research and Innovation, Grant/Award Number: NE/P019455/1Peer reviewedPublisher PD

Alkali metal derivatives of an ortho-phenylene diamine

Treatment of the ortho-phenylene diamine C6H4-1,2-{N(H)Tripp}2 (1, PDAH2, Tripp = 2,4,6-triisopropylphenyl) with two equivalents of MR (M = Li, R = Bun; M = Na or K, R = CH2C6H5) afforded the dimetallated alkali metal ortho-phenylene diamide dianion complexes [(PDALi2)(THF)3] (2), [{(PDANa2)(THF)2}2] (3), and [{(PDAK2)(THF)3}2] (4). In contrast, treatment of 2 with two equivalents of rubidium or cesium 2-ethylhexoxide, or treatment of 1 with two equivalents of MR (M = Rb or Cs, R = CH2C6H5) did not afford the anticipated dialkali metal ortho-phenylene diamide dianion derivatives and instead formally afforded the monometallic ortho-diiminosemiquinonate radical anion species [PDAM] (M = Rb, 5; M = Cs, 6). The structure of 2 is monomeric with one lithium coordinated to the two nitrogen centres and the other lithium η4-coordinated to the diazabutadiene portion of the PDA scaffold. Similar structural cores are observed for 3 and 4, except that the larger sodium and potassium ions give dimeric structures linked by multi-hapto interactions from the PDA backbone phenyl ring to an alkali metal centre. Complex 5 was not characterised in the solid state, but the structure of 6 reveals coordination of cesium ions to both PDA amide centres and multi-hapto interactions to a PDA backbone phenyl ring in the next unit to generate a one-dimensional polymer. Complexes 2–6 have been variously characterised by X-ray crystallography, multi-nuclear NMR, FTIR, and EPR spectroscopies, and CHN microanalyses

Assessment of Heat-Related Health Impacts in Brisbane, Australia: Comparison of Different Heatwave Definitions

Background: There is no global definition of a heatwave because local acclimatisation and adaptation influence the impact of extreme heat. Even at a local level there can be multiple heatwave definitions, based on varying temperature levels or time periods. We investigated the relationship between heatwaves and health outcomes using ten different heatwave definitions in Brisbane, Australia. ---------- Methodology/Principal Findings: We used daily data on climate, air pollution, and emergency hospital admissions in Brisbane between January 1996 and December 2005; and mortality between January 1996 and November 2004. Case-crossover analyses were used to assess the relationship between each of the ten heatwave definitions and health outcomes. During heatwaves there was a statistically significant increase in emergency hospital admissions for all ten definitions, with odds ratios ranging from 1.03 to 1.18. A statistically significant increase in the odds ratios of mortality was also found for eight definitions. The size of the heat-related impact varied between definitions.---------- Conclusions/Significance Even a small change in the heatwave definition had an appreciable effect on the estimated health impact. It is important to identify an appropriate definition of heatwave locally and to understand its health effects in order to develop appropriate public health intervention strategies to prevent and mitigate the impact of heatwaves

Silent slips, trips and broken hips in the under 60s: a review of the literature

This critical review of the literature regarding the recovery experiences and healthcare needs of people under 60 following a fragility hip fracture seeks to identify the associated implications for nursing practice and inform care delivery. Forty papers were included following a structured database, citation and grey literature search and filtering of results in line with specified inclusion criteria. Hip fracture is a common, serious and complex injury and an important cause of morbidity, mortality and rising healthcare costs worldwide. This review indicates that although commonly associated with the elderly, incidence and impact in the under 60s has been under-explored. Current health policy, professional and social norms almost exclusively focus on the elderly, surgical interventions and short-term outcomes, rendering the under 60s an inadvertently marginalised, relatively 'silent' sub-set of the hip fracture population. Nurses must be aware, however, of the different recovery needs of this younger group. The limited evidence available indicates these include work related needs and long term physical and psychosocial limitations in this socially and economically active group. Priorities are identified for research to inform policy and practice. Meanwhile, nurses can address the needs of this group by listening to and involving them and their families as healthcare partners. [Abstract copyright: Copyright © 2018. Published by Elsevier Ltd.

Recommendations for enterovirus diagnostics and characterisation within and beyond Europe.

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden

Investigating the Host Binding Signature on the Plasmodium falciparum PfEMP1 Protein Family

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family plays a central role in antigenic variation and cytoadhesion of P. falciparum infected erythrocytes. PfEMP1 proteins/var genes are classified into three main subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles in binding and disease. To investigate whether these subfamilies have diverged in binding specificity and test if binding could be predicted by adhesion domain classification, we generated a panel of 19 parasite lines that primarily expressed a single dominant var transcript and assayed binding against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC var genes were isolated, indicating that UpsA var gene expression is rare under in vitro culture conditions. Consequently, three UpsA variants were obtained by rosette purification and selection with specific monoclonal antibodies to create a more representative panel. Binding assays showed that CD36 was the most common adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that CD36 and ICAM-1 binding variants were highly predicted by adhesion domain sequence classification. Binding to other host receptors, including CSA, VCAM-1, HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor “X”, and Fractalkine, was rare or absent. Our findings identify a category of larger PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They also support that the UpsA group, in contrast to UpsB and UpsC var genes, has diverged from binding to the major microvasculature receptor CD36 and likely uses other mechanisms to sequester in the microvasculature. These results demonstrate that CD36 and ICAM-1 have left strong signatures of selection on the PfEMP1 family that can be detected by adhesion domain sequence classification and have implications for how this family of proteins is specializing to exploit hosts with varying levels of anti-malaria immunity

Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics

Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory

Clinical and Demographic Factors Associated with COVID-19, Severe COVID-19, and SARS-CoV-2 Infection in Adults: A Secondary Cross-Protocol Analysis of 4 Randomized Clinical Trials

Importance: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. Objective: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. Design, Setting, and Participants: This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. Exposures: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. Main Outcomes and Measures: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. Results: A total of 57692 participants (median [range] age, 51 [18-95] years; 11720 participants [20.3%] aged ≥65 years; 31058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17678 Hispanic or Latino participants (30.6%), and 40745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P <.001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P <.001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P <.001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P <.001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P =.002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P <.001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P =.005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P =.008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P <.001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P =.001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P =.001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P <.001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P <.001). Conclusions and Relevance: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics