Search

Rapid screening of hospital admissions to detect asymptomatic carriers of resistant bacteria can prevent pathogen outbreaks. However, the resulting isolates rarely have their genome sequenced due to cost constraints and long turn-around times to get and process the data, limiting their usefulness to the practitioner. Here we used real-time, on-device target enrichment (“adaptive”) sequencing as a highly multiplexed assay covering 1,147 antimicrobial resistance genes. We compared its utility against standard and metagenomic sequencing, focusing on an isolate of Raoultella ornithinolytica harbouring three carbapenemases (NDM, KPC, VIM). Based on this experimental data, we then modelled the influence of several variables on the enrichment results and predicted the large effect of nucleotide identity (higher is better) and read length (shorter is better). Lastly, we showed how all relevant resistance genes are detected using adaptive sequencing on a miniature (“Flongle”) flow cell, motivating its use in a clinical setting to monitor similar cases and their surroundings.

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials.

Interpretation of kidney graft biopsies using the Banff classification is still heterogeneous. In this study, extreme gradient boosting classifiers learned from two large training datasets (n = 631 and 304 cases) where the "reference diagnoses" were not strictly defined following the Banff rules but from central reading by expert pathologists and further interpreted consensually by experienced transplant nephrologists, in light of the clinical context. In three external validation datasets (n = 3744, 589, and 360), the classifiers yielded a mean ROC curve AUC (95%CI) of: 0.97 (0.92-1.00), 0.97 (0.96-0.97), and 0.95 (0.93-0.97) for antibody-mediated rejection (ABMR); 0.94 (0.91-0.96), 0.94 (0.92-0.95), and 0.91 (0.88-0.95) for T cell-mediated rejection;0.96 (0.90-1.00) with all three for interstitial fibrosis-tubular atrophy. We also developed a classifier to discriminate active and chronic active ABMR with 95% accuracy. In conclusion, we built highly sensitive and specific artificial intelligence classifiers able to interpret kidney graft scoring together with a few clinical data and automatically diagnose rejection, with excellent concordance with the Banff rules and reference diagnoses made by a group of experts. Some discrepancies may point toward possible improvements that could be made to the Banff classification.

Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques.The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens.In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24.Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

Unidad de excelencia María de Maeztu CEX2019-000940-M In an increasingly urbanized world, where cardiometabolic issues in cities have raised public health concerns, urban greenness is known to be beneficial for some of the most common health issues. However, the examination of the contribution of sex and gender regarding the benefits of urban greenness for people's cardiometabolic health is lacking. For that reason, we conducted a systematic review of previous literature on the topic following the PRISMA methodology. Additionally, we assessed the quality of the included articles, which we found satisfactory as most papers were of very good or good quality. We explored the relationship between urban greenness exposure and cardiovascular risk factors, cardiovascular diseases, and mortality from cardiovascular diseases. Results suggest that urban greenness is protective against cardiovascular risk factors, diseases, and mortality. When stratifying results by sex and gender, findings point to urban greenness being more beneficial for women and females in stroke and cardiovascular risk factors, except for hypertension and lipid accumulation product. On the other hand, males were more protected by urban greenness in terms of cardiovascular diseases and CVD-related mortality, thus proving that sex and gender health inequalities exist. Furthermore, looking towards the future, research needs to use the proper terminology for sex and gender and policy makers should design urban greenness with a gender perspective.

International audience; Transport and mobility systems need to be transformed to meet climate change goals and reduce negative environmental and social effects. Despite EU policies having targeted such problems for more than three decades, transitions have been slow and geographically uneven. For effective change to happen, transport and mobility research needs fresh perspectives and better integration of knowledge from the Social Sciences and Humanities. Based on a Horizon Scanning approach, which allowed for a great deal of openness and variety in scholarly viewpoints, this paper presents a novel research agenda consisting of 8 themes and 100 research questions that may contribute to achieving environmentally sustainable mobility transitions within Europe. This research agenda highlights the need to not only support technological solutions for low-carbon mobility, but the importance of transformative policies that include new processes of knowledge production, civic participation and epistemic justice. We contend that the agenda points to the need for further research on the dynamics of science-society interactions.

International audience; The VOR is the version of the article after copy-editing and typesetting, and connected to open research data, open protocols, and open code where available. Any supplementary information can be found on the journal website, connected to the VOR. For research integrity purposes it is best practice to cite the published Version of Record (VOR), where available (for example, see ICMJE's guidelines on overlapping publications). Where users do not have access to the VOR, any citation must clearly indicate that the reference is to an Accepted Manuscript (AM) version.

Here we report on Neanderthal engravings on a cave wall at La Roche-Cotard (LRC) in central France, made more than 57±3 thousand years ago. Following human occupation, the cave was completely sealed by cold-period sediments, which prevented access until its discovery in the 19 th century and first excavation in the early 20 th century. The timing of the closure of the cave is based on 50 optically stimulated luminescence ages derived from sediment collected inside and from around the cave. The anthropogenic origin of the spatially-structured, non-figurative marks found within the cave is confirmed using taphonomic, traceological and experimental evidence. Cave closure occurred significantly before the regional arrival of H . sapiens , and all artefacts from within the cave are typical Mousterian lithics; in Western Europe these are uniquely attributed to H . neanderthalensis . We conclude that the LRC engravings are unambiguous examples of Neanderthal abstract design.

Introduction: Tacrolimus, an immunosuppressive drug prescribed to a majority of organ transplant recipients is nephrotoxic, through still unclear mechanisms. This study on a lineage of proximal tubular cells using a multi-omics approach aims to detect off-target pathways modulated by tacrolimus that can explain its nephrotoxicity. Methods: LLC-PK1 cells were exposed to 5 µM of tacrolimus for 24 h in order to saturate its therapeutic target FKBP12 and other high-affine FKBPs and favour its binding to less affine targets. Intracellular proteins and metabolites, and extracellular metabolites were extracted and analysed by LC-MS/MS. The transcriptional expression of the dysregulated proteins PCK-1, as well as of the other gluconeogenesis-limiting enzymes FBP1 and FBP2, was measured using RT-qPCR. Cell viability with this concentration of tacrolimus was further checked until 72 h. Results: In our cell model of acute exposure to a high concentration of tacrolimus, different metabolic pathways were impacted including those of arginine (e.g., citrulline, ornithine) (p < 0.0001), amino acids (e.g., valine, isoleucine, aspartic acid) (p < 0.0001) and pyrimidine (p < 0.01). In addition, it induced oxidative stress (p < 0.01) as shown by a decrease in total cell glutathione quantity. It impacted cell energy through an increase in Krebs cycle intermediates (e.g., citrate, aconitate, fumarate) (p < 0.01) and down-regulation of PCK-1 (p < 0.05) and FPB1 (p < 0.01), which are key enzymes in gluconeogenesis and acid-base balance control. Discussion: The variations found using a multi-omics pharmacological approach clearly point towards a dysregulation of energy production and decreased gluconeogenesis, a hallmark of chronic kidney disease which may also be an important toxicity pathway of tacrolimus.

Experimental measurements and numerical simulations of turbulent flows are characterised by a trade-off between accuracy and resolution. In this study, we bridge this gap using Physics Informed Neural Networks (PINNs) constrained by the Reynolds-Averaged Navier-Stokes (RANS) equations and accurate sparse pointwise mean velocity measurements for data assimilation (DA). Firstly, by constraining the PINN with sparse data and the under-determined RANS equations without closure, we show that the mean flow is reconstructed to a higher accuracy than a RANS solver using the Spalart-Allmaras (SA) turbulence model. Secondly, we propose the SA turbulence model augmented PINN (PINN-DA-SA), which outperforms the former approach - up to 73% reduction in mean velocity reconstruction error with coarse measurements. The additional SA physics constraints improve flow reconstructions in regions with high velocity and pressure gradients and separation. Thirdly, we compare the PINN-DA-SA approach to a variational data assimilation using the same sparse velocity measurements and physics constraints. The PINN-DA-SA achieves lower reconstruction error across a range of data resolutions. This is attributed to discretisation errors in the variational methodology that are avoided by PINNs. We demonstrate the method using high fidelity measurements from direct numerical simulation of the turbulent periodic hill at Re=5600.

The objectives of this study were to evaluate the effect of cessation of active smoking during the 1st, 2nd, and 3rd trimesters of pregnancy on the risk of reduced birth weight and prematurity using an exhaled carbon monoxide biomarker with a cut-off value ≥3 ppm as well as the effects of passive smoking.This was a multicenter prospective cohort study involving pregnant smokers and non-smokers. Pregnant smokers were identified at the first prenatal visit before 15 weeks of amenorrhea by the number of cigarettes smoked per day and by the carbon monoxide breath test. Women were classified into 6 groups: non-smokers, passive smokers, first trimester cessation, second trimester cessation, third trimester cessation, and smoking throughout pregnancy. Smoking cessation was defined if the pregnant woman reported quitting smoking and if she achieved an exhaled CO level of3 ppm. The association between smoking cessation and fetal growth restriction or prematurity was assessed by multivariate logistic regression. Passive smoking was defined for non-smoking women on declarative smoking status and exhaled CO ≥3 ppm. The association between passive smoking and fetal growth restriction or prematurity was assessed by multivariate logistic regression.The number of patients included was 5244. The incidence of fetal growth restriction below the 10th percentile was 10.6%, 12.1%, 8.5%, 9.1%, 21.1%, and 22.9%, respectively, for the non-smoking, passive smoking, first, second, third trimester cessation, and full-pregnancy smoking, groups. The risk of FGR compared to non-smokers was OR=2.3 (95% CI: 1.18-4.30, p=0.014) for patients who quit smoking in the third trimester, OR=2.5 (95% CI: 2.03-3.12, p0.001) for women who smoked throughout pregnancy. After logistic regression, FGR (AOR=1.9; 95% CI: 0.96-3.82) for women who quit smoking in the 3rd trimester (AOR=1.8; 95% CI: 1.38-2.31, p0.001). The risk of FGR5th percentile was AOR=1.96 (95% CI: 1.36-2.48, p0.001).Active or passive smoking during pregnancy is associated with an increased risk of intrauterine growth restriction and low birth weight. Cessation in the 1st and 2nd trimester reduces the risk of intrauterine growth restriction or low birth weight. Passive smoking has a deleterious impact on fetal development, intermediate to that of active smoking.

La production documentaire en Asie, entendue ici comme catégorie géographique, est riche et ancienne. Les chercheurs se sont donc penchés de longue date sur les sources produites dans cette région du monde, et leurs travaux ont souvent été pivots dans le renouvellement de l’histoire des savoirs. Le choix d’aborder la question des savoirs à l’échelle des empires permet de considérer ensemble plusieurs espaces asiatiques généralement étudiés séparément, pour des raisons évidentes de langue, de ...

Metformin (MtF) is a treatment used for type 2 diabetes. Lactic acidosis (LA) is a frequent complication that can be either induced by or associated with elevated MtF plasma concentrations. When coupled with a mass spectrometry (MS) system, the probe electrospray ionization (PESI) method allows direct and rapid analysis of different types of matrices without pretreatment. In this study, we developed a PESI–MS method for the determination of MtF in plasma. We used a tandem mass spectrometer equipped with a PESI source in the reaction monitoring mode for the quantitation of MtF. MtF-d6 was chosen as the internal standard (IS), following an isotope dilution (ID) approach. The method was fully validated with six concentration levels (0.5–50 mg/L). The matrix effect was evaluated for each level, and the specificity was tested with a mix of potential co-medications. Using patient samples, the performance was compared with two classical LC–MS-MS and LC–diode array detector (DAD) methods used in external labs. Sample preparation consisted in mixing 10 µL plasma in 1,000 µL ethanol/ammonium formate buffer including MtF-d6 at a fixed concentration of 5 mg/L. The total run time was 0.31 min. ID gave satisfactory results of accuracy and precision (min–max: −12.1 to 15.8% and 1.0–17.1%, respectively). The matrix effect was fully corrected by the internal standard (bias 5 mg/L and 7% not detected), we observed almost identical results when comparing LC–DAD and LC–MS-MS to PESI–MS (r2 > 0.99). We propose a specific, sensitive, accurate and ultrafast solution for the measurement of MtF in patient plasma, with no sample preparation or calibration curve building. This could be helpful in a core lab when rapid diagnosis of LA is needed.

Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic model is frequently used to estimate pharmacokinetic parameters in individuals, however with some uncertainty (bias). Recent works have shown that the performance in individual estimation or pharmacokinetic parameters can be improved by combining population pharmacokinetic and machine learning algorithms.The objective of this work was to investigate the use of a hybrid machine learning/population pharmacokinetic approach to improve individual iohexol clearance estimation.The reference iohexol clearance values were derived from 500 simulated profiles (samples collected between 0.1 and 24.7 h) using a population pharmacokinetic model we recently developed in Monolix and obtained using all the concentration timepoints available. Xgboost and glmnet algorithms able to predict the error of MAP-BE clearance estimates based on a limited sampling strategy (0.1 h, 1 h, and 9 h) versus reference values were developed in a training subset (75%) and were evaluated in a testing subset (25%) and in 36 real patients.The MAP-BE limited sampling strategy estimated clearance was corrected by the machine learning predicted error leading to a decrease in root mean squared error by 29% and 24%, and in the percentage of profiles with the mean prediction error out of the ± 20% bias by 60% and 40% in the external validation dataset for the glmnet and Xgboost machine learning algorithms, respectively. These results were attributable to a decrease in the eta-shrinkage (shrinkage for a MAP-BE limited sampling strategy = 32.4%, glmnet = 18.2%, and Xgboost = 19.4% in the external dataset).In conclusion, this hybrid algorithm represents a significant improvement in comparison to MAP-BE estimation alone.

Everolimus is an immunosuppressant with a small therapeutic index and large between-patient variability. The area under the concentration versus time curve (AUC) is the best marker of exposure but measuring it requires collecting many blood samples. The objective of this study was to train machine learning (ML) algorithms using pharmacokinetic (PK) profiles from kidney transplant recipients, simulated profiles, or both types, and compare their performance for everolimus AUC

Aim: Addressing global environmental challenges requires access to biodiversity data across wide spatial, temporal and taxonomic scales. Availability of such data has increased exponentially recently with the proliferation of biodiversity databases. However, heterogeneous coverage, protocols, and standards have hampered integration among these databases. To stimulate the next stage of data integration, here we present a synthesis of major databases, and investigate (a) how the coverage of databases varies across taxonomy, space, and record type; (b) what degree of integration is present among databases; (c) how integration of databases can increase biodiversity knowledge; and (d) the barriers to database integration. Location: Global. Time period: Contemporary. Major taxa studied: Plants and vertebrates. Methods: We reviewed 12 established biodiversity databases that mainly focus on geographic distributions and functional traits at global scale. We synthesized information from these databases to assess the status of their integration and major knowledge gaps and barriers to full integration. We estimated how improved integration can increase the data coverage for terrestrial plants and vertebrates. Results: Every database reviewed had a unique focus of data coverage. Exchanges of biodiversity information were common among databases, although not always clearly documented. Functional trait databases were more isolated than those pertaining to species distributions. Variation and potential incompatibility of taxonomic systems used by different databases posed a major barrier to data integration. We found that integration of distribution databases could lead to increased taxonomic coverage that corresponds to 23 years’ advancement in data accumulation, and improvement in taxonomic coverage could be as high as 22.4% for trait databases. Main conclusions: Rapid increases in biodiversity knowledge can be achieved through the integration of databases, providing the data necessary to address critical environmental challenges. Full integration across databases will require tackling the major impediments to data integration: taxonomic incompatibility, lags in data exchange, barriers to effective data synchronization, and isolation of individual initiatives.

Estimation of vancomycin area under the curve (AUC) is challenging in the case of discontinuous administration. Machine learning approaches are increasingly used and can be an alternative to population pharmacokinetic (POPPK) approaches for AUC estimation. The objectives were to train XGBoost algorithms based on simulations performed in a previous POPPK study to predict vancomycin AUC from early concentrations and a few features (i.e. patient information) and to evaluate them in a real-life external dataset in comparison to POPPK.Six thousand simulations performed from 6 different POPPK models were split into training and test sets. XGBoost algorithms were trained to predict trapezoidal rule AUC a priori or based on 2, 4 or 6 samples and were evaluated by resampling in the training set and validated in the test set. Finally, the 2-sample algorithm was externally evaluated on 28 real patients and compared to a state-of-the-art POPPK model-based averaging approach.The trained algorithms showed excellent performances in the test set with relative mean prediction error (MPE)/ imprecision (RMSE) of the reference AUC = 3.3/18.9, 2.8/17.4, 1.3/13.7% for the 2, 4 and 6 samples algorithms respectively. Validation in real patient showed flexibility in sampling time post-treatment initiation and excellent performances MPE/RMSE1.5/12% for the 2 samples algorithm in comparison to different POPPK approaches.The Xgboost algorithm trained from simulation and evaluated in real patients allow accurate and precise prediction of vancomycin AUC. It can be used in combination with POPPK models to increase the confidence in AUC estimation.

Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception. The objective of this study was to assess diabetic patients' knowledge about pregnancy and to describe their contraceptive use.An observational study was conducted from February to July 2020 at Reims University Hospital, France. Inclusion criteria were: women aged 18 to 40years, with type 1 (T1D) or type 2 diabetes (T2D). Patients filled out a survey about contraceptive use and knowledge regarding diabetic pregnancy and data were completed from medical records.Eighty-nine T1D and 33 T2D patients were included, with mean ages of 27.9±6.3 and 32.6±4.6years, respectively. Seventy-five percent reported that they had been informed about pregnancy-related risks and 67% about the need to plan pregnancy. The preconception HbA1c target was known by 33% of patients. Appropriate knowledge about pregnancy was greater in T1D patients (65.9%, versus 36.4% in T2D patients; P=0.003). The rate of patients using an effective contraceptive method was 66.4%. Fifteen percent patients for whom contraception was recommended reported having no contraceptive method; 12.5% of contraception users were using a contraindicated method.A large majority of diabetic women were aware of pregnancy-related risks and the importance of pregnancy planning, but there are still gaps, especially in T2D patients. We need to improve our practices by providing more information and better access to appropriate effective contraception.NCT04350879.

Background. Patients who have short peripheral venous catheters (PVC) face an elevated risk of developing bloodstream infections. Preventing catheter-related infections relies on implementing multiple measures, including practicing proper hand hygiene (HH) during catheter placement.Methods. We conducted a four-part study : (1) an evaluation of HH practices through direct observation of PVC placements, coupled with the study of the microbial flora of the HCWs fingers just before the placement; (2) the development of an educational tool based on the collected observational and microbiological data; (3) the training to the HCWs observed during the first part, using this tool; and (4) the subsequent observation of the trained HCWs to measure the impact of the training on practice improvement.Results. Compliant HH was observed in 23.5% of the 647 HCWs observed during PVC placement before training. The microbiological study revealed fewer pathogens on the fingertips of the HCWs practicing compliant HH compared other HCWs (2.6 vs 11,7%; p = 0.003). The comparison of practices before and after training, assessed amng 180 HCWs, showed an increase in the proportion of HCWs performing compliant HH (63.2 vs 25.0%; p Conclusions. Training HCWs using our educational tool, which combines reminders of best practices and risk factors associated with PVC-related infections, engaging HCWs (presentation of practice evaluation), identifying professionals deviating from best practices (simulation videos), and objectively assessing fingertip contamination (microbiological study), significantly improved compliance with HH gestures and glove usage. We encourage infection control teams to utilize this tool to raise awareness among HCWs responsible for PVC placement about the risk of infection associated inadequate hand hygiene.

A fundamental step in the influenza A virus (IAV) replication cycle is the coordinated packaging of eight distinct genomic RNA segments (i.e. vRNAs) into a viral particle. Although this process is thought to be controlled by specific vRNA–vRNA interactions between the genome segments, few functional interactions have been validated. Recently, a large number of potentially functional vRNA–vRNA interactions have been detected in purified virions using the RNA interactome capture method SPLASH. However, their functional significance in coordinated genome packaging remains largely unclear. Here, we show by systematic mutational analysis that mutant A/SC35M (H7N7) viruses lacking several prominent SPLASH-identified vRNA–vRNA interactions involving the HA segment package the eight genome segments as efficiently as the wild-type virus. We therefore propose that the vRNA–vRNA interactions identified by SPLASH in IAV particles are not necessarily critical for the genome packaging process, leaving the underlying molecular mechanism elusive.

Curcumin was shown to exert beneficial effects on nerve function in peripheral neuropathies. Despite its prominent biological activities, curcumin presents with unfavorable pharmacokinetics. For this purpose, we have developed curcumin-loaded cyclodextrin/cellulose nanocrystals (NanoCur) to bypass this limitation. The current study aims to assess the potency of NanoCur in Charcot-Marie-Tooth disease type 1A (CMT1A) rodent models and compare its efficacy to Theracurmin® (Thera), a commercially available curcumin formulation, while elaborating on its mechanism of action. For that, a low dose of NanoCur was chronically administered for rodents and CMT1A neuropathology was assessed through a battery of functional, histological and biochemical tests. Toxicity and mechanism of action of NanoCur were evaluated both in-vivo & in-vitro. The overall study supports an improved motor function, associated with an amelioration in peripheral myelination in the NanoCur, but not Thera-treated CMT1A animals, combined to a high margin of safety. Furthermore, NanoCur appears to perform its effect through an alleviation of inflammatory pathways, involving macrophage recruitment to the diseased nerve. This study shows that NanoCur associates with therapeutic benefits at the cellular and functional levels in CMT1A with minimal systemic toxicity, promoting it as a potential therapeutic candidate for CMT1A disease and, possibly, other forms of neuropathy.

In the TRITIUM project, an on-site monitoring system is being developed to measure tritium (3H) levels in water near nuclear power plants. The quite low-energy betas emitted by 3H have a very short average path in water (5 μm as shown by simulations for 18 keV electrons). This path would be further reduced by impurities present in the water, resulting in a significant reduction of the detection efficiency. Therefore, one of the essential requirements of the project is the elimination of these impurities through a filtration process and the removal of salts in solution. This paper describes a water treatment system developed for the project that meets the following requirements: the water produced should be of near-pure water quality according to ISO 3696 grade 3 standard (conductivity < 10 μS/cm); the system should operate autonomously and be remotely monitored. published

The Organic Anion Transporter 1 is a membrane transporter known for its central role in drug elimination by the kidney.hOAT1 is an antiporter translocating substrate in exchange forα-ketoglutarate. The understanding ofhOAT1 structure and function remains limited due to the absence of resolved structure ofhOAT1. Benefiting from conserved structural and functional patterns shared with other Major Facilitator Superfamily transporters, the present study intended to investigate fragments ofhOAT1 transport function and modulation of its activity in order to make a step forward the understanding of its transport cycle.μs-long molecular dynamics simulation ofhOAT1 were carried out suggesting two plausible binding sites for a typical substrate, adefovir, in line with experimental observations. The well-known B-like motif binding site was observed in line with previous studies. However, we here propose a new inner binding cavity which is expected to be involved in substrate translocation event. Binding modes ofhOAT1 co-substrateα-ketoglutarate were also investigated suggesting that it may binds to highly conserved intracellular motifs. We here hypothesize thatα-ketoglutarate may disrupt the pseudo-symmetrical intracellular charge-relay system which in turn may participate to the destabilisation of OF conformation. Investigations regarding allosteric communications alonghOAT1 also suggest that substrate binding event might modulate the dynamics of intracellular charge relay system, assisted by surrounding lipids as active partners. We here proposed a structural rationalisation of transport impairments observed for two single nucleotide polymorphisms, p.Arg50His and p.Arg454Gln suggesting that the present model may be used to transport dysfunctions arising fromhOAT1 mutations.HighlightsAdefovir has at least two binding pockets onhOAT1 in the outward-facing conformation.The highly conserved B-motif within MFS is strongly involved in substrate binding.α-Ketoglutarate binds to the intracellular domain ofhOAT1 and destabilizes its OF conformation.The lipid membrane bilayer plays an active role in the allosteric communication between intracellular and extracellular domains ofhOAT1.Graphical AbstractThe present work (from left): (i) reveals binding modes of adefovir (top) andα-ketoglutarate (bottom) tohOAT1; (ii) maps Single Nucleotide Polymorphisms on outward-facing (top) and inward-facing (bottom) conformation ofhOAT1; (iii) asses the allosteric effect of lipidic environment and presence of substrates.

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1α, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms. [Cancer Res 2007;67(17):8325–34]

Supplementary Figure 4 from Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

Methods and Materials, Figure 4 Legend from Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

Despite the radical impact of climate change on Australian communities, there has been very little research in the Australian performing arts sector’s response to the climate crisis and aspiration to do so. While cultural organisations are embracing greener strategies in other countries, we are yet to fully grasp what the definition of climate leadership means in the Australian cultural context. The environmental impacts of the Australian performing arts sector are yet to be adequately researched, documented, and disseminated. Furthermore, there have not been any systematic attempts to examine how organisations are pursuing ecological values and processes, or the policies supporting them to do so. Many companies do not have publicly accessible environmental policies or climate action plans. This makes it difficult to determine how sustainability is being addressed across programming, practice and policy structures. This report explores how a small selection of Australian performing arts organisations are currently responding to the global ecological crisis. The study was conducted at Griffith University in 2022-2023 with the intention of highlighting leaders in the field. The research aims were: 1. To examine how the Australian performing arts sector is currently addressing environmental issues through programming, practices and policies; 2. To identify industry leaders at the intersection of live performance and environmental advocacy, and investigate examples of best practice; 3. To begin to draw from these examples strategies for artists and organisations to lead on the climate agenda, including identifying resources and support structures required to facilitate the transformation. This report provides an overview of the research context and results, from interviews with 13 performing arts companies across Australia, and a desktop study of publicly available information and email exchanges with various companies. The snapshot detailed in this report aims to provide an impression of sustainable advocacy, implemented at small, medium and large performing arts company levels across Australia. A summary of the key findings is as follows: Programming: • Performing arts organisations are demonstrating a strong desire to tell ecological stories and embrace environmental themes, especially in a local context. • Performing arts organisations are showing how ecological programming can be successfully integrated into seasons of performances across a range of genres and disciplines. • The potential to positively impact communities (e.g. through site-specific creation, civic engagement, arts-science communication and educational initiatives) is a key driver in many companies to make ecologically-focused work. Practice: • Performing arts organisations are grappling with a variety of ethically-focused, sustainability initiatives across a range of production processes, from embracing small scale, resourceful aesthetics, to using sustainability tools and consultancies to facilitate positive change. • There are still many challenges to overcome in this area, including transitioning to greener production practices and materials (some that may be at odds with conventional practices). • There is a clear and strong desire to share resources and materials across companies but an absence of support structures enabling them to do so. Policy: • Performing arts companies are requesting training, tools and resources to support them to create environmentally sustainable policies and processes across their organisations. • Policy designs are used as a starting point to evidence an organisation’s sustainability commitment with a focus on: the reduction of emissions; best practices in sustainable design and procurement; becoming an agent of change; and the sharing of knowledge. • Companies engaged in this study believe that resources and investment in climate justice should be integrated into Australia’s national cultural policy, and that this would foster sector-wide change. Our study indicated that while an ecological focus is emerging across the Australian performing arts sector, there is a clear need to investigate policy frameworks and funding models to support the transition to sustainable practices. While the report demonstrates that the work currently being accomplished is emerging, especially in the smallto-medium sector, this information could be made more publicly visible. This is perhaps the most startling discovery of the study. While performing arts organisations all over the world are beginning to actively cite their sustainability credentials, Australian performing arts organisations appear more hesitant to showcase their eco-initiatives. This is a missed opportunity. Moreover, based on our broader contextual review of publicfacing ecological commitments, it appears that Australia’s major cultural organisations are less active in pursuing formal sustainability practices and policies, and fomenting organisational change compared to other parts of the world, such as the UK or Canada. This is not surprising when one considers that most Australian companies have had little government funding or access to resources to pursue their eco-initiatives. Sustainability goals have fallen as an extra burden on organisations already stretched to the limit due to the impacts of COVID-19 in a historically underfunded industry. It is our hope this pilot study is recognised as urgent and timely, and that its findings will act as a foundation for future research into the Australian performing arts sector’s response to the existential threat of climate change. Further work is obviously needed to collectively understand the vital role the performing arts can play in advancing Australia’s environmental, cultural and social prosperity. The ambition of the project is to foresee the impact the climate crisis will have on the cultural sector and to showcase not only how climate action can be enabled at individual and organisational levels, but also how it is perceived by those who are leading this transition already.