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Context: The use of methadone for cancer pain management is gaining wider acceptance. However, switching to methadone treatment can still pose challenges. Consequently, there is ongoing development of its use in low doses in combination with other opioids, despite a lack of clinical evidence regarding its efficacy and safety. Objectives: This study aimed to evaluate the efficacy and tolerability of low-dose methadone in combination with another opioid in patients with moderate-to-severe cancer-related pain in a clinical setting. Patients and methods: This was a prospective, open-label study conducted in 19 pain and/or palliative care centres treating patients with cancer-related pain. Pain intensity, patients' global impression of change, and adverse effects were assessed on day 7 and day 14. The main outcome measure was the proportion of responders. Results: The study included 92 patients. The daily dose of methadone was 3 [3–6] mg at baseline, 9 [4–10] mg on day 7 and 10 [6–15] mg on day 14. The NRS pain ratings significantly decreased from 7 [6–8] at baseline to 5 [3–6] on visit 2 (p <.0001) and 4 [3–6] on visit 3 (p <.0001). Similarly, the VRS pain ratings decreased from 3 [3–3] at baseline to 2 [2–3] on visit 2 (p = 0.026) and 2 [1–3] (p < 0.001) on visit 3. At Visits 1 and 2, half of the patients were considered Responders. Of those responders, 73.5% were High-Responders at Visit 1 and 58.7% were High-Responders at Visit 2. No adverse events related to the risk of QT prolongation, overdose, or drug interactions were reported. Conclusion: For patients experiencing moderate to severe cancer-related pain despite initial opioid treatment, our study found that low-dose methadone, when used in combination with another opioid, was both safe and effective. This supports the use of methadone as an adjunct to opioid-based treatment for cancer pain. [ABSTRACT FROM AUTHOR]

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH. [ABSTRACT FROM AUTHOR]

Intestinal smooth muscle differentiation is a complex physico-biological process involving several different pathways. Here, we investigate the properties of Ca2+ waves in the developing intestinal mesenchyme using GCamp6f expressing mouse embryos and investigate their relationship with smooth muscle differentiation. We find that Ca2+ waves are absent in the pre-differentiation mesenchyme and start propagating immediately following α-SMA expression. Ca2+ waves are abrogated by CaV1.2 and gap-junction blockers, but are independent of the Rho pathway. The myosine light-chain kinase inhibitor ML-7 strongly disorganized or abolished Ca2+ waves, showing that perturbation of the contractile machinery at the myosine level also affected the upstream Ca2+ handling chain. Inhibiting Ca2+ waves and contractility with CaV1.2 blockers did not perturb circular smooth muscle differentiation at early stages. At later stages, CaV1.2 blockers abolished intestinal elongation and differentiation of the longitudinal smooth muscle, leading instead to the emergence of KIT-expressing interstitial cells of Cajal at the gut periphery. CaV1.2 blockers also drove apoptosis of already differentiated, CaV1.2-expressing smooth muscle and enteric neural cells. We provide fundamental new data on Ca2+ waves in the developing murine gut and their relation to myogenesis in this organ. Calcium waves underpin smooth muscle contractions in the gut. The authors examine their developmental dynamics, molecular properties and their impact on differentiation of smooth muscle and interstitial cells of Cajal in the mouse embryo. [ABSTRACT FROM AUTHOR]

CFTR is an anion channel that has evolved from the mold of an ABC transporter. It possesses specific structural features, including a lateral portal between the cytoplasmic extensions of its transmembrane helices TM4 and TM6. This TM4-TM6 portal is lined by basic residues attracting anions from the cytosol towards the intracellular vestibule. Even though a symmetric, open portal is not observed at the level of the TM10/TM12 interface, basic amino acids are also present at this level, exposed to solvent in the vicinity of the regulatory R region, whose phosphorylation enables channel activation. Here, using all-atom molecular dynamics simulations in combination with functional and biochemical assays, we investigate the importance of these basic amino acids (R1158 and R1030), and of a neighboring aromatic amino acid (W846) in the regulation of CFTR activity. Results indicate that mutation of these amino acids globally increased channel activity and enabled channel opening by potentiators without the need to elevate cAMP levels. These effects (i) were observed even when the binding site of the potentiator VX-770 was mutated, revealing a probable independent mechanism, and (ii) were additive to one gain-of-function mutant within the selectivity filter. Taken together, our results indicate that the region of the membrane-spanning domain 2 (MSD2), symmetric to the lateral portal located between MSD1 TM4 and TM6, is a novel critical actor of CFTR regulation. [ABSTRACT FROM AUTHOR]

This study explores coherent structures in a swirling turbulent jet. Stationary axisymmetric solutions of the Reynolds–Averaged Navier–Stokes equations at R e = 200 , 000 were obtained using an open source computational fluid dynamics code and the Spalart–Allmaras eddy viscosity model. Then, resolvent analysis with the same eddy viscosity field provided coherent structures of the turbulent fluctuations on the base flow. As in many earlier studies, a large gain separation is identified between the optimal and sub-optimal resolvent modes, permitting a focus on the most amplified response mode and its corresponding optimal forcing. At zero swirl, the results indicate that the jet's coherent response is dominated by axisymmetric ( m = 0 ) structures, which are driven by the usual Kelvin–Helmholtz shear amplification mechanism. However, as swirl is increased, different coherent structures begin to dominate the response. For example, double and triple spiral ( | m | = 2 and | m | = 3 ) modes are identified as the dominant structures when the axial and azimuthal velocity maxima of the base flow are comparable. In this case, distinct co- and counter-rotating | m | = 2 modes experience vastly different degrees of amplification. The physics of this selection process involve several amplification mechanisms contributing simultaneously in different regions of the mode. This is analysed in more detail by comparing the alignment between the wavevector of the dominant response mode and the principal shear direction of the base flow. Additional discussion also considers the development of structures along the exterior of the jet nozzle. [ABSTRACT FROM AUTHOR]

Three new organic–inorganic hybrid phosphites salts, namely, (enH2)[M(H2O)6](HPO3)2, with [M = Co (1), Ni (2) and Mg (3), and "en" refers to ethylenediamine C2N2H8] have been synthesized at room temperature by the slow evaporation method. The solid-state structures were solved from single crystal X-ray diffraction data. These compounds are isostructural, all crystallizing in the orthorhombic system, space group, Pbca (no 61). The FTIR spectroscopy shows the expected bands of ethylenediamine (en), water molecules, and hydrogen-phosphite oxoanion groups. The thermal stability until 100 °C of the three compounds was confirmed using combined analyses (TGA/DTA, powder X-ray diffraction and Raman spectroscopy). Two catalytic activity performances were investigated: the catalytic efficiency on the water decontamination of the three compounds by the reduction of three nitrophenol isomers and the Hydrogen Evolution Reaction (HER) in an alkaline environment. The three hybrid compounds turned out to be very efficient new catalysts for reducing the three nitrophenol isomers. The fastest electron transport and the most favorable HER reaction kinetics are displayed by (enH2)[Ni(H2O)6](HPO3)2, while the highest current density with the lowest overpotential was obtained for (enH2)[Co(H2O)6](HPO3)2. [ABSTRACT FROM AUTHOR]

Fish domestication progresses through five levels: from the initial acclimatization to captivity (Level 1), to the life cycle completion in captivity (Level 4), and even to the implementation of selective breeding programs (Level 5). Domestication leads to phenotypic changes over generations, sometimes from the very first generation. Behavioral traits are among the first to change. However, in fish, potential behavioral changes during early domestication have been little studied. Therefore, we studied potential behavioral changes among early and advanced levels of domestication in a model species, the zebrafish (Danio rerio), using a mirror test experiment, commonly used to assess traits involved in activity, aggressiveness, and stress in this species. We compared these traits between wild zebrafish in captivity (F0; Level 1), the first generation of their captive-born offspring (F1; Level 4), and three laboratory strains (AB, TU, and WIK; Level 5). Each fish was individually filmed and tracked using an automated procedure for 5 min. Nine behavioral traits and one activity-related trait were characterized for each individual based on the movements and positioning of the fish. We applied a principal component analysis (PCA) and tested the significance of potential differences between groups using an analysis of similarities (ANOSIM). We applied an indicator value analysis (IndVal) to determine which traits were most expressed by each group. We detected differences between groups and across domestication levels. More specifically, we highlighted differentiations between different levels of domestication (e.g. between F1, AB, TU, and WIK) as early as the beginning of the domestication process (i.e. F0 vs. F1), but also within the same level of domestication (i.e. AB vs. TU). Based on PCA and IndVal, (i) F0 and F1 tended to show stronger expression of stress-related traits than the other groups, (ii) F0 was more active than others, and (iii) TU was more aggressive than AB. Our results confirmed that domestication can change fish behavior, even in the first generation born in captivity, although these modifications remain limited. In contrast, we did not observe any general trends correlated with domestication levels, given that AB and TU diverged in their aggressiveness levels, and WIK differed only from F1. This result needs to be generalized to other species but also considered for domestication for aquaculture. If future studies confirm that the changes observed at the beginning of the domestication process remain limited and that there is no consistent evolutionary trend across generations in fish, this would highlight the crucial importance of selecting the right species from the outset of domestication. It would also emphasize the need to design selective breeding programs that shape fish stocks with the most desirable characteristics. To our knowledge, this study is one of the few to examine the behavior of wild zebrafish alongside laboratory strains, offering a unique insight into the early stages of domestication. [ABSTRACT FROM AUTHOR]

Current poultry vaccines against influenza A viruses target the globular head region of the hemagglutinin (HA1), providing limited protection against antigenically divergent strains. Experimental subunit vaccines based on the conserved ectodomain of the matrix protein 2 (M2e) induce cross-reactive antibody responses, but fail to fully prevent virus shedding after low pathogenic avian influenza (LPAI) virus challenge, and are ineffective against highly pathogenic avian influenza (HPAI) viruses. This study assessed the benefits of combining nanoparticles bearing three tandem M2e repeats (NR-3M2e nanorings or NF-3M2e nanofilaments) with an HA1 subunit vaccine in protecting chickens against a heterologous HPAI H5N1 virus challenge. Chickens vaccinated with the combined formulations developed M2e and HA1-specific antibodies, were fully protected from clinical disease and mortality, and showed no histopathological lesions or virus shedding, unlike those given only HA1, NR-3M2e, or NF-3M2e. Thus, the combined vaccine formulations provided complete cross-protection against HPAI H5N1 virus, and prevented environmental virus shedding, crucial for controlling avian influenza outbreaks. [ABSTRACT FROM AUTHOR]

The oscillator bases expansion stands as an efficient approximation method for the time-independent Schrödinger equation. The method, originally formulated with one non-linear variational parameter, can be extended to incorporate two such parameters. It handles both non- and semi-relativistic kinematics with generic two-body interactions. In the current work, focusing on systems of three identical bodies, the method is generalised to include the management of a given class of three-body forces. The computational cost of this generalisation proves to not exceed the one for two-body interactions. The accuracy of the generalisation is assessed by comparing with results from Lagrange mesh method and hyperspherical harmonic expansions. Extensions for systems of N identical bodies and for systems of two identical particles and one distinct are also discussed. [ABSTRACT FROM AUTHOR]

To explain how populations with distinct warning signals coexist in close parapatry, we experimentally assessed intrinsic mechanisms acting as reproductive barriers within three poison-frog species from the Peruvian Amazon belonging to a Müllerian mimetic ring (Ranitomeya variabilis, Ranitomeya imitator and Ranitomeya fantastica). We tested the role of prezygotic and postzygotic isolation barriers between phenotypically different ecotypes of each species, using no-choice mating experiments and offspring survival analysis. Our results show that prezygotic mating preference did not occur except for one specific ecotype of R. imitator, and that all three species were able to produce viable inter-population F1 hybrids. However, while R. variabilis and R. imitator hybrids were able to produce viable F2 generations, we found that for R. fantastica, every F1 hybrid males were sterile while females remained fertile. This unexpected result, echoing with Haldane’s rule of speciation, validated phylogenetic studies which tentatively diagnose these populations of R. fantastica as two different species. Our work suggests that postzygotic genetic barriers likely participate in the extraordinary phenotypic diversity observed within Müllerian mimetic Ranitomeya populations, by maintaining species boundaries. [ABSTRACT FROM AUTHOR]

Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems do not recapitulate the histoarchitecture and cellular composition of respiratory tissues. To address this, we developed an innovative ex vivo model of whole human lung infection with SARS-CoV-2, leveraging a lung transplantation technique. Through single-cell RNA-seq, we identified that alveolar and monocyte-derived macrophages (AMs and MoMacs) were initial targets of the virus. Exposure of isolated lung AMs, MoMacs, classical monocytes and non-classical monocytes (ncMos) to SARS-CoV-2 variants revealed that while all subsets responded, MoMacs produced higher levels of inflammatory cytokines than AMs, and ncMos contributed the least. A Wuhan lineage appeared to be more potent than a D614G virus, in a dose-dependent manner. Amidst the ambiguity in the literature regarding the initial SARS-CoV-2 cell target, our study reveals that AMs and MoMacs are dominant primary entry points for the virus, and suggests that their responses may conduct subsequent injury, depending on their abundance, the viral strain and dose. Interfering on virus interaction with lung macrophages should be considered in prophylactic strategies. [ABSTRACT FROM AUTHOR]

Little is known regarding radiation-induced matrikines and the possible degradation of extracellular matrix following therapeutic irradiation. The goal of this study was to determine if irradiation can cut collagen proteins at specific sites, inducing potentially biologically active peptides against cartilage cells. Chondrocytes cultured as 3D models were evaluated for extracellular matrix production. Bystander molecules were analyzed in vitro in the conditioned medium of X-irradiated chondrocytes. Preferential breakage sites were analyzed in collagen polypeptide by mass spectrometry and resulting peptides were tested against chondrocytes. 3D models of chondrocytes displayed a light extracellular matrix able to maintain the structure. Irradiated and bystander chondrocytes showed a surprising radiation sensitivity at low doses, characteristic of the presence of bystander factors, particularly following 0.1 Gy. The glycine-proline peptidic bond was observed as a preferential cleavage site and a possible weakness of the collagen polypeptide after irradiation. From the 46 collagen peptides analyzed against chondrocytes culture, 20 peptides induced a reduction of viability and 5 peptides induced an increase of viability at the highest concentration between 0.1 and 1 µg/ml. We conclude that irradiation promoted a site-specific degradation of collagen. The potentially resulting peptides induce negative or positive regulations of chondrocyte growth. Taken together, these results suggest that ionizing radiation causes a degradation of cartilage proteins, leading to a functional unbalance of cartilage homeostasis after exposure, contributing to cartilage dysfunction. [ABSTRACT FROM AUTHOR]

Owing to the demand for chemical analysis of low concentrations of the Brilliant Green (BG) dye released into the environment, molecularly imprinted polymer (MIP) materials have been investigated for their use in SPME preconcentration devices. Thin coatings of MIP on solid supports allow fast adsorption of the analyte and higher selectivity of adsorption. Biosourced fibers of Posidonia oceanica (Pos) were taken as a the solid support to which a thin film of MIP was chemically attached. The material synthesis involved two steps: chemical grafting of methacrylate groups onto Pos by a silane coupling, and copolymerization with the free functional monomer and cross-linker in the presence of BG. Polymerization of the functional monomers methacrylic acid and acrylamide yielded the materials PosMAA@MIP and PosAA@MIP respectively. The strength of their interaction with BG and the stoichiometry of the pre-polymerization complex were assessed by 1H NMR experiments in DMSO-d6 solution. Characterization by IR spectroscopy and thermogravimetric analysis validated the successful syntheses. The points of zero charge were at pH 3.31 and 4.50 for PosMAA@MIP and PosAA@MIP, respectively, influencing the optimal adsorption of BG at pH 4. Kinetic studies revealed the rapid adsorption of more than 90% of the BG within 20 min. All MIPs exhibited higher adsorption capacity for BG compared to non-imprinted materials. PosAA@MIP showed the highest adsorption efficiency and selectivity, with an imprinting factor of 1.9. The thermodynamics of adsorption was studied by fitting the Langmuir–Volmer and Volmer models to the experimental data, from which the selective adsorption capacities of BG on PosMAA@MIP and PosAA@MIP were 289 and 313 µmol·g−1, respectively. Additionally, PosAA@MIP exhibited higher extraction efficiency for BG than for its metabolites eosin and methylene blue, underscoring its superior ability to selectively capture target molecules. [ABSTRACT FROM AUTHOR]

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection. Here, Chevalier et al show that Streptococcus pneumoniae induces the histone modifications H3K4me2 in epithelial cells, where it persists beyond bacterial clearance and affects cell responses to secondary infection. [ABSTRACT FROM AUTHOR]

Multi-scale numerical homogenisation strategies have been used in the recent years to efficiently compute the effective elastic properties of heterogeneous materials. Coupled with a stochastic approach, they can be applied to natural material such as wood to take into account the variability of their properties. In the case of Pinus pinaster (Ait.), available elastic properties are based on those of generic softwood species due to a lack of data in the literature, reducing the overall precision of the results. This paper proposes an efficient numerical framework based on both a general numerical homogenisation method and the well-known Monte Carlo approach to determine the equivalent elastic properties at the macroscopic scale, with the associated variability, of the Pinus pinaster (Ait.) species. The coherence of the numerical model is established by comparison with analytical and experimental results available in the literature. The obtained results reveal very good accuracy in terms of equivalent elastic properties with a macroscopic behaviour characterised by an orthotropic symmetry. Moreover, the influence of the distance from the pith on the equivalent macroscopic elastic response is highlighted. [ABSTRACT FROM AUTHOR]

The thermal condition plays an important role in the final thickness distribution and in the mechanical behavior of the Polyethylene Terephthalate (PET) bottle obtained from the stretch blow molding (SBM) process. A complete 3D modelling of the heating stage during the SBM process under industrial condition is very time-consuming. Based on a simplified approach to quickly achieve the numerical simulation of the preform heating, an optimization procedure is proposed to adjust the settings of the infrared lamps by comparing our simulation results to the target temperature profile. In this numerical approach, the radiation source is simulated by using a model for intensity of the incident radiation and the Beer-Lambert law. On the other hand, the ventilation effect under industrial conditions is taken into account by modelling the forced convection around a cylinder. The infrared (IR) flux and ventilation effects are implemented as thermal boundary conditions in COMSOL software for a 3D computation of the thermal problem for the preform only. Since the simulation has a very reasonable computational time, an optimization procedure can be generated to adjust the setting of IR lamps. This optimization tool provides quickly a first set of parameters to help industry to obtain the desired temperature profile. [ABSTRACT FROM AUTHOR]

Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT scan assuming exponential kidney volume growth and height-adjusted total kidney volume at birth to be 150 mL/m. However, when multiple scans are available, how this information should be combined to improve prediction accuracy is unclear. Herein, we studied ADPKD subjects ( n = 36 ) with 8+ years imaging follow-up (mean = 11 years) to establish ground truth kidney growth trajectory. MIC annual kidney growth rate predictions were compared to ground truth as well as 1- and 2-parameter least squares fitting. The annualized mean absolute error in MIC for predicting total kidney volume growth rate was 2.1 % ± 2 % compared to 1.1 % ± 1 % ( p = 0.002 ) for a 2-parameter fit to the same exponential growth curve used for MIC when 4 measurements were available or 1.4 % ± 1 % ( p = 0.01 ) with 3 measurements averaging together with MIC. On univariate analysis, male sex ( p = 0.05 ) and PKD2 mutation ( p = 0.04 ) were associated with poorer MIC performance. In ADPKD patients with 3 or more CT/MRI scans, 2-parameter least squares fitting predicted kidney volume growth rate better than MIC, especially in males and with PKD2 mutations where MIC was less accurate. [ABSTRACT FROM AUTHOR]

We recently developed an immuno-oncotherapy against human papillomavirus (HPV)-induced tumors based on a lentiviral vector encoding the Early E6 and E7 oncoproteins of HPV16 and HPV18 genotypes, namely "Lenti-HPV-07". The robust and long-lasting anti-tumor efficacy of Lenti-HPV-07 is dependent on CD8+ T-cell induction and remodeling of the tumor microenvironment. Here, we first established that anti-vector immunity induced by Lenti-HPV-07 prime has no impact on the efficacy of a homologous boost to amplify anti-HPV T-cell immunity. To longitudinally monitor the evolution of the T-cell repertoire generated after the prime, homologous or heterologous boost with Lenti-HPV-07, we tracked T-cell clonotypes by deep sequencing of T-Cell Receptor (TCR) variable β and α chain mRNA, applied to whole peripheral blood cells (PBL) and a T cell population specific of an immunodominant E7HPV16 epitope. We observed a hyper-expansion of clonotypes post prime, accompanied by increased frequencies of HPV-07-specific T cells. Additionally, there was a notable diversification of clonotypes post boost in whole PBL, but not in the E7HPV16-specific T cells. We then demonstrated that the effector functions of such Lenti-HPV-07-induced T cells synergize with anti-checkpoint inhibitory treatments by systemic administration of anti-TIM3 or anti-NKG2A monoclonal antibodies. While Lenti-HPV-07 is about to enter a Phase I/IIa clinical trial, these results will help better elucidate its mode of action in immunotherapy against established HPV-mediated malignancies. [ABSTRACT FROM AUTHOR]

Purpose: Surgical management of ovarian masses in girls still challenging. The aim of the study is to report an 8-year experience in managing children with ovarian masses, and to demonstrate the advantages and the limitations of laparoscopy for such lesions. Methods: Data of girls aged less than 18 years operated because of an ovarian mass between January 2015 and February 2023 were retrospectively reviewed. Patients were divided into two groups: group A including children operated by laparoscopy, and Group B of patients who underwent open surgery. Results: Eighty-eight children were enrolled. Laparoscopy was performed in 56 patients (63.6%). Group A patients had smaller tumor size (53.6±38.5 vs. 122.2±75.4 mm, P<0.0001), shorter operative time (50.4±20.3 vs. 71.5±36.5 min, P = 0.004), reduced length of hospital stay (1.4±1.1 vs. 3±2.3 days, P<0.0001), and absence of postoperative complications. Only 3 cases (5.7%) of recurrence were seen exclusively within patients followed for benign tumors during a mean follow-up period of 4.6±3 years. Conclusion: Laparoscopy should be done in benign ovarian lesions or/and if a torsion is seen. For tumors at high risk of malignancy, laparoscopy can be performed to establish a clear macroscopic diagnosis, for staging of the disease, and resection of small tumors. Conversion to open surgery is indicated in case of doubt. [ABSTRACT FROM AUTHOR]

Many-body forces, and specially three-body forces, are sometimes a relevant ingredient in various fields, such as atomic, nuclear or hadronic physics. As their precise structure is generally difficult to uncover or to implement, phenomenological effective forces are often used in practice. A form commonly used for a many-body variable is the square-root of the sum of two-body variables. Even in this case, the problem can be very difficult to treat numerically. But this kind of many-body forces can be handled at the same level of difficulty than two-body forces by the envelope theory. The envelope theory is a very efficient technique to compute approximate, but reliable, solutions of many-body systems, specially for identical particles. The quality of this technique is tested here for various three-body forces with non-relativistic systems composed of three identical particles. The energies, the eigenfunctions, and some observables are compared with the corresponding accurate results computed with a numerical variational method. [ABSTRACT FROM AUTHOR]

The preparation of atom-thick porous lattice hosting Å-scale pores is attractive to achieve a large ion-ion selectivity in combination with a large ion flux. Graphene film is an ideal selective layer for this if high-precision pores can be incorporated, however, it is challenging to avoid larger non-selective pores at the tail-end of the pore size distribution which reduces ion-ion selectivity. Herein, we develop a strategy to overcome this challenge using an electrochemical repair strategy that successfully masks larger pores in large-area graphene. 10-nm-thick electropolymerized conjugated microporous polymer (CMP) layer is successfully deposited on graphene, thanks to a strong π-π interaction in these two materials. While the CMP layer itself is not selective, it effectively masks graphene pores, leading to a large Li+/Mg2+ selectivity from zero-dimensional pores reaching 300 with a high Li+ ion permeation rate surpassing the performance of reported materials for ion-ion separation. Overall, this scalable repair strategy enables the fabrication of monolayer graphene membranes with customizable pore sizes, limiting the contribution of nonselective pores, and offering graphene membranes a versatile platform for a broad spectrum of challenging separations. The preparation of atom-thick lattices with Å-scale pores is desirable for achieving ion selectivity and high ion flux. Here authors present a cm-scale membrane made of atom-thick graphene film hosting zero-dimensional pores spanning only a few Å, repaired using an in situ electrochemical strategy, yielding high Li+/Mg2+ separation performance. [ABSTRACT FROM AUTHOR]

Over the past 30 years, research on meniscal kinematics has been limited by challenges such as low-resolution imaging and capturing continuous motion from static data. This study aimed to develop a computational knee model that overcomes these limitations and enables the continuous assessment of meniscal dynamics. A high-resolution MRI dataset (n = 11) was acquired in 4 configurations of knee flexion. In each configuration, the menisci were modeled based on the underlying osseous anatomy. Principal Polynomial Shape Analysis (PPSA) was employed for continuous meniscal modeling. Maximal medial anterior horn displacement occurred in 60° of flexion, equaling 6.24 mm posteromedial, while the posterior horn remained relatively stable. At 90° of flexion, the lateral anterior and posterior horn displaced posteromedially, amounting 5.70 mm and 6.51 mm respectively. The maximal observed Average Surface Distance (ASD) equaled 0.70 mm for lateral meniscal modeling in 90° of flexion. Based on our results, a strong relation between meniscal dynamics and tibiofemoral kinematics was confirmed. Expanding on static meniscal modeling and employing PPSA, we derived and validated a standardized and systematic methodological workflow. [ABSTRACT FROM AUTHOR]

Intraspecific variation in body size, both among populations and between sexes, is an important factor influencing life-history strategies. This variation might be the response to different environmental conditions, as well as natural and sexual selection, and can result in differences in behavior and reproductive strategies among populations. Here, we use the dyeing poison frog (Dendrobates tinctorius) as a model to investigate how interpopulation variation in body size and sexual size dimorphism affects reproductive strategies. As body size increased, sexual size dimorphism also increased, i.e., females were larger than males, and more so in populations with overall larger frogs. This indicates that there is a stronger selection for body size in females than in males, likely as a response to divergent reproductive investment between the sexes. Females from larger-bodied populations produced larger clutches, but the overall number of froglets produced per clutch did not differ among populations. We discuss potential causes and mechanisms that might be responsible for the observed divergence in body size, sexual size dimorphism, and reproductive strategies among populations that likely represent local adaptations. Our findings demonstrate the importance of cross-population studies, cautioning against drawing general conclusions about a species' ecology without accounting for intraspecific variation. [ABSTRACT FROM AUTHOR]

The Newmark displacement (ND) method, which reproduces the interactions between waves, solids, and fluids during an earthquake, has experienced numerous modifications. We compare the performances of a traditional and a modified version of the ND method through the analysis of co-seismic landslides triggered by the 2022 Ms 6.8 Luding earthquake (Sichuan, China). We implemented 23 ND scenarios with each equation, assuming different landslide depths, as well as various soil-rock geomechanical properties derived from previous studies in regions of similar lithology. These scenarios allowed verifying the presence or absence of such landslides and predict the likely occurrence locations. We evaluated the topographic and slope aspect amplification effects on both equations. The oldest equation has a better landslide predictive ability, as it considers both slope stability and earthquake intensity. Contrarily, the newer version of the ND method has a greater emphasis on slope stability compared to the earthquake intensity and hence tends to give high ND values only when the critical acceleration is weak. The topographic amplification does not improve the predictive capacity of these equations, most likely because few or no massive landslides were triggered from mountain peaks. This approach allows structural, focal mechanism, and site effects to be considered when designing ND models, which could help to explain and predict new landslide distribution patterns such as the abundance of landslides on the NE, E, S, and SE-facing slopes observed in the Luding case. [ABSTRACT FROM AUTHOR]

Purpose: Patient-reported outcomes (PROs) are essential for assessing potential late effects experienced by young adult cancer survivors (YACS), but stigma and social desirability bias may limit their effectiveness for assessing sensitive topics (e.g., suicidal ideation, sexual health). This study compared two methods of item administration to determine the optimal method for obtaining sensitive information in YACS. Methods: Two hundred forty-four YACS (ages 18–40) were randomized to complete measures of suicidal ideation and sexual health (i.e., sensitive items) by paper survey or by telephone automated computer assisted structured interview (TACASI). Participants also provided information on acceptability of administration mode and sensitive items. Results: The proportion of participants reporting symptoms did not significantly vary between paper and TACASI administration: respectively, 10% vs. 12% reported suicidal ideation and 55% vs. 58% reported sexual health concerns. The majority (≥ 78%) of participants reported feeling comfortable answering sensitive items on paper and TACASI and there were no significant differences in acceptability based on administration mode. Although participants endorsing sensitive symptoms were significantly more likely to feel upset answering sensitive items, the majority (93%) of participants experiencing symptoms still felt they were important to ask. Conclusions: Despite their potentially sensitive nature, questions about suicidal ideation and sexual health were highly acceptable to YACS across administration modes. Moreover, YACS almost universally endorse the importance of providers asking about these topics. Implications for Cancer Survivors: Findings should bolster provider confidence that screening for suicidal ideation and sexual health concerns can and should be integrated into clinical care for YACS using paper or technology-assisted methods. [ABSTRACT FROM AUTHOR]

Sustaining changes in teachers' practices is a challenge that determines the success of curricular reforms, from which Digital Education (DE) is not exempt. As the literature on sustainability is considered "scarce" and "scattered", long-term studies modelling the factors impacting teachers' sustained uptake of DE pedagogical content are lacking. Thus, we investigate whether and how 287 in-service teachers sustained a primary school DE curricular reform over a year after they completed their two-year DE professional development program. We model the sustainability of the reform through Structural Equation Modelling, and identify critical sustainability-factors. The validated Sustainable Adoption of Digital Education (SADE) model confirms that sustainability in the fourth year of the reform depends on perceived usefulness of teaching the new content, ease of implementation, and access to sufficient support in schools. Such factors should thus be evaluated, accounted for in the implementation phase of the reform, and sustained over time. The findings confirm that the DE curricular reform model contributes to positive self-efficacy to teach DE, provides sufficient in-school support, and promotes increasing adoption over time. However, as teachers' practices have not yet stabilised, and teachers may still adopt more to cover the breadth of DE-concepts, it is important to remain attentive to remaining sustainability barriers: lack of time, effort required to teach DE with teachers preferring to delegate, and lack of student-learning evidence, the latter being a significant challenge to address in the literature. These barriers must therefore be jointly addressed by researchers and practitioners in the field in order to promote the sustainability of the reform. [ABSTRACT FROM AUTHOR]

This work focuses on the dynamic behavior of bridge piers subjected to scour. Here, the paper is divided into two parts. The first part considers the model of bridge pier by assuming a rocking solid partially embedded in a Winkler soil with translational and rotational conditions at its base. Simple geometry and boundary conditions of bridge pier are represented because the aim of this work is to show the feasibility of a new method based on free response analysis for bridge piers subjected to scour in general case. In fact, this physical model coupling solid mechanics for the structure and the continuum mechanics for the soil makes it possible for us to identify experimentally two rocking modes. In that way, the second part shows an experimental campaign in laboratory implemented on reduced pier models embedded in Fontainebleau sand with different geometries and inertias. From frequency decomposition of signals, natural frequencies and shape modes highlighted by the model are identified and compared from experiments. Analytical formulations and experiments show the interest to use vibration-based monitoring for scouring. [ABSTRACT FROM AUTHOR]

Phthalates constitute a family of anthropogenic chemicals developed to be used in the manufacture of plastics, solvents, and personal care products. Their dispersion and accumulation in many environments can occur at all stages of their use (from synthesis to recycling). However, many phthalates together with other accumulated engineered chemicals have been shown to interfere with hormone activities. These compounds are also in close contact with microorganisms that are free-living, in biofilms or in microbiota, within multicellular organisms. Herein, the activity of several phthalates and their substitutes were investigated on the opportunistic pathogen Legionella pneumophila, an aquatic microbe that can infect humans. Beside showing the toxicity of some phthalates, data suggested that Acetyl tributyl citrate (ATBC) and DBP (Di-n-butyl phthalate) at environmental doses (i.e. 10–6 M and 10–8 M) can modulate Legionella behavior in terms of motility, biofilm formation and response to antibiotics. A dose of 10–6 M mostly induced adverse effects for the bacteria, in contrast to a dose of 10–8 M. No perturbation of virulence towards Acanthamoeba castellanii was recorded. These behavioral alterations suggest that L. pneumophila is able to sense ATBC and DBP, in a cross-talk that either mimics the response to a native ligand, or dysregulates its physiology. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer. Methods: Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding. Results: We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth. Conclusion: Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients. [ABSTRACT FROM AUTHOR]

The International Study of Kidney Disease in Children (ISKDC), begun in 1966, conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology and one of the first in either pediatrics or nephrology. For this trial, the ISKDC developed the criteria, such as those for response and relapse, used today to describe the clinical course of the nephrotic syndrome, and the trial generated the nephropathologic terminology and criteria which largely remain the current standards. Over an approximately 20-year span, the ISKDC followed the natural history and evaluated the therapeutic effectiveness of therapies in over 500 children with the nephrotic syndrome from three continents. It published 14 peer-reviewed studies and several reports and commentaries, many of which helped create current standards of practice for therapy of childhood nephrotic syndrome and consequently remain highly cited today. The ISKDC continues to be an important model for subsequent collaborative studies and was the impetus for the development of regional and national pediatric nephrology societies leading to the recognition and growth of pediatric nephrology as a separate subspecialty. [ABSTRACT FROM AUTHOR]

1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO) was obtained with high chemoselectivity and excellent yield, through an efficient and simple cyclotrimerization of isocyanatocyclohexane, performed at room temperature and under mild reaction condition. The newly synthesized TCy-TAZTO was characterized with FT-IR, 1H, and 13C NMR spectra. Single-crystal X-ray diffraction was used to investigate its molecular structure. The Hirshfeld surface, curvedness, shape index, and 2D-fingerprint plots were used to evaluate various intermolecular interactions within the crystal structure. DFT calculations, intrinsic reaction coordinate (IRC), Wiberg bond index, and FOMs computational studies were performed to get more insights into the stability and the reaction mechanism. Furthermore, the molecular docking of the TCy-TAZTO was studied against different proteins to investigate the efficacy against selected drug targets of platelet aggregation, blood coagulation, antithrombotic, and anti HIV-1 disease. [ABSTRACT FROM AUTHOR]

Background: Early exposure to Computer Science (CS) and Computational Thinking (CT) for all is critical to broaden participation and promote equity in the field. But how does the introduction of CS and CT into primary school curricula impact learning, perception, and gaps between groups of students? Methodology: We investigate a CS-curricular reform and teacher Professional Development (PD) programme from an equity standpoint by applying hierarchical regression and structural equation modelling on student learning and perception data from three studies with, respectively, 1384, 2433 and 1644 grade 3–6 students (ages 7–11) and their 83, 142 and 95 teachers. Results: Regarding learning, exposure to CS instruction appears to contribute to closing the performance gap between low-achieving and high-achieving students, as well as pre-existing gender gaps. Despite a lack of direct influence of what was taught on student learning, there is no impact of teachers' demographics or motivation on student learning, with teachers' perception of the CS-PD positively influencing learning. Regarding perception, students perceive CS and its teaching tools (robotics, tablets) positively, and even more so when they perceive a role model close to them as doing CS. Nonetheless, gender differences exist all around with boys perceiving CS more positively than girls despite access to CS education. However, access to CS-education affects boys and girls differently: larger gender gaps are closing (namely those related to robotics), while smaller gaps are increasing (namely those related to CS and tablets). Conclusion: This article highlights how a CS curricular reform impacts learning, perception, and equity and supports the importance of (i) early introductions to CS for all; (ii) preparing teachers to teach CS all the while removing the influence of teacher demographics and motivation on student outcomes; and (iii) having developmentally appropriate activities that signal to all groups of students. [ABSTRACT FROM AUTHOR]

The combination of ongoing urban expansion and electrification of uses challenges the power grid. In such a context, information regarding customers' consumption is vital to assess the expected load at strategic nodes over time, and to guide power system planning strategies. Comprehensive household consumption databases are widely available today thanks to the roll-out of smart meters, while the consumption of tertiary premises is seldom shared mainly due to privacy concerns. To fill this gap, the French main distribution system operator, Enedis, commissioned Mines Paris to derive load profiles of industrial and tertiary sectors for its prospective tools. The ELMAS dataset is an open dataset of 18 electricity load profiles derived from hourly consumption time series collected continuously over one year from a total of 55,730 customers. These customers are divided into 424 fields of activity, and three levels of capacity subscription. A clustering approach is employed to gather activities sharing similar temporal patterns, before averaging the associated time series to ensure anonymity. [ABSTRACT FROM AUTHOR]

Imeglimin (PXL008, EMD-387008, Twymeeg®) is a first-in-class novel oral hypoglycemic agent, launched in Japan, for the treatment of type 2 diabetes mellitus. Its mechanism of action targets mitochondrial bioenergetics to ameliorate insulin resistance and to enhance β-cell function. This review summarizes the properties underlying the pharmacokinetic profile of imeglimin, a small cationic drug belonging to the tetrahydrotriazine chemical class, with a complex mechanism of absorption involving an active transport through organic cation transporters (OCTs). Imeglimin absorption decreases when dose increases due to the saturation of the active uptake transport. Post absorption, imeglimin is rapidly and primarily distributed to organs and tissues, and has a half-life ranging from 9.03 to 20.2 h. Plasma protein binding of imeglimin is low, which explains the rapid distribution to the organs observed in all species. Imeglimin is excreted unchanged in urine, indicating a low extent of metabolism. Imeglimin is a substrate of multidrug and toxic compound extrusion (MATE) 2-K and a substrate and inhibitor of OCT1, OCT2, and MATE1. Clinical drug–drug interaction studies confirmed the absence of relevant clinical interaction with substrates or inhibitors of these transporters. Overall, the drug–drug interaction potential of imeglimin is low. Its pharmacokinetics profile has also been characterized in special populations, showing no influence of mild and moderate hepatic impairment but an impact of renal function on imeglimin renal clearance. Dosage adjustment is thus required in moderately and severely renally impaired patients. Imeglimin pharmacokinetics was shown to be insensitive to ethnicity and food intake and to have no effect on QTcF interval. [ABSTRACT FROM AUTHOR]

Introduction: 18F-FDG-PET/CT is recommended to improve the diagnosis of prosthetic valve infective endocarditis (PVIE) and is a major criterion in the ESC-2015 classification. However, there is little evidence for its usefulness in the follow-up of medically treated PVIE patients. Methods: A monocentric retrospective analysis of patients hospitalized for PVIE between January 2013 and December 2019 who were not treated with surgery and who had at least two 18F-FDG-PET/CT examinations during their medical management. Results: Among 170 patients with PVIE, 117 were treated with antibiotic therapy but no surgery. Of these, 36 (31%) had at least two 18F-FDG-PET/CT examinations. At initial imaging, 28 patients had heterogeneous FDG uptake on their prosthetic valve and eight on their associated aortic graft. Hypermetabolism of spleen and bone marrow (HSBM) was observed in 18 and 19 patients, respectively. At the first follow-up 18F-FDG-PET/CT, 21 (58%) patients still had heterogeneous uptake, indicating persistent active endocarditis. HSBM was still present at the last follow-up imaging in four of the six patients with recurrent PVIE. Conclusion: 18F-FDG-PET/CT monitoring of medically treated patients with PVIE provides valuable additional information and prospective multicentric study should be conducted to assess its usefulness. [ABSTRACT FROM AUTHOR]

Purpose: Of all childhood cancers, adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for late mortality as well as neurocognitive, physical, and psychosocial late effects. Their identity with cancer survivorship, the relationship of their identity to health outcomes, and how their identity differs from other childhood cancer survivors is poorly understood. Methods: A total of 127 young adults previously treated for pediatric CNS tumors enrolled in Project REACH, a locally-treated childhood cancer survivor cohort. Participants completed self-report measures on the effects of cancer on identity, someone who had cancer, victim and survivor identity, frequency of thoughts of diagnosis, and health outcomes. Results: The majority of participants identified as a survivor (83%). Survivor identity was linked to diagnosis and treatment but not health outcomes. A minority (9%) endorsed a victim identity, and they were more likely to have poorer mental health (p = 0.03) and depression (p = 0.04) than non-victims. Participants who reported a stronger effect of cancer on their identity also had poorer mental health (p = 0.005). A higher frequency of diagnosis-related thoughts was associated with significantly poorer mental health (p < 0.001), more severe anxiety (p = 0.008), depression (p < 0.001), and neurocognitive impairments (p < 0.01). Those who experienced relapse, radiation, and/or chemotherapy were more likely to identify as someone who had cancer, independent of diagnosis. Implications for Cancer Survivors: Our findings suggest the relationships previously reported between identity and sociodemographic, treatment, and health outcomes after adult and pediatric non-CNS cancers cannot be generalized to pediatric CNS tumors. Understanding the unique features of how this population identifies is important for patient-centered care. [ABSTRACT FROM AUTHOR]

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk. TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO. [ABSTRACT FROM AUTHOR]

New therapeutic approaches are needed for the management of the highly chemo- and radioresistant chondrosarcoma (CHS). In this work, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to augment the cytotoxic effects of carbon ions in comparison to photon radiation therapy. The in vitro biological effects were investigated in SW1353 chondrosarcoma cells focusing on the following parameters: cell survival using clonogenic test, detection of micronuclei (MN) by cytokinesis blocked micronucleus assay and morphology together with spectral fingerprints of nuclei using enhanced dark-field microscopy (EDFM) assembled with a hyperspectral imaging (HI) module. The combination of IONPDOX with ion carbon or photon irradiation increased the lethal effects of irradiation alone in correlation with the induction of MN. Alterations in the hyperspectral images and spectral profiles of nuclei reflected the CHS cell biological modifications following the treatments, highlighting possible new spectroscopic markers of cancer therapy effects. These outcomes showed that the proposed combined treatment is promising in improving CHS radiotherapy. [ABSTRACT FROM AUTHOR]

Gibberellins (GA) are a very important signal for fruit set and growth. Exogenous application of these hormones can replace pollination and promote parthenocarpic fruit growth in many species. We have previously shown strong variations between tomato cultivars in the pericarp cell pattern after fruit set, including the number of cell layers, cell size and level of endoreduplication. Here, the effect of GA addition on this pattern was compared to pollination throughout fruit growth in the cherry tomato cultivar WVa106. The effect of a range of GA levels was also investigated in four tomato cultivars, namely WVa106, Micro-Tom, Money Maker and Ailsa Craig, with a different cell pattern in the pericarp. The level of GA was found to be a limiting factor in cell size and ploidy in the tomato pericarp of all cultivars, with dramatic effects in WVa106, Money Maker and Ailsa Craig, and a much more attenuated response in Micro-Tom. GA treatment maintained a robust correlation between cell size and ploidy that was common to all cultivars, and thus at the species level. Radial cell elongation was strongly stimulated by GA treatment in two cultivars only, WVa106 and Ailsa Craig. It was moderately increased in Micro-Tom and Money Maker, indicating a possible uncoupling between cell expansion and elongation. GA also enabled the cell divisions that produce new cell layers in the pericarp of all cultivars, in a way that suggests a different pathway from that regulating cell expansion. Overall, these results clarify our knowledge of the action of GA on the tomato pericarp cell pattern, and beyond on fruit growth in angiosperms. [ABSTRACT FROM AUTHOR]

Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) and severe congenital neutropenia type 4 (SCN4), associated with deficiencies of the glucose-6-phosphate transporter (G6PT/SLC37A4) and the phosphatase G6PC3, respectively, are the result of the accumulation of 1,5-anhydroglucitol-6-phosphate in neutrophils. This is an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol in blood. 1,5-AG is presumed to be reabsorbed in the kidney by a sodium-dependent-transporter of uncertain identity, possibly SGLT4/SLC5A9 or SGLT5/SLC5A10. Lowering blood 1,5-AG with an SGLT2-inhibitor greatly improved neutrophil counts and function in G6PC3-deficient and GSD1b patients. Yet, this effect is most likely mediated indirectly, through the inhibition of the renal 1,5-AG transporter by glucose, when its concentration rises in the renal tubule following inhibition of SGLT2. To identify the 1,5-AG transporter, both human and mouse SGLT4 and SGLT5 were expressed in HEK293T cells and transport measurements were performed with radiolabelled compounds. We found that SGLT5 is a better carrier for 1,5-AG than for mannose, while the opposite is true for human SGLT4. Heterozygous variants in SGLT5, associated with a low level of blood 1,5-AG in humans cause a 50–100% reduction in 1,5-AG transport activity tested in model cell lines, indicating that SGLT5 is the predominant kidney 1,5-AG transporter. These and other findings led to the conclusion that (1) SGLT5 is the main renal transporter of 1,5-AG; (2) frequent heterozygous mutations (allelic frequency > 1%) in SGLT5 lower blood 1,5-AG, favourably influencing neutropenia in G6PC3 or G6PT deficiency; (3) the effect of SGLT2-inhibitors on blood 1,5-AG level is largely indirect; (4) specific SGLT5-inhibitors would be more efficient to treat these neutropenias than SGLT2-inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Gliflozins have historically been indicated for type 2 diabetes in France. However, their efficacy has recently been demonstrated in heart failure and chronic kidney disease (CKD), with positive recommendations by Haute Autorité de Santé for gliflozin therapies in these indications. The study objective was to investigate the 5-year budget impact associated with the introduction of gliflozins in addition to standard therapy in people with CKD and elevated albuminuria, regardless of diabetes status, from the perspective of the French healthcare system. Methods: A budget impact model was developed to estimate the 5-year implications of incorporating gliflozins in the treatment of patients with CKD in France, using efficacy data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. Direct medical costs associated with drug acquisition and management, treatment-related adverse events, dialysis and kidney transplantation, and adverse clinical outcomes were considered. Market share forecasts were estimated from historical data and expert opinions. Event rates were derived from trial data, while cost data were sourced from published estimates. Results: The introduction of gliflozins was estimated to be cost saving compared to the no gliflozins scenario, with an expected cumulative 5-year budget impact of -€650 million, driven by slowed disease progression in patients treated with gliflozins, with fewer patients cumulatively progressing to end-stage kidney disease (84,526 vs. 92,062). This, in addition to fewer hospitalisations for heart failure and deaths from any cause, led to substantial medical care cost offsets (kidney-related: − €894 million; hospitalisation for heart failure: − €14.3 million; end-of-life care: − €17.3 million) to the additional drug acquisition (€273 million) and treatment-related adverse events costs (€2.98 million). Conclusion: In concert with early diagnosis and proactive management of CKD, the expansion of the gliflozin indications into the French CKD population presents the opportunity to reduce the substantial burden associated with cardio-renal complications which outweighs the additional cost of the new treatment. Infographic: [ABSTRACT FROM AUTHOR]

Yalimapo beach, near the Maroni River estuary in French Guiana, is an important turtle nesting site. The interaction of massive mud banks migrating alongshore from the distant Amazon River with discharge from the Maroni River generates strong beach morpho-sedimentary changes. The eventual degradation of the marine turtle nesting habitats resulting from these changes represents a threat to the offspring, and consequently, to the turtle population. Field operator counts of green and leatherback turtle nests were combined with high-resolution topographic measurements of the beach over four field surveys in 2012 and 2014 to map the topographic modifications susceptible to affect nesting on Yalimapo beach. We assumed that the survival of nests was at stake when the depth of sand between the egg chamber and the topographic surface (i.e. the top) of the beach was < 50 cm, and that beach surface lowering > 10 cm represented unfavourable conditions for nest safety with unequal nest survival across the beach. Erosion of the beach surface exceeding a depth of 50 cm therefore results in nest destruction. Digital elevation models were produced to quantify the topographic modification of nesting on Yalimapo beach and highlight the endangered nesting areas. As the modification of the beach is not linear, some sectors are more eroded than others, resulting in unequal nest survival across the beach. Overall, up to 40% of the nests were presumed destroyed over the 2 years of survey, but true losses would depend on the species and the preferential locations of their nesting habitats. The relatively unfavourable conditions that prevailed during the 2 years of the survey are consistent with persistent erosion of Yalimpao beach since 2011. This ongoing erosion could explain in part the drastic decline of the leatherback turtle population in western French Guiana over the period 2001–2018. The substrate quality and dynamics of the nesting beach in relation to the preferred nesting habitat of each species are therefore critical issues that should be considered in the conservation strategies of marine turtles. The beach nesting conditions of marine turtles in French Guiana, as elsewhere, could be further aggravated in the future by climate change effects, including sea-level rise. [ABSTRACT FROM AUTHOR]

Objectives: Parametric cardiac magnetic resonance (CMR) techniques have improved the diagnosis of pathologies. However, the primary tool for differentiating non-ST elevation myocardial infarction (NSTEMI) from myocarditis is still a visual assessment of conventional signal-intensity-based images. This study aimed at analyzing the ability of parametric compared to conventional techniques to visually differentiate ischemic from non-ischemic myocardial injury patterns. Methods: Twenty NSTEMI patients, twenty infarct-like myocarditis patients, and twenty controls were examined using cine, T2-weighted CMR (T2w) and late gadolinium enhancement (LGE) imaging and T1/T2 mapping on a 1.5 T scanner. CMR images were presented in random order to two experienced fully blinded observers, who had to assign them to three categories by a visual analysis: NSTEMI, myocarditis, or healthy. Results: The conventional approach (cine, T2w and LGE combined) had the best diagnostic accuracy with 92% (95%CI: 81–97) for NSTEMI and 86% (95%CI: 71–94) for myocarditis. The diagnostic accuracies using T1 maps were 88% (95%CI: 74–95) and 80% (95%CI: 62–91), 84% (95%CI: 67–93) and 74% (95%CI: 54–87) for LGE, and 83% (95%CI: 66–92) and 73% (95%CI: 53–87) for T2w. The accuracies for cine (72% (95%CI: 52–86) and 60% (95%CI: 38–78)) and T2 maps (62% (95%CI: 40–79) and 47% (95%CI: 28–68)) were significantly lower compared to the conventional approach (p < 0.001 and p < 0.0001). Conclusions: The conventional approach provided a reliable visual discrimination between NSTEMI, myocarditis, and controls. The diagnostic accuracy of a visual pattern analysis of T1 maps was not significantly inferior, whereas the diagnostic accuracy of T2 maps was not sufficient in this context. Clinical relevance statement: The ability of parametric compared to conventional CMR techniques to visually differentiate ischemic from non-ischemic myocardial injury patterns can avoid potentially unnecessary invasive coronary angiography and help to shorten CMR protocols and to reduce the need of gadolinium contrast agents. Key Points: •A visual differentiation of ischemic from non-ischemic patterns of myocardial injury is reliably achieved by a combination of conventional CMR techniques (cine, T2-weighted and LGE imaging). •There is no significant difference in accuracies between visual pattern analysis on native T1 maps without providing quantitative values and a conventional combined approach for differentiating non-ST elevation myocardial infarction, infarct-like myocarditis, and controls. •T2 maps do not provide a sufficient diagnostic accuracy for visual pattern analysis for differentiating non-ST elevation myocardial infarction, infarct-like myocarditis, and controls. [ABSTRACT FROM AUTHOR]

UV-induced processes are commonly studied in acetylacetone analogues. In this contribution, we revisit the existing work on the photoisomerization process in some of the fluorinated analogues of acetylacetone, i.e., trifluoroacetylacetone (F3-acac) and hexafluoroacetylacetone (F6-acac). We performed selective UV laser excitation of these molecules trapped in soft cryogenic matrices, namely neon and para-hydrogen, and probed by vibrational spectroscopy. Clear spectroscopy of 3 isomers of F6-acac and 6 isomers of F3-acac is obtained, including the first characterization of a second open enol isomer of hexafluoroacetylacetone. In addition, we present the electronic absorption spectra of both molecules in cryogenic matrices before and after specific UV irradiations, giving new data on the electronic transitions of photoproducts. Vibrational and electronic experimental results are analyzed and discussed within comparisons with DFT and TD-DFT calculations. Our findings contribute to a deeper understanding of the photoisomerization process in these molecules after electronic excitation in gas and condensed phase. [ABSTRACT FROM AUTHOR]

Genetic diversity sustains species adaptation. However, it may also support key ecosystems functions and services, for example biomass production, that can be altered by the worldwide loss of genetic diversity. Despite extensive experimental evidence, there have been few attempts to empirically test whether genetic diversity actually promotes biomass and biomass stability in wild populations. Here, using long-term demographic wild fish data from two large river basins in southwestern France, we demonstrate through causal modeling analyses that populations with high genetic diversity do not reach higher biomasses than populations with low genetic diversity. Nonetheless, populations with high genetic diversity have much more stable biomasses over recent decades than populations having suffered from genetic erosion, which has implications for the provision of ecosystem services and the risk of population extinction. Our results strengthen the importance of adopting prominent environmental policies to conserve this important biodiversity facet. Experimental evidence indicates that genetic diversity can promote biomass stability, but does this process occur in wild populations? Focusing on three freshwater fish species from two river basins in southwestern France, this study shows that the biomass of genetically diversified populations has been more stable in recent decades than populations that have suffered from genetic erosion. [ABSTRACT FROM AUTHOR]