Identification of the ‘NORE’ (N-Oct-3 responsive element), a novel structural motif and composite element

N-Oct-3 is a neuronal transcription factor widely expressed in the developing mammalian central nervous system, and necessary to maintain neural cell differentiation. The key role of N-Oct-3 in the transcriptional regulation of a multiplicity of genes is primarily due to the structural plasticity of its so-called ‘POU’ (acronym of Pit, Oct, Unc) DNA-binding domain. We have recently reported about the unusual dual neuro-specific transcriptional regulation displayed by N-Oct-3 [Blaud,M., Vossen,C., Joseph,G., Alazard,R., Erard,M. and Nieto,L. (2004) J. Mol. Biol., 339, 1049–1058]. To elucidate the underlying molecular mechanisms, we have now made use of molecular modeling, DNA footprinting and electrophoretic mobility shift assay techniques. This combined approach has allowed us to uncover a novel mode of homodimerization adopted by the N-Oct-3 POU domain bound to the neuronal aromatic amino acids de-carboxylase and corticotropin-releasing hormone gene promoters and to demonstrate that this pattern is induced by a structural motif that we have termed ‘NORE’ (N-Oct-3 responsive element), comprising the 14 bp sequence element TNNRTAAATAATRN. In addition, we have been able to explain how the same structural motif can also induce the formation of a heterodimer in association with hepatocyte nuclear factor 3β(/Forkhead box a2). Finally, we discuss the possible role of the NORE motif in relation to neuroendocrine lung tumor formation, and in particular the development of small cell lung cancer

Advancing Our Understanding of Martian Proton Aurora through a Coordinated Multi-Model Comparison Campaign

Proton aurora are the most commonly observed yet least studied type of aurora at Mars. In order to better understand the physics and driving processes of Martian proton aurora, we undertake a multi-model comparison campaign. We compare results from four different proton/hydrogen precipitation models with unique abilities to represent Martian proton aurora: Jolitz model (3-D Monte Carlo), Kallio model (3-D Monte Carlo), Bisikalo/Shematovich et al. model (1-D kinetic Monte Carlo), and Gronoff et al. model (1-D kinetic). This campaign is divided into two steps: an inter-model comparison and a data-model comparison. The inter-model comparison entails modeling five different representative cases using similar constraints in order to better understand the capabilities and limitations of each of the models. Through this step we find that the two primary variables affecting proton aurora are the incident solar wind particle flux and velocity. In the data-model comparison, we assess the robustness of each model based on its ability to reproduce a MAVEN/IUVS proton aurora observation. All models are able to effectively simulate the data. Variations in modeled intensity and peak altitude can be attributed to differences in model capabilities/solving techniques and input assumptions (e.g., cross sections, 3-D versus 1-D solvers, and implementation of the relevant physics and processes). The good match between the observations and multiple models gives a measure of confidence that the appropriate physical processes and their associated parameters have been correctly identified and provides insight into the key physics that should be incorporated in future models

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Turbulent induced vibration of a guide tube in experimental reactor

International audienceThe design of advanced experimental nuclear reactors consists in integrating safety and operational requirements as well as reaching targets in terms of thermal power and neutron spectrum. In order to meet theses constraints, slender structures with little supports and crossing the entire reactor vessel are implemented in the reactor and are subjected to an axial flow that generates flow-induced vibration (FIV). From the industrial point of view, the mastering of the occurrence of FIV and its associated wear in case of contacts is requested. The stationary fluid forces applying on slender tubular structure in response to its motion are of primary interest since they can significantly affect the vibration amplitudes and even the stability of the system, especially in case of confined axial flow with high velocities (typically higher than 10 m/s). In this study it proposed to compare two approaches to estimate the vibration induced by turbulent excitation of an industrial device encountered in a research nuclear reactor. The control-rod guide-tube mock-up of the Jules Horowitz Reactor, previously tested in an hydraulic channel at the Technical Center from Le Creusot in France, is retained for this benchmark. Two models are proposed, one based on derivation of leakage flow theory and the other one was based on potential flow theory with adjusted coefficients given by CFD simulations. The flow induced vibration amplitude is consistent with the experimental data. Also, the calculation and experiment provide similar trends when the boundary conditions are changed

Delaying anterior cruciate ligament reconstruction increases the rate and severity of medial chondral injuries

Aims The aim of this study was to evaluate the association between chondral injury and interval from anterior cruciate ligament (ACL) tear to surgical reconstruction (ACLr). Methods Between January 2012 and January 2022, 1,840 consecutive ACLrs were performed and included in a single-centre retrospective cohort. Exclusion criteria were partial tears, multiligament knee injuries, prior ipsilateral knee surgery, concomitant unicompartmental knee arthroplasty or high tibial osteotomy, ACL agenesis, and unknown date of tear. A total of 1,317 patients were included in the final analysis, with a median age of 29 years (interquartile range (IQR) 23 to 38). The median preoperative Tegner Activity Score (TAS) was 6 (IQR 6 to 7). Patients were categorized into four groups according to the delay to ACLr: six to 12 months (248; 19%), and > 12 months (254; 19%). Chondral injury was assessed during arthroscopy using the International Cartilage Regeneration and Joint Preservation Society classification, and its association with delay to ACLr was analyzed using multivariable analysis. Results In the medial compartment, delaying ACLr for more than 12 months was associated with an increased rate (odds ratio (OR) 1.93 (95% confidence interval (CI) 1.27 to 2.95); p = 0.002) and severity (OR 1.23 (95% CI 1.08 to 1.40); p = 0.002) of chondral injuries, compared with 50 years old. No association was found for shorter delays, but the overall dose-effect analysis was significant for the rate (p = 0.015) and severity (p = 0.026) of medial chondral injuries. Increased TAS was associated with a significantly reduced rate (OR 0.88 (95% CI 0.78 to 0.99); p = 0.036) and severity (OR 0.96 (95% CI 0.92 to 0.99); p = 0.017) of medial chondral injuries. In the lateral compartment, no association was found between delay and chondral injuries. Conclusion Delay was associated with an increased rate and severity of medial chondral injuries in a dose-effect fashion, in particular for delays > 12 months. Younger patients seem to be at higher risk of chondral injury when delaying surgery. The timing of ACLr should be optimally reduced in this population. Cite this article: Bone Joint J 2023;105-B(9):953–960

The wheat response to deoxynivalenol: Does maintenance of hormone homeostasis and alleviation of oxidative stress play an important role in toxin tolerance?

The Fusarium mycotoxin deoxynivalenol (DON) is a potent inhibitor of eukaryotic protein synthesis and acts as a virulence factor during infection of wheat heads. Some wheat genotypes can tolerate DON and resist its deleterious effects; others cannot. Transcriptome studies identified several genes up-regulated in spikelets of the DON-resistant wheat cultivar CM82036 in response to DON treatment. We will discuss how the finding presented herein and other recent findings contribute to the hypothesis that management of hormone homeostasis and alleviation of oxidative stress in DON-challenged wheat might facilitate cell survival and thereby retard fungal colonisation

Characteristics, comorbidities, 30-day outcome and in-hospital mortality of patients hospitalised with COVID-19 in a Swiss area – a retrospective cohort study

BACKGROUND Since its first description in December 2019, coronavirus disease 19 (COVID-19) has spread worldwide. There is limited information about presenting characteristics and outcomes of Swiss patients requiring hospitalisation. Furthermore, outcomes 30 days after onset of symptoms and after hospital discharge have not been described. AIMS To describe the clinical characteristics, outcomes 30 days after onset of symptoms and in-hospital mortality of a cohort of patients hospitalised for COVID-19 in a Swiss area. METHODS In this retrospective cohort study, we included all inpatients hospitalised with microbiologically confirmed COVID-19 between 1 March and 12 April 2020 in the public hospital network of a Swiss area (Fribourg). Demographic data, comorbidities and outcomes were recorded. Rate of potential hospital-acquired infection, outcomes 30 days after onset of symptoms and in-hospital mortality are reported. RESULTS One hundred ninety-six patients were included in the study. In our population, 119 (61%) were male and the median age was 70 years. Forty-nine patients (25%) were admitted to the intensive care unit (ICU). The rate of potential hospital-acquired infection was 7%. Overall, 30 days after onset of symptoms 117 patients (60%) had returned home, 23 patients (12%) were in a rehabilitation facility, 18 patients (9%) in a medical ward, 6 patients (3%) in ICU and 32 (16%) patients had died. Among patients who returned home within 30 days, 73 patients (63%) reported persistent symptoms. The overall in-hospital mortality was 17%. CONCLUSION We report the first cohort of Swiss patients hospitalised with COVID-19. Thirty days after onset of the symptoms, 60% had returned home. Among them, 63% still presented symptoms. Studies with longer follow-up are needed to document long-term outcomes in patients hospitalised with COVID-19