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MotivationTranscriptional regulation is performed by transcription factors (TF) binding to DNA in context-dependent regulatory regions and determines the activation or inhibition of gene expression. Current methods of transcriptional regulatory circuits inference, based on one or all of TF, regions and genes activity measurements require a large number of samples for ranking the candidate TF-gene regulation relations and rarely predict whether they are activations or inhibitions. We hypothesize that transcriptional regulatory circuits can be inferred from fewer samples by (1) fully integrating information on TF binding, gene expression and regulatory regions accessibility, (2) reducing data complexity and (3) using biology-based likelihood constraints to determine the global consistency between a candidate TF-gene relation and patterns of genes expressions and region activations, as well as qualify regulations as activations or inhibitions.ResultsWe introduce Regulus, a method which computes TF-gene relations from gene expressions, regulatory region activities and TF binding sites data, together with the genomic locations of all entities. After aggregating gene expressions and region activities into patterns, data are integrated into a RDF (Resource Description Framework) endpoint. A dedicated SPARQL (SPARQL Protocol and RDF Query Language) query retrieves all potential relations between expressed TF and genes involving active regulatory regions. These TF-region-gene relations are then filtered using biological likelihood constraints allowing to qualify them as activation or inhibition. Regulus provides signed relations consistent with public databases and, when applied to biological data, identifies both known and potential new regulators. Regulus is devoted to context-specific transcriptional circuits inference in human settings where samples are scarce and cell populations are closely related, using discretization into patterns and likelihood reasoning to decipher the most robust regulatory relations.

The importance of mitochondria in tissue homeostasis, stress responses and human diseases, combined to their ability to transition between various structural and functional states, makes them excellent organelles for monitoring cell health. There is therefore a need for technologies to accurately analyze and quantify changes in mitochondrial organization in a variety of cells and cellular contexts. Here we present an innovative computerized method that enables accurate, multiscale, fast and cost-effective analysis of mitochondrial shape and network architecture from confocal fluorescence images by providing more than thirty features. In order to facilitate interpretation of the quantitative results, we introduced two innovations: the use of Kiviat-graphs (herein named MitoSpider plots) to present highly multidimensional data and visualization of the various mito-cellular configurations in the form of morphospace diagrams (called MitoSigils). We tested our fully automated image analysis tool on rich datasets gathered from live normal human skin cells cultured under basal conditions or exposed to specific stress including UVB irradiation and pesticide exposure. We demonstrated the ability of our proprietary software (named MitoTouch) to sensitively discriminate between control and stressed dermal fibroblasts, and between normal fibroblasts and other cell types (including cancer tissue-derived fibroblasts and primary keratinocytes), showing that our automated analysis captures subtle differences in morphology. Based on this novel algorithm, we report the identification of a protective natural ingredient that mitigates the deleterious impact of hydrogen peroxide (H2O2) on mitochondrial organization. Hence we conceived a novel wet-plus-dry pipeline combining cell cultures, quantitative imaging and semiotic analysis for exhaustive analysis of mitochondrial morphology in living adherent cells. Our tool has potential for broader applications in other research areas such as cell biology and medicine, high-throughput drug screening as well as predictive and environmental toxicology.

Introduction and hypothesisIn order to improve the knowledge POP physiopathology and POP repair, a generic biomechanical model of the female pelvic system has been developed. In the literature, no study has currently evaluated apical prolapse repair by posterior sacrospinous ligament fixation using a generic model nor a patient-specific model that personalize the management of POP and predict surgical outcomes based on the patient's pre-operative Magnetic Resonance Imaging. The aim of our study was to analyze the influence of a right and/or left sacrospinous ligament fixation and the distance between the anchorage area and the ischial spine on the pelvic organ mobility using a generic and a patient-specific Finite Element model (FEM) of the female pelvic system during posterior sacrospinous ligament fixation (SSF).MethodsFirstly, we used a generic 3D FEM of the female pelvic system previously made by our team that allowed us to simulate the mobility of the pelvic system. To create a patient-specific 3D FEM of the female pelvic system, we used a preoperative dynamic pelvic MRI of a 68 years old woman with a symptomatic stage III apical prolapse and cystocele. With these 2 models, a SSF was simulated. A right and/or left SSF and different distances between the anchorage area and the ischial spine (1 cm, 2 cm and 3 cm.) were compared. Outcomes measures were the pelvic organ displacement using the pubococcygeal line during maximal strain: Ba point for the most posterior and inferior aspect of the bladder base, C point the cervix's or the vaginal apex and Bp point for the anterior aspect of the anorectal junction.ResultsOverall, pelvic organ mobility decreased regardless of surgical technique and model. According to the generic model, C point was displaced by 14.1 mm and 11.5 mm, Ba point by 12.7 mm, and 12 mm and Bp point by 10.6 mm and 9.9 mm after left and bilateral posterior SSF, respectively. C point was displaced by 15.4 mm and 11.6 mm and Ba point by 12.5 mm and 13.1mm when the suture on the sacrospinous ligament was performed at 1 cm and 3 cm from the ischial spine respectively (bilateral posterior SSF configuration). According to the patient-specific model, the displacement of Ba point could not be analyzed because of a significative and asymmetric organ displacement of the bladder. C point was displaced by 4.74 mm and 2.12 mm, and Bp point by 5.30 mm and 3.24 mm after left and bilateral posterior SSF respectively. C point was displaced by 4.80 mm and 4.85 mm and Bp point by 5.35 mm and 5.38 mm when the suture on the left sacrospinous ligament was performed at 1 cm and 3 cm from the ischial spine, respectively.ConclusionAccording to the generic model from our study, the apex appeared to be less mobile in bilateral SSF. The anchorage area on the sacrospinous ligament seems to have little effect on the pelvic organ mobilities.Trial registrationClinicalTrials.gov Identifier: NCT04551859.

Desde 2013, a China tem sido a principal fonte de turismo internacional, tanto em termos de receita quanto de número de visitantes. Cientes da importância desse mercado em um setor que contribui com quase 10% do PIB global, as autoridades do país estão buscando usar esses fluxos de saída para aumentar a esfera de influência da China. Embora isso funcione no caso dos países em desenvolvimento, que geralmente são ilhas e/ou ainda não desenvolveram sua própria imaginação turística, os principais destinos turísticos internacionais parecem ser menos abertos a esse tipo de instrumentalização. Na França, por exemplo, podemos ver que as práticas dos turistas chineses tendem a se tornar mais individualizadas e que esses visitantes parecem estar cada vez mais em busca de experiências imersivas e personalizadas. Nesta contribuição, procuramos elucidar esse aparente paradoxo: como podemos explicar o crescente empoderamento dos turistas chineses, quando o partido-Estado sempre procurou controlar os fluxos de saída da China? Tentaremos responder a essa pergunta usando o caso das luas de mel na França como exemplo, e mostraremos que os turistas chineses mantêm certa margem de manobra graças a representações que pré-existem às narrativas construídas pelo Partido, mas também graças ao processo de aprendizado pelo qual passam enquanto viajam.

La Chine constitue le premier foyer émetteur du tourisme international aussi bien en termes de recettes que du nombre d’individus, et ce, depuis 2013. Conscientes de l’importance de ce marché au sein d’un secteur contribuant à près de 10 % du PIB mondial, les autorités du pays cherchent à instrumentaliser ces flux en partance du territoire pour accroitre la sphère d’influence de la Chine. Si cela fonctionne auprès de pays en voie de développement, souvent insulaires et/ou pour lesquels l’imaginaire touristique était encore à construire, les grandes destinations du tourisme international semblent moins donner prise à ce type d’instrumentalisation. En France par exemple, on observe que les pratiques des touristes chinois tendent à s’individualiser et que ces visiteurs semblent de plus en plus en quête d’expériences immersives et personnalisées. Dans cette contribution, nous cherchons à élucider cet apparent paradoxe : comment expliquer l’autonomisation croissante des touristes chinois, alors que l’État-Parti a toujours cherché à contrôler les flux émetteurs de la Chine ? Nous tenterons de répondre à cette question à partir du cas des lunes de miel en France et verrons que les touristes chinois conservent une marge de manœuvre grâce à des représentations préexistant aux récits construits par le Parti, mais aussi grâce aux apprentissages qu’ils opèrent au gré de leurs mobilités.

Since 2013, China has been the leading source of outbound international tourism, both in terms of revenue and visitor numbers. Fully aware of the importance of this market in a sector that represents almost 10% of global GDP, the Chinese authorities are looking to exploit these outbound flows to increase China’s sphere of influence. This strategy may work with developing countries – who are often islands and/or yet to develop their own tourism image – however, major international tourism destinations seem to be less receptive to this form of instrumentalization. In France, for example, there is evidence that the practices of Chinese tourists are becoming more individualized with visitors increasingly looking for immersive and personalized experiences. The present article sets out to shed some light on this paradox: how can we explain the growing autonomy of Chinese tourists when the Party-State has always sought to control China’s outbound flows? We will focus on the case of honeymoons in France and show that Chinese tourists still have some room for manoeuvre because of the representations that existed before the Party-constructed narratives, and of the learning processes they undergo as a result of their travels.

ABSTRACTGastrointestinal (GI) colonization by Klebsiella pneumoniae is a risk factor for subsequent infection as well as transmission to other patients. Additionally, colonization is achieved by many strain types that exhibit high diversity in genetic content. Thus, we aimed to study strain-specific requirements for K. pneumoniae GI colonization by applying transposon insertion sequencing to three classical clinical strains: a carbapenem-resistant strain, an extended-spectrum beta-lactamase-producing strain, and a non-epidemic antibiotic-susceptible strain. The transposon insertion libraries were screened in a murine model of GI colonization. At 3 days post-inoculation, 27 genes were required by all three strains for colonization. Isogenic deletion mutants for three genes/operons (acrA, carAB, and tatABCD) confirmed colonization defects in each of the three strains. Additionally, deletion of acrA reduced bile tolerance in vitro, while complementation restored both bile tolerance in vitro and colonization ability in vivo. Transposon insertion sequencing suggested that some genes were more important for the colonization of one strain than the others. For example, deletion of the sucrose porin-encoding gene scrY resulted in a colonization defect in the carbapenemase-producing strain but not in the extended-spectrum beta-lactamase producer or the antibiotic-susceptible strain. These findings demonstrate that classical K. pneumoniae strains use both shared and strain-specific strategies to colonize the mouse GI tract.IMPORTANCEKlebsiella pneumoniae is a common cause of difficult-to-treat infections due to its propensity to express resistance to many antibiotics. For example, carbapenem-resistant K. pneumoniae has been named an urgent threat by the United States Centers for Disease Control and Prevention. Gastrointestinal colonization in patients with K. pneumoniae has been linked to subsequent infection, making it a key process to control in the prevention of multidrug-resistant infections. However, the bacterial factors which contribute to K. pneumoniae colonization are not well understood. Additionally, individual strains exhibit large amounts of genetic diversity, begging the question of whether some colonization factors are strain dependent. This study identifies the enteric colonization factors of three classical strains using transposon mutant screens to define a core colonization program for K. pneumoniae as well as detecting strain-to-strain differences in colonization strategies.

Background: Restoration of the glenoid joint line in shoulder arthroplasty is important for implant positioning and function. Medialization of the glenohumeral joint line due to glenoid bone loss is commonly encountered in primary and revision of shoulder arthroplasty albeit the direction and location of bone loss varies with different pathology. Three-Dimensional (3D) planning software has assisted in preoperative planning of complex glenoid deformities. However, limited literature is available defining a reliable 3D method to evaluate the glenoid joint line preoperatively. Aims: The purpose of this study is to identify a set of reliable scapular landmarks to be used as reference points to measure the premorbid glenoid joint line using 3D segmented models of healthy scapulae. Methods: Bilateral computed tomography scans from 79 patients eligible for primary stabilization procedures were retrospectively selected from our institutional surgical database (mean age 35 ± 10 years, 58 males and 21 females). 3D models of the contralateral healthy scapulae were created via computed tomography scan segmentation using Mimics 24.0 software (Materialise, Leuven, Belgium). Anatomical landmarks were identified using 3-Matic 16.0 software (Materialise, Leuven, Belgium). The distance between identified landmarks and a sagittal plane created on the deepest point of the glenoid was recorded for each scapula and reliability of each landmark was assessed. Inter- and intra-observer reliabilities were also evaluated using intraclass correlation coefficients (ICCs). Results: Four landmarks showed statistically significant results: the scapular notch (SN), the centroid of the coracoid (CC), a point on the most medial border of the scapula in line with the scapular spine (TS), and the most lateral point of the acromion (AL). The mean (± standard deviation) joint line measured from the SN, CC, TS and AL were 28.36 ± 2.97 mm, 11.66 ± 2.07 mm, 107.52 ± 8.1 mm, and 29.72 ± 4.46 mm, respectively. Inter-observer reliability analysis for SN, TS, and AL showed excellent agreement with ICC values of 0.966, 0.997, and 0.944, respectively, and moderate agreement for CC with ICC of 0.728. Conclusion: The results from this study assist in estimating joint line medialization preoperatively and in planning its subsequent restoration. A set of reliable landmarks can be used as references to estimate the premorbid glenoid joint line preoperatively.

Abstract The aim of this work was to evaluate and compare the incidence of perineal tears and Obstetrical anal sphincter injuries (OASIS) after vaginal delivery following a in utero fetal death (IUFD) compared with those with a live-birth. We conducted a single-center, retrospective cohort study using a database of all women who underwent a spontaneous vaginal delivery in the level III maternity ward. Exclusion criteria were breech presentation, cesarean section birth, instrumental delivery, multiple pregnancy, delivery before 24 + 6 weeks of gestation (WG) and termination of pregnancy for medical reasons. Women from the database were divided into two groups: an "in utero fetal death" (IUFD) group and a control group. Women were included in the IUFD group if they had a spontaneous vaginal delivery following a fetal demise after 24 + 6 WG in cephalic presentation between January 2006 and June 2020. Women in the "control" group were selected from the same database and were included if they underwent a spontaneous vaginal delivery of a live fetus in cephalic presentation, after 24 + 6 WG, during the same period. Each woman in the "IUFD" group was matched to two women (ratio 1:2) in the control group for parity, maternal age, body mass index, gestation and birth weight. The primary outcome was the presence of a sutured or unsutured perineal tear. During the study period, 31,208 patients delivered at a level III maternity hospital. Among them, 215 and 430 women were included in the IUFD group and the control group respectively. The two groups were comparable for all demographic and clinical characteristics except for an epidural analgesia (92% versus 70% in the control group, p

Abstract Thiolation of uridine 34 in the anticodon loop of several tRNAs is conserved in the three domains of life and guarantees fidelity of protein translation. U34-tRNA thiolation is catalyzed by a complex of two proteins in the eukaryotic cytosol (named Ctu1/Ctu2 in humans), but by a single NcsA enzyme in archaea. We report here spectroscopic and biochemical experiments showing that NcsA from Methanococcus maripaludis (MmNcsA) is a dimer that binds a [4Fe-4S] cluster, which is required for catalysis. Moreover, the crystal structure of MmNcsA at 2.8 Å resolution shows that the [4Fe-4S] cluster is coordinated by three conserved cysteines only, in each monomer. Extra electron density on the fourth nonprotein-bonded iron most likely locates the binding site for a hydrogenosulfide ligand, in agreement with the [4Fe-4S] cluster being used to bind and activate the sulfur atom of the sulfur donor. Comparison of the crystal structure of MmNcsA with the AlphaFold model of the human Ctu1/Ctu2 complex shows a very close superposition of the catalytic site residues, including the cysteines that coordinate the [4Fe-4S] cluster in MmNcsA. We thus propose that the same mechanism for U34-tRNA thiolation, mediated by a [4Fe-4S]-dependent enzyme, operates in archaea and eukaryotes.

This dataset consists of three groups of hyperspectral images of apple tree plants. The first group of images consists of a temporal monitoring of seven apple tree plants, infected with fire blight (Erwinia amylovora), and six control plants over a period of 15 days. The second group of images includes a temporal monitoring of three infected plants, seven plants subjected to water stress, and seven control plants. The third group of images corresponds to acquisitions made in the orchard on nine trees showing symptoms of fire blight and six control trees. The pixel locations of infected areas have been provided for all images featuring symptomatic plants.

ABSTRACT In an attempt to identify novel bacterial species, microbiologists have examined a wide range of environmental niches. We describe the serendipitous discovery of a novel gram-negative bacterial species from a different type of extreme niche: a purchased vial of antibiotic. The vial of antibiotic hygromycin B was found to be factory contaminated with a bacterial species, which we designate Pseudomonas hygromyciniae sp. nov. The proposed novel species belongs to the P. fluorescens complex and is most closely related to P. brenneri, P. proteolytica, and P. fluorescens. The type strain Pseudomonas hygromyciniae sp. nov. strain SDM007T (SDM007T) harbors a novel 250 kb megaplasmid which confers resistance to hygromycin B and contains numerous other genes predicted to encode replication and conjugation machinery. SDM007T grows in hygromycin concentrations of up to 5 mg/mL but does not use the antibiotic as a carbon or nitrogen source. While unable to grow at 37°C ruling out its ability to infect humans, it grows and survives at temperatures between 4 and 30°C. SDM007T can infect plants, as demonstrated by the lettuce leaf model, and is highly virulent in the Galleria mellonella infection model but is unable to infect mammalian A549 cells. These findings indicate that commercially manufactured antibiotics represent another extreme environment that may support the growth of novel bacterial species. IMPORTANCE Physical and biological stresses in extreme environments may select for bacteria not found in conventional environments providing researchers with the opportunity to not only discover novel species but to uncover new enzymes, biomolecules, and biochemical pathways. This strategy has been successful in harsh niches such as hot springs, deep ocean trenches, and hypersaline brine pools. Bacteria belonging to the Pseudomonas species are often found to survive in these unusual environments, making them relevant to healthcare, food, and manufacturing industries. Their ability to survive in a variety of environments is mainly due to the high genotypic and phenotypic diversity displayed by this genus. In this study, we discovered a novel Pseudomonas sp. from a desiccated environment of a sealed antibiotic bottle that was considered sterile. A close genetic relationship with its phylogenetic neighbors reiterated the need to use not just DNA-based tools but also biochemical characteristics to accurately classify this organism.

As part of the move to reduce SO2 in wines, the empirical use of chitosan to eliminate the spoilage yeast Brettanomyces bruxellensis is becoming a frequent alternative. Chitosan treatment has an effect on a number of microbial species, at least temporarily, but there is wide variability in response within strains of each species. In addition, the effectiveness of chitosan also depends on the physical and chemical parameters of the wine. However, when chitosan treatment is effective, it appears to be long-lasting.

In recent years, clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) protein have emerged as a revolutionary gene editing tool to treat inherited disorders affecting different organ systems, such as blood and muscles. Both hematological and neuromuscular genetic disorders benefit from genome editing approaches but face different challenges in their clinical translation. The ability of CRISPR/Cas9 technologies to modify hematopoietic stem cells ex vivo has greatly accelerated the development of genetic therapies for blood disorders. In the last decade, many clinical trials were initiated and are now delivering encouraging results. The recent FDA approval of Casgevy, the first CRISPR/Cas9-based drug for severe sickle cell disease and transfusion-dependent β-thalassemia, represents a significant milestone in the field and highlights the great potential of this technology. Similar preclinical efforts are currently expanding CRISPR therapies to other hematologic disorders such as primary immunodeficiencies. In the neuromuscular field, the versatility of CRISPR/Cas9 has been instrumental for the generation of new cellular and animal models of Duchenne muscular dystrophy (DMD), offering innovative platforms to speed up preclinical development of therapeutic solutions. Several corrective interventions have been proposed to genetically restore dystrophin production using the CRISPR toolbox and have demonstrated promising results in different DMD animal models. Although these advances represent a significant step forward to the clinical translation of CRISPR/Cas9 therapies to DMD, there are still many hurdles to overcome, such as in vivo delivery methods associated with high viral vector doses, together with safety and immunological concerns. Collectively, the results obtained in the hematological and neuromuscular fields emphasize the transformative impact of CRISPR/Cas9 for patients affected by these debilitating conditions. As each field suffers from different and specific challenges, the clinical translation of CRISPR therapies may progress differentially depending on the genetic disorder. Ongoing investigations and clinical trials will address risks and limitations of these therapies, including long-term efficacy, potential genotoxicity, and adverse immune reactions. This review provides insights into the diverse applications of CRISPR-based technologies in both preclinical and clinical settings for monogenic blood disorders and muscular dystrophy and compare advances in both fields while highlighting current trends, difficulties, and challenges to overcome.

Abstract Background Socioeconomic deprivation (SED) is a risk factor for complications during pregnancy and childbirth, the impact of which has been studied poorly in rural areas. Aims To explore the perceptions and behaviour of women living in SED in a rural area with regard to their pregnancy follow‐up. Methods A qualitative study using semi‐structured individual interviews was carried out in a rural area in central France. To participate, the women had to have an Evaluation of Deprivation and Inequalities in Health Examination Centres deprivation score ≥ 30.17, be living in a rural area and have given birth during the month before the interview. The interviews were analysed using a thematic approach inspired by grounded theory. Results Seventeen women were interviewed. The difficulties of life in a rural area were linked to geographical remoteness, travel costs, lack of public services, inadequacy of nearby healthcare and social isolation. In all cases, pregnancy was an additional difficulty. The adaptive capability was related to the presence of an efficient family and social network. Most of the time, any increase in the limitations exceeded the ability to adapt and affected the medical follow‐up of the pregnancy, although follow‐up appointments were rarely abandoned altogether. Perceptions of birth preparation and parenting sessions were often limited to advice on pain management. Due to their affiliation with their rural area or their choice of lifestyle, the women complained only minimally. Conclusion Women often minimize any limitations and implement adaptive techniques that make identification by social and medical services more difficult. Patient or Public Contribution Eighteen women in SED were contacted by Childhood Medical Protection, midwives and general practitioners practising in rural areas. One woman declined participation and seventeen were interviewed.

Abstract To compare pelvic organ prolapse (POP) recurrence and morbidity between first and second line sacrocolpopexies. We conducted a retrospective chart review of all laparoscopic or robotic sacrocolpopexies for POP-Q stage ≥ 2, with or without a history of previous prolapse repair, performed with a similar technique between January 2012 and June 2019 in 3 European Gynecologic Surgery Departments. Patients were separated into two groups: first line sacrocolpopexy (FLS) and second line sacrocolpopexy (SLS). Each patient from the SLS group was age-matched with a patient from the FLS group. The primary outcome measure was reoperation procedures for recurrent POP defined as a symptomatic POP-Q stage ≥ 2 POP in at least one vaginal compartment. Secondary outcomes included operative time, intraoperative organ trauma, intraoperative blood loss, postoperative POP recurrence (operated on or not), global reoperation and mesh-related complications. During this period, 332 patients were included. After age-matching, 170 patients were analyzed: 85 patients in the FLS and SLS groups, respectively. After a mean follow-up of 3 years, there was no statistically significant difference between the two groups in terms of recurrent POP (9.4% versus 10.6%, p = 0.7), recurrent POP reoperation (3.5% versus 5.9% p = 0.7), mesh-related reoperation (0% versus 2.4%, p = 0.5), global reoperation (3.5 versus 8.2%, p = 0.3), operative time (198 ± 67 min versus 193 ± 60 min, p = 0.5), intraoperative complications such as organ injury (4.7% versus 7.1%, p = 0.7) and blood loss > 500 mL (2.4% versus 0%, p = 0.5). Patients who underwent a first or a second line sacrocolpopexy seemed to have similar rates of prolapse recurrence and complications.

AimTo study the association between lockdown in France due to the SARS-CoV-2 pandemic and premature births at the Nice University Hospital.MethodsData concerning neonates born at the level III maternity of the Nice University Hospital and immediately hospitalised in the neonatal reanimation unit or the neonatology department of the hospital with their mothers between the 1st of January 2017 and the 31st of December 2020, included.ResultsWe did not find a significant decrease in the global number of premature births

Soil aggregate stability is an important indicator of soil condition and is directly related to soil degradation processes such as erosion and crusting. Aggregate stability is conventionally measured by testing the aggregate resistance to water disturbance mechanisms. Such measurements, however, are costly and time-consuming, which make them difficult to implement at a regional or country scale. In this study, we explore two different approaches to estimate soil aggregate stability by means of commonly-measured soil properties or mid-infrared spectroscopy measurements. The first approach relies on land use and soil properties. In the second approach aggregate stability is estimated by a model fitted with mid-infrared spectroscopic data. We tested the two approaches with a dataset composed of 202 soil samples from mainland France, in which aggregate stability was measured with a fast wetting test. We found that simple linear models based on common soil properties and models based on mid-infrared spectral data yielded similar results. Interpretation of the models revealed well-known relationships: land use had a major role in predicting aggregate stability, followed by organic carbon and clay content. Overall, we conclude that both approaches offer a reliable, cheap and time-efficient alternative to estimating soil aggregate stability. These approaches offer a tool to estimate aggregate stability over large geographical areas, which can support the development of erosive risk management plans and the implementation of adaptive management strategies to mitigate threats to soil and improve the overall soil condition.

Abstract Background Klebsiella pneumoniae strains have been divided into two major categories: classical K. pneumoniae, which are frequently multidrug-resistant and cause hospital-acquired infections in patients with impaired defenses, and hypervirulent K. pneumoniae, which cause severe community-acquired and disseminated infections in normal hosts. Both types of infections may lead to bacteremia and are associated with significant morbidity and mortality. The relative burden of these two types of K. pneumoniae among bloodstream isolates within the United States is not well understood. Methods We evaluated consecutive K. pneumoniae isolates cultured from the blood of hospitalized patients at Northwestern Memorial Hospital (NMH) in Chicago, Illinois between April 2015 and April 2017. Bloodstream isolates underwent whole genome sequencing, and sequence types (STs), capsule loci (KLs), virulence genes, and antimicrobial resistance genes were identified in the genomes using the bioinformatic tools Kleborate and Kaptive. Patient demographic, comorbidity, and infection information, as well as the phenotypic antimicrobial resistance of the isolates were extracted from the electronic health record. Candidate hypervirulent isolates were tested in a murine model of pneumonia, and their plasmids were characterized using long-read sequencing. We also extracted STs, KLs, and virulence and antimicrobial resistance genes from the genomes of bloodstream isolates submitted from 33 United States institutions between 2007 and 2021 to the National Center for Biotechnology Information (NCBI) database. Results Consecutive K. pneumoniae bloodstream isolates (n = 104, one per patient) from NMH consisted of 75 distinct STs and 51 unique capsule loci. The majority of these isolates (n = 58, 55.8%) were susceptible to all tested antibiotics except ampicillin, but 17 (16.3%) were multidrug-resistant. A total of 32 (30.8%) of these isolates were STs of known high-risk clones, including ST258 and ST45. In particular, 18 (17.3%) were resistant to ceftriaxone (of which 17 harbored extended-spectrum beta-lactamase genes) and 9 (8.7%) were resistant to meropenem (all of which harbored a carbapenemase genes). Four (3.8%) of the 104 isolates were hypervirulent K. pneumoniae, as evidenced by hypermucoviscous phenotypes, high levels of virulence in a murine model of pneumonia, and the presence of large plasmids similar to characterized hypervirulence plasmids. These isolates were cultured from patients who had not recently traveled to Asia. Two of these hypervirulent isolates belonged to the well characterized ST23 lineage and one to the re-emerging ST66 lineage. Of particular concern, two of these isolates contained plasmids with tra conjugation loci suggesting the potential for transmission. We also analyzed 963 publicly available genomes of K. pneumoniae bloodstream isolates from locations within the United States. Of these, 465 (48.3%) and 760 (78.9%) contained extended-spectrum beta-lactamase genes or carbapenemase genes, respectively, suggesting a bias towards submission of antibiotic-resistant isolates. The known multidrug-resistant high-risk clones ST258 and ST307 were the predominant sequence types. A total of 32 (3.3%) of these isolates contained aerobactin biosynthesis genes and 26 (2.7%) contained at least two genetic features of hvKP strains, suggesting elevated levels of virulence. We identified 6 (0.6%) isolates that were STs associated with hvKP: ST23 (n = 4), ST380 (n = 1), and ST65 (n = 1). Conclusions Examination of consecutive isolates from a single center demonstrated that multidrug-resistant high-risk clones are indeed common, but a small number of hypervirulent K. pneumoniae isolates were also observed in patients with no recent travel history to Asia, suggesting that these isolates are undergoing community spread in the United States. A larger collection of publicly available bloodstream isolate genomes also suggested that hypervirulent K. pneumoniae strains are present but rare in the USA; however, this collection appears to be heavily biased towards highly antibiotic-resistant isolates (and correspondingly away from hypervirulent isolates).

Defining life is an arduous task that has puzzled philosophers and scientists for centuries. Yet biology suffers from a lack of clear definition, putting biologists in a paradoxical situation where one can describe at the atomic level complex objects that remain globally poorly defined. One could assume that such descriptions make it possible to perfectly characterize living systems. However, many cases of misinterpretation put this assumption into perspective. In this article, we focus on critical parameters such as time, water, entropy, space, quantum properties, and electrostatic potential to redefine the nature of living matter, with special emphasis on biological coding. Where does the DNA double helix come from, why cannot the reproduction of living organisms occur without mutations, what are the limitations of the genetic code, and why do not all proteins have a stable three-dimensional structure? There are so many questions that cannot be resolved without considering the aforementioned parameters. Indeed, (i) time and space constrain many biological mechanisms and impose drastic solutions on living beings (enzymes, transporters); (ii) water controls the fidelity of DNA replication and the structure/disorder balance of proteins; (iii) entropy is the driving force of many enzymatic reactions and molecular interactions; (iv) quantum mechanisms explain why a molecule as simple as hydrocyanic acid (HCN) foreshadows the helical structure of DNA, how DNA is stabilized, why mutations occur, and how the Earth magnetic field can influence the migration of birds; (v) electrostatic potential controls epigenetic mechanisms, lipid raft functions, and virus infections. We consider that raising awareness of these basic parameters is critical for better understanding what life is, and how it handles order and chaos through a combination of genetic and epigenetic mechanisms. Thus, we propose to incorporate these parameters into the definition of life.

Equitation in the French tradition is a school of riding that emphasizes harmonious relations between humans and horses. The best-known community is the Cadre Noir of Saumur, whose specialty is the air above the ground (AAG). No study has yet looked at the horse–rider interaction in this specific context. The purpose of this study was to identify and quantify indicators of AAGs based on the empirical perception of the écuyers expressed by a method of self-confrontation interviews. Fourteen training sessions were the subject of phenomenological and biomechanical approaches. Contact, balance, and hoof-beat, decisive for performance quality, were characterized for 49 AAGs, performed by five horses trained by two expert écuyers, with rein tension meters integrated in their double bridle (curb and snaffle reins) and six inertial measurement units fixed on the limbs, sternum, and croup. Their action was characterized by a peak of 65 ± 39 N on the inside curb rein. They considered that their horse was in balance (forehand inclined 13 ± 7° and −12 ± 9° for the hind hand). After the peak, during the 3.3 ± 2 s the horse’s trunk was stable and the écuyers released the contact until the AAG was perceived as satisfactory by the écuyer. The mixed approach allowed a pattern of action to be envisaged for the écuyer based on contact, balance, and hoof-beat in the execution of AAGs. The quantification of rein tension, trunk movements, and acceleration of the four limbs objectified the expert écuyers’ feeling of developing aptitudes for their actions in the human–horse interactions for improved transmission to young écuyers. The mixed approach used in this study has given rise to new training methods that are transferable to other equestrian activities.

A brief abstract. Investigation of the structure of personality (neurotic personality traits) and coping behavior in patients with panic disorder and agoraphobia demonstrates the use of less adaptive behavior mechanisms. In the neurotic personality development rational defenses give way to the primary mechanisms such as giperkompensatornoe high self-esteem, repression of painful experiences, and the secondary defense mechanisms - rationalization to justify its failure disease, illness care, are exempt from responsibility for decision making.

BackgroundCurrently, no markers accurately differentiate benign from malignant renal masses. CD34 and FSHR are transmembrane proteins involved in neo-angiogenetic pathways and are differently expressed in several normal and cancerous tissues. However, little evidence exists on their distribution in different renal tumors. We aimed to evaluate their expressions in various renal tumors and adjacent normal tissue.MethodsWe retrieved 810 histological samples from 26 patients who underwent surgery for suspected RCa. In each case a core of 10 × 1 mm was selected perpendicular to the tumor capsule between normal kidney and tumor. Within this core 30 regions of interest (ROI), each measuring 669 μm × 500 μm, were acquired at 20× magnification (n = 2 adjacent normal tissue; n = 2 tumor capsule; n = 26 tumor). The surface area of FSHR and CD34 immunostaining was quantified in each ROI using number of stained pixels. The results were compared between RCa and normal kidney.ResultsImmunostaining was significantly different in normal, tumor capsular, and tumor tissues (both CD34 and FSHR P < 0.0001), with overall highest expression in normal and lowest in tumor tissues, where CD34 and FSHR were differently expressed amongst different tumor subtypes (both P < 0.0001). CD34 and FSHR were more expressed in benign versus malignant (both P < 0.0001) and in chromophobe carcinoma versus oncocytoma tumor tissues (CD34 P = 0.0003; FSHR P < 0.0001). The discriminating ability of FSHR alone for benign versus malignant (AUC 0.805; 95% CI 0.771 to 0.837) and chromophobe carcinoma versus oncocytoma (AUC 0.973; 95% CI 0.939 to 0.991) was high. In both cases FSHR AUC was significantly higher than CD34 (both P < 0.0001) and equivalent to the combination of CD34 and FSHR (both P > 0.9). The correlation amongst levels of staining in tumor tissues and distance from the capsule were overall weak (Spearman coefficient CD34 to 0.0644; FSHR-0.16322).ConclusionCD34 and FSHR are differentially expressed across renal tumor subtypes and between tumor and surrounding tissues. FSHR expression alone may be a useful tool to differentiate benign from malignant tumors and chromophobe carcinoma from oncocytoma.

Abstract Background In life sciences, there has been a long-standing effort of standardization and integration of reference datasets and databases. Despite these efforts, many studies data are provided using specific and non-standard formats. This hampers the capacity to reuse the studies data in other pipelines, the capacity to reuse the pipelines results in other studies, and the capacity to enrich the data with additional information. The Regulatory Circuits project is one of the largest efforts for integrating human cell genomics data to predict tissue-specific transcription factor-genes interaction networks. In spite of its success, it exhibits the usual shortcomings limiting its update, its reuse (as a whole or partially), and its extension with new data samples. To address these limitations, the resource has previously been integrated in an RDF triplestore so that TF-gene interaction networks could be generated with two SPARQL queries. However, this triplestore did not store the computed networks and did not integrate metadata about tissues and samples, therefore limiting the reuse of this dataset. In particular, it does not enable to reuse only a portion of Regulatory Circuits if a study focuses on a subset of the tissues, nor to combine the samples described in the datasets with samples from other studies. Overall, these limitations advocate for the design of a complete, flexible and reusable representation of the Regulatory Circuits dataset based on Semantic Web technologies. Results We provide a modular RDF representation of the Regulatory Circuits, called Linked Extended Regulatory Circuits (LERC). It consists in (i) descriptions of biological and experimental context mapped to the references databases, (ii) annotations about TF-gene interactions at the sample level for 808 samples, (iii) annotations about TF-gene interactions at the tissue level for 394 tissues, (iv) metadata connecting the knowledge graphs cited above. LERC is based on a modular organisation into 1,205 RDF named graphs for representing the biological data, the sample-specific and the tissue-specific networks, and the corresponding metadata. In total it contains 3,910,794,050 triples and is available as a SPARQL endpoint. Conclusion The flexible and modular architecture of LERC supports biologically-relevant SPARQL queries. It allows an easy and fast querying of the resources related to the initial Regulatory Circuits datasets and facilitates its reuse in other studies. Associated website https://regulatorycircuits-lod.genouest.org

Summary: Non-lethal caspase activation (NLCA) has been linked to neurodevelopmental processes. However, how neurons control NLCA remains elusive. Here, we focused on Bcl-xL, a Bcl-2 homolog regulating caspase activation through the mitochondria. We generated a mouse model, referred to as ER-xL, in which Bcl-xL is absent in the mitochondria, yet present in the endoplasmic reticulum. Unlike bclx knockout mice that died at E13.5, ER-xL mice survived embryonic development but died post-partum because of altered feeding behavior. Enhanced caspase-3 activity was observed in the brain and the spinal cord white matter, but not the gray matter. No increase in cell death was observed in ER-xL cortical neurons, suggesting that the observed caspase-3 activation was apoptosis-independent. ER-xL neurons displayed increased caspase-3 activity in the neurites, resulting in impaired axon arborescence and synaptogenesis. Together, our findings suggest that mitochondrial Bcl-xL finely tunes caspase-3 through Drp-1-dependent mitochondrial fission, which is critical to neural network design.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

BackgroundTocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra.MethodsOur retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation.ResultsAmong 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44).ConclusionOur study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

This article proposes to consider the publication process in the nineteenth century based on the echoes left by t a biographical event in literature: Alfred de Musset’s stay at the « Hôtel des haricots », the remand center of the National Guard, in September 1843. It examines the different writing gestures resulting from this incarceration, their reception and resonance in the print culture, and finally the materiality of a poetic writing, both configured by and configuring the place where it occurs. It will be the occasion to unfold the dialectic at work between various publications that contribute to narrate, describe, and represent the “Hôtel des haricots” as an artistic and literary place, their diversity and their complementarity. By evoking the overwhelming presence of the printed form in our research which is imposed by temporal distance, the article invites us to closely examine the texts by paying attention to the still perceptible echoes of their stories.

The genetic code is textbook scientific knowledge that was soundly established without resorting to Artificial Intelligence (AI). The goal of our study was to check whether a neural network could re-discover, on its own, the mapping links between codons and amino acids and build the complete deciphering dictionary upon presentation of transcripts proteins data training pairs. We compared different Deep Learning neural network architectures and estimated quantitatively the size of the required human transcriptomic training set to achieve the best possible accuracy in the codon-to-amino-acid mapping. We also investigated the effect of a codon embedding layer assessing the semantic similarity between codons on the rate of increase of the training accuracy. We further investigated the benefit of quantifying and using the unbalanced representations of amino acids within real human proteins for a faster deciphering of rare amino acids codons. Deep neural networks require huge amount of data to train them. Deciphering the genetic code by a neural network is no exception. A test accuracy of 100% and the unequivocal deciphering of rare codons such as the tryptophan codon or the stop codons require a training dataset of the order of 4–22 millions cumulated pairs of codons with their associated amino acids presented to the neural network over around 7–40 training epochs, depending on the architecture and settings. We confirm that the wide generic capacities and modularity of deep neural networks allow them to be customized easily to learn the deciphering task of the genetic code efficiently.

IntroductionThe human immune system contains cells with either effector/memory or regulatory functions. Besides the well-established CD4+CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells.MethodsBased on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models.Results and discussionWe found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties.