Continuous low-level dietary exposure to glyphosate elicits dose and sex-dependent synaptic and microglial adaptations in the rodent brain.

Prolonged exposure to low levels of dietary contaminants is a context in modern life that could alter organ physiology gradually. Here, we aimed to investigate the impact of continuous exposure to acceptable daily intake (ADI) and non-observable adverse effect level (NOAEL) of glyphosate from gestation to adulthood using C57BL/6J mice and incorporating these levels into their food pellets. From adulthood, we analyzed neurophysiological and neuro-glia cellular adaptations in male and female animals. Using ex-vivo hippocampal slice electrophysiology, we found a reduced efficacy of Schaffer collateral-to-CA1 excitatory synapses in glyphosate-exposed dietary conditions, with ADI and NOAEL dose-dependent effects. Short-term facilitation of excitatory synaptic transmission was specifically increased in NOAEL conditions, with a predominant influence in males, suggesting a reduced probability of neurotransmitter release. Long-term synaptic potentiation (LTP) was decreased in NOAEL-exposed mice. Next, we explore whether these neurophysiological modifications are associated with neuro-glia changes in the somatosensory cortex and hippocampus. High-resolution confocal microscopy analyses unveil a dose-dependent increased density of excitatory Vglut1+ Homer1+ synapses. Microglial Iba1+ cells displayed a shortening of their ramifications, a sign of cellular reactivity that was more pronounced in males at NOAEL levels. The morphology of GFAP+ astrocytes was generally not modified. Finally, we asked whether mouse-specific cross-correlations exist among all data sets generated. This examination included the novel object recognition (NOR) test performed before ex vivo functional and immunohistochemical examinations. We report a negative linear regression between the number of synapses and NOR or LTP maintenance when plotting ADI and NOAEL datasets. These results outline synaptic and microglial cell adaptations resulting from prenatal and continuous dietary low levels of glyphosate, discernible in, but not limited to, adult males exposed to the NOAEL. We discuss the potential significance of these findings to real-world consumer situations and long-term brain resilience.

Life in a Central European warm-temperate to subtropical open forest: Paleoecology of the rhinocerotids from Ulm-Westtangente (Aquitanian, Early Miocene, Germany).

The Ulm-Westtangente locality has yielded the most abundant vertebrate fauna from the Aquitanian stage in Germany. Its dating to the Mammal Neogene Zone 2a, a turnover in Cenozoic climate, makes it a crucial source for the understanding of faunal, paleoecological and paleoenvironmental specifics of the European Aquitanian. However, while most taxa from Ulm-Westtangente have been studied, little to no research has been conducted on the large herbivores, particularly on the two rhinocerotids Mesaceratherium paulhiacense and Protaceratherium minutum. Here, we used a multi-proxy approach to investigate the paleoecology of these two species. The remains of the smaller species P. minutum (438 to 685 kg) are twice as abundant as those of the larger M. paulhiacense (1389 to 2327 kg), but both display a similar age structure (~ 10% of juveniles, 20% of subadults and 70% of adults), mortality curves, and mild prevalence of hypoplasia (~ 17%). Results from dental mesowear, microwear, and carbon isotopes indicate different feeding preferences: both were C3 feeders but M. paulhiacense had a more abrasive diet and was probably a mixed feeder. Our study on rhinocerotids also yielded new paleoenvironmental insights, such as the mean annual temperature (15.8 °C) and precipitation (317 mm/year) suggesting rather warm and dry conditions.

Impact of saponification and silver-nitrate purification on lacustrine alkenone distributions and alkenone-based indices.

A growing interest in lacustrine alkenones as a proxy for continental paleotemperature reconstructions accompanied important methodological improvements over the past two decades. New gas chromatography (GC) columns were used for alkenone analysis, that drastically improved alkenone separation, especially for freshwater lakes. However, these recent advances are sometimes not sufficient in separating compounds that interfere with alkenones in the resulting chromatograms and concurrently, new chemical procedures were implemented to further clean up the samples. Here we investigate the impact of two clean-up procedures, saponification and silver-nitrate purification, on alkenone distribution, alkenone quantification, and C37 alkenone-based indices, including the U37K index. The silver-nitrate purification modified the C37 alkenone distribution and thus the C37 alkenone-based indices, especially the U37K index, in 6 out of the 9 studied samples by further retaining alkenones with more double bonds. These changes would result on an average error of 3 °C in reconstructed temperatures. Saponification also influenced the C37 alkenone distribution mainly by removing co-eluting compounds, thereby improving the quality of the results. Both saponification and purification resulted in the reduction of the C37 alkenone concentration by almost half. Clean-up steps should thus be used carefully, paying particular attention to any change in alkenone distribution and concentration. Limiting the use of additional clean-up steps reduces the risk of modifying the alkenone distribution.

Dietary Amino Acid Source Elicits Sex-Specific Metabolic Response to Diet-Induced NAFLD in Mice.

SCOPE: Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, the metabolic and hepatic effects of dietary amino acid (AA) source is assessed in Western diet (WD)-induced NAFLD in male and female mice. METHODS AND RESULTS: The AA source is either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD display glucose intolerance, fasting hyperglycemia, and insulin-resistance and develop NAFLD associated with changes in hepatic gene expression and microbiota dysbiosis. In contrast, males fed the AA-based WD show no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females are protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. CONCLUSIONS: Free dietary AA intake prevents the unhealthy metabolic outcomes of a WD preferentially in male mice.

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism.

Background & Aims: The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated. Methods: The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle. Results: Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline. Conclusions: More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury. Impact and implications: CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.

Design, Synthesis, and Evaluation of Neomycin-Imidazole Conjugates for RNA Cleavage.

Targeting RNA with synthetic small molecules attracted much interest during recent years as a particularly promising therapeutic approach in a large number of pathologies spanning from genetic disorders, cancers as well as bacterial and viral infections. In this work, we took advantage of a known RNA binder, neomycin, to prepare neomycin-imidazole conjugates mimicking the active site of ribonuclease enzymes able to induce a site-specific cleavage of HIV-1 TAR RNA in physiological conditions. These new conjugates were prepared using a straightforward synthetic methodology and were studied for their ability to bind the target, inhibit Tat/TAR interaction and induce selective cleavage using fluorescence-based assays and molecular docking. We found compounds with nanomolar affinity, promising cleavage activity and the ability to inhibit Tat/TAR interaction with submicromolar IC50 s.

Influence of exposure conditions on helium transport and bubble growth in tungsten.

Helium diffusion, clustering and bubble nucleation and growth is modelled using the finite element method. The existing model from Faney et al. (Model Simul Mater Sci Eng 22:065010, 2018; Nucl Fusion 55:013014, 2015) is implemented with FEniCS and simplified in order to greatly reduce the number of equations. A parametric study is performed to investigate the influence of exposure conditions on helium inventory, bubbles density and size. Temperature is varied from 120 K to 1200 K and the implanted flux of 100 eV He is varied from [Formula: see text] to [Formula: see text]. Bubble mean size increases as a power law of time whereas the bubble density reaches a maximum. The maximum He content in bubbles was approximately [Formula: see text] He at [Formula: see text]. After 1 h of exposure, the helium inventory varies from [Formula: see text] at low flux and high temperature to [Formula: see text] at high flux and low temperature. The bubbles inventory varies from [Formula: see text] bubbles m[Formula: see text] to [Formula: see text] bubbles m[Formula: see text]. Comparison with experimental measurements is performed. The bubble density simulated by the model is in quantitative agreement with experiments.

Cost-effectiveness of screening of coronary artery disease in patients with type 2 DIABetes at a very high cardiovascular risk (SCADIAB study) rational and design.

BACKGROUND: Screening for coronary artery disease (CAD) remains broadly performed in patients with type 2 diabetes (T2DM), although the lack of evidence. We conduct a real-world evidence (RWE) study to assess the risk of major clinical outcomes and economic impact of routine CAD screening in T2DM individuals at a very high cardiovascular risk. METHODS: SCADIAB is a comparative nationwide cohort study using data from the French National Health Data System. The main inclusion criteria are: age ≥ 40 years, DT2 diagnosed for ≥ 7 years, with ≥ 2 additional cardiovascular risk factors plus a history of microvascular or macrovascular disease, except CAD. We estimated ≥ 90,000 eligible participants for our study. Data will be extracted from 01/01/2008 to 31/12/2019. Eligible participants will be identified during a first 7-year selection period (2008-2015). Each participant will be assigned either in experimental (CAD screening procedure during the selection period) or control group (no CAD screening) on 01/01/2015, and followed for 5 years. The primary endpoint is the incremental cost per life year saved over 5 years in CAD screening group versus no CAD screening. The main secondary endpoints are: total 5-year direct costs of each strategy; incidence of major cardiovascular (acute coronary syndrome, hospitalization for heart failure, coronary revascularization or all-cause death), cerebrovascular (hospitalization for transient ischemic attack, stroke, or carotid revascularization) and lower-limb events (peripheral artery disease, ischemic diabetic foot, lower-limb revascularization or amputation); and the budget impact for the French Insurance system to promote the cost-effective strategy. Analyses will be adjusted for a high-dimension propensity score taking into account known and unknown confounders. SCADIAB has been funded by the French Ministry of Health and the protocol has been approved by the French ethic authorities. Data management and analyses will start in the second half of 2021. DISCUSSION: SCADIAB is a large and contemporary RWE study that will assess the economic and clinical impacts of routine CAD screening in T2DM people at a very high cardiovascular risk. It will also evaluate the clinical practice regarding CAD screening and help to make future recommendations and optimize the use of health care resources. Trial registration ClinicalTrials.gov Identifier: NCT04534530 ( https://clinicaltrials.gov/ct2/show/NCT04534530 ).

Feasibility of chitosan crosslinked with genipin as biocoating for cellulose-based materials.

Crosslinking with genipin increases the acidic stability of chitosan-based materials, opening an opportunity to explore new applications. In this work, the viability of using chitosan-genipin solutions on cellulose-based materials coating was studied. Non-calendered paper and cardboard were used as raw materials. Different number of chitosan-genipin coating layers (1, 3, 6, 20, and 30) were applied and their influence on the materials mechanical, physicochemical, and barrier properties was studied. The small thickness and basis weight of non-calendered paper resulted in an inefficient adhesion of chitosan-genipin coating to the cellulose fibers. However, in cardboard, chitosan-genipin created a dense layer onto the cellulosic-fibers surface without impairing their mechanical properties. It conferred a greenish color, whose intensity increased with the layers number. The chitosan-genipin coating decreased the cardboard air and water vapor permeability up to 71 % and 52 %, respectively, and acted as a physical barrier for cardboard compounds leaching, being suitable for covering cellulose-based materials.

Tailoring Rheological Properties of Thermoresponsive Hydrogels through Block Copolymer Adsorption to Cellulose Nanocrystals.

This study investigates the adsorption of a block copolymer composed of a poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) cationic polyelectrolyte and a poly(di(ethylene glycol) methyl ethermethacrylate) (PDEGMA) on oxidized cellulose nanocrystals (TO-CNCs) to produce hydrogels. PDMEAMA- b-PDEGMA was synthesized by atom-transfer radical polymerization. The extent and dynamics of the adsorption of PDMAEMA- b-PDEGMA on TO-CNCs were determined by electromechanical microbalance and optical techniques. Electrostatic adsorption was identified on TO-CNCs with the quaternized block copolymer. Small-angle neutron scattering experiments were performed to investigate the polymer behavior on the TO-CNC surfaces. Depending on the temperature, block copolymer induces the aggregation of nanocrystals after adsorption by connecting CNCs bundles with block copolymer chains. A reversible liquid-to-gel transition, triggered by temperature, was clearly detected by rheological measurements for the copolymer-CNC mixtures. At the optimal copolymer to CNC ratio the viscosity increased by 4 orders of magnitude at low shear rates. These stimuli-responsive CNC-based materials could be used as injectable biomedical systems.

[Orthognathic surgery of mandibular asymmetry: which results can we expect with and without chin wing? A cohort out of 51 cases]. / Traitement ortho-chirurgical de la latéromandibulie : quels résultats escompter avec et sans chirurgie du contour mandibulaire ? Une étude de cohorte sur 51 cas.

INTRODUCTION: The aim of this retrospective cohort is to evaluate the amount of postsurgical correction of soft and hard tissues in patients with mandibular asymmetries and to compare the results with and without surgery of the lower mandibular contour (chin wing…). MATERIAL AND METHOD: Mandibular asymmetries cases of three surgeons were systematically included. The angles of deviation of the chin, bi-commissural, bi-gonic and occlusal were measured on face photography and radiography. A pre and post-surgical comparison was performed and the amount of correction was analyzed via the Wilcoxon statistical test. RESULTS: 51 patients (44 women and 7 men) were included. After surgery, the correction is significant for all measurements with an improvement of 44 to 60% depending on the measured angles. No patient is normalized but the small initial mandibular asymmetries are the closest to normal after surgery. The correction of the bi-commissural angle is controlled without being optimal (60% correction). The difficulty remains the horizontalization of the bi-gonial plan which is only corrected at 45%. Patients with mandibular margin surgery (chin wing…) showed the greatest improvement in bi-gonial (p = 0.0142) and occlusal (p = 0.0154) angles. CONCLUSION: If surgery allows a significant correction of facial dissymmetry, this is not complete. Surgical procedures on the lower edge of the mandible such as the chin wing could provide a better correction especially for bi-gonial and occlusal angles.

Spectroscopic Measurements of Methane Solid-Gas Equilibrium Clapeyron Curve between 40 and 77 K.

The infrared gas-phase absorption spectrum of methane was used to determine its Clapeyron solid-gas equilibrium curve in the 40-77 K temperature range. For comparative purposes and to obtain more reliable results, two different optical experimental setups were used. At higher temperatures (53-77 K), a single pass cryogenically cooled cell was coupled to a standard low-resolution Fourier transform infrared spectrometer. The second system was a state-of-the-art vertical-external-cavity surface-emitting laser tunable source operating at around 2.3 µm, combined with a 7 m path Herriott cell, to record methane absorption features down to 40 K. From the measurements, the vapor pressure curve ln( p/Pa) = -(1191.92 ± 8.92)/( T/K) + (22.49 ± 0.16) was derived in the range 40-77 K. This corresponds to a value of 9910 ± 75 J mol-1 for the sublimation enthalpy. The relation was validated down to 40 K, increasing our knowledge of the saturation pressure by 2 orders of magnitude. Data were compared with available pressure measurements from the literature, obtained by manometric or mass spectrometry techniques, and the sublimation enthalpy was compared with a thermodynamic approach based on heat capacity measurements in the solid and gas phases.

Correction: Thrombospondin-targeting TAX2 peptide impairs tumor growth in preclinical mouse models of childhood neuroblastoma.

The authors "Revital Rattenbach", "ltschak Lamensdorf", and "Celine Martin" were not included in the author list of this published article however should be considered to be authors since they contributed substantially to the work. The updated author list of this article can be found in the associated correction.

Adsorption versus grafting of poly(N-Isopropylacrylamide) in aqueous conditions on the surface of cellulose nanocrystals.

This study proposes a grafting strategy of thermo-sensitive amine-terminated oligomers of Poly(N-Isopropylacrylamide) (Pnipam2500) onto the surface of Cellulose Nanocrystals (CNCs). Pnipam2500 grafting in aqueous condition via peptidic coupling was explored to obtain CNC hydrogel with thermo-reversible aggregation and new colloidal properties. A discussion between grafting vs adsorption /presence of the Pnipam2500 is proposed. A large range of experimental techniques was used to investigate the properties of the CNC decorated with polymer and to confirm the grafting. Elemental analysis, infrared spectroscopy, solid state NMR and conductometric titration of washed CNC-g-Pnipam2500 demonstrate that at least a part of Pnipam2500 was covalently bonded with CNC. A thermo-reversible aggregation was observed by Dynamic Light Scattering experiments and thermo-sensitive behavior is observed by rheological experiments. For grafted polymer the viscosity increases from 0.008 to 40 Pa∙s at low shear rate when the LCST is reached, whereas, in the case of polymer adsorption, the viscosity increases only from 0.002 to 0.3 Pa∙s. This thermo-reversible, bio-based and biocompatible system paves the way for the design of injectable hydrogel and biomedical nanocomposite materials.

[Discontinuation of Orthodontic Treatment: what are the early predictive factors?] / Abandons de traitement orthodontique : quels sont les facteurs predictifs precoces ?

INTRODUCTION: Discontinuation of orthodontic treatment has iatrogenic, psychological, ergonomic and financial consequences. The objective of this study was to investigate early risk factors (prior to installation) of discontinuation of orthodontic treatment. MATERIALS AND METHODS: We performed a case-control study between a group of patients who dropped their orthodontic treatment ("A") and a randomly selected group of patients who had completed their orthodontic treatment ("NA"). The two groups were compared, with descriptive, uni and multivariate analyzes. The risk factors assessed were age, gender, socioeconomic status, type of treatment, dysmorphism, malocclusion, need for treatment, compliance. RESULTS: In the dropout group 55 patients were included ("A") and 100 in the non-abandoned ("NA") group randomly selected. The subject at risk of abandonment was a girl of less than 11 years of age with a low socio-economic level with antero-posterior and vertical skeletal dysmorphisms, a molar class II, a teeth crowding, a small aesthetic prejudice or, on the contrary, very important, complex treatment (with extractions or with surgery) and having delays or missed appointments before the installation of the orthodontic appliance. CONCLUSION: Patients' motivation needs to be strengthened for both extremes: treatments that appear simple and conversely for complex cases requiring strong cooperation.

[Mandibular asymmetry: determination of a reliable skin measurement technique]. / Latéromandibulie : détermination d'une mesure cutanée fiable.

INTRODUCTION: Clinical measurements in the frontal view underevaluate chin deviation in mandibular asymmetry. The aim of this descriptive study is to search for a reliable method of measuring deviant chins using a facial X-ray as reference. MATERIAL AND METHOD: Seventy patients with mandibular asymmetry who had consulted a maxillofacial surgeon were systematically included. Age, sex, cephalometric characteristics, reasons for patient consultation and type of surgery were collected. Two cephalometric methods were tested with respect to the medial sagittal plane (PSM) to compare the assessment of mandibular asymmetry on soft tissue and by cephalometry. RESULTS: On average, the patients selected were young (26 years +/- 9), women (75% of cases), presented open bite (average FMA: 28° +/- 8°), a skeletal class III tendency, a left-side shift of the chin (63% of cases). They consulted for both aesthetic and functional reasons (51% of cases) and required bimaxillary surgery (66% of cases). Comparison between the photographic angle (formed by the PSM and the line passing through the nasion and reaching the chin point) and the radiographic angle (formed by the PSM and the line passing through the Crista Galli process and the bony chin point angle) showed no significant difference (p = 0.937) and is thus reliable.

Record of Nile seasonality in Nubian neonates.

The oxygen isotope compositions of bones (n = 11) and teeth (n = 20) from 12 Sudanese individuals buried on Sai Island (Nubia) were analysed to investigate the registration of the evolution of the Nile environment from 3700 to 500 years BP and the potential effects of ontogeny on the oxygen isotope ratios. The isotopic compositions were converted into the composition of drinking water, ultimately originating from the Nile. δ18O values decrease during ontogeny; this is mainly related to breastfeeding and physiology. Those of neonates present very large variations. Neonates have a very high bone turnover and are thus able to record seasonal δ18O variations of the Nile waters. These variations followed a pattern very similar to the present one. Nile δ18O values increased from 1.4 to 4.4 ‰ (Vienna Standard Mean Ocean Water) from the Classic Kerma (∼3500 BP) through the Christian period (∼1000 BP), traducing a progressive drying of Northeast Africa.

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.

Screening strategy to generate cell specific recombination: a case report with the RIP-Cre mice.

Conditional gene knockout technology is a powerful tool to study the function of a gene in a specific tissue, organ or cell lineage. The most commonly used procedure applies the Cre-LoxP strategy, where the choice of the Cre driver promoter is critical to determine the efficiency and specificity of the system. However, a considered choice of an appropriate promoter does not always protect against the risk of unwanted recombination and the consequent deletion of the gene in other tissues than the desired one(s), due to phenomena of non-specific activation of the Cre transgene. Furthermore, the causes of these phenomena are not completely understood and this can potentially affect every strain of Cre-mice. In our study on the deletion of a same gene in two different tissues, we show that the incidence rate of non-specific recombination in unwanted tissues depends on the Cre driver strain, ranging from 100%, rendering it useless (aP2-Cre strain), to ~5%, which is still compatible with their use (RIP-Cre strain). The use of a simple PCR strategy conceived to detect this occurrence is indispensable when producing a tissue-specific knockout mouse. Therefore, when choosing the Cre-driver promoter, researchers not only have to be careful about its tissue-specificity and timing of activation, but should also include a systematical screening in order to exclude mice in which atypical recombination has occurred and to limit the unnecessary use of laboratory animals in uninterpretable experiments.