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Tin(IV) oxide is a very attractive material with promising applications in new-generation devices. In this work, we reported a powerful but cheap and sustainable approach for preparing SnO2 nanocrystals based on the use of a non-thermal plasma burning in humid air. Physicochemical characterizations by Raman, Infrared and X-ray photoelectron spectroscopies revealed the presence of few hydroxyl groups and few oxygen vacancy (Ov) defects in the material obtained after 30 min under plasma (hereafter called NC-Sn30). By increasing the synthesis duration up to 120 min, the number of Ov decreased while the material became more hydroxylated. Furthermore, the material obtained after 120 min under plasma (i.e. NC-Sn120) was more crystallized. When tested as photocatalyst in iodide oxidation, NC-Sn120 showed lowest activity compared to NC-Sn30. After further calcination under air or nitrogen atmosphere at 550 °C, the crystallites size of pristine materials increased and their specific surface area values which were 190 and 206 m2 g−1 for NC-Sn30 and NC-Sn120, respectively, dropped to about 30 m2 g−1. Meanwhile, the Ov density increased leading to the rise of the valence band maximum and the decrease of the band gap energy of materials. The calcined samples with higher Ov density showed better photocatalytic performances, as the rate of formation of reactive iodine species (i.e. I3−, I2) normalized with the surface area of calcined photocatalysts was about 4 times higher than that of their corresponding pristine SnO2. These results open the door to a new route synthesis of SnO2 nanocrystals with tunable “O” vacancies density and photocatalytic performances.

International audience; A safe, cheap and straightforward on-demand hydrogen generation method has been developed using a polymethylhydrosiloxane (PMHS) emulsion as a hydride donor in a highly alkaline solution without the need of any other harmful catalyst. This system was used as a chemical blowing agent in the preparation of kraft black liquor foams.

Understanding the emergence of lymphoid committed cells from multipotent progenitors (MPP) is a great challenge in hematopoiesis. To gain deeper insight into the dynamic expression changes associated with these transitions, we report the quantitative transcriptome of two MPP subsets and the common lymphoid progenitor (CLP). While the transcriptome is rather stable between MPP2 and MPP3, expression changes increase with differentiation. Among those, we found that pioneer lymphoid genes such as Rag1, Mpeg1, and Dntt are expressed continuously from MPP2. Others, such as CD93, are CLP specific, suggesting their potential use as new markers to improve purification of lymphoid populations. Notably, a six-transcription factor network orchestrates the lymphoid differentiation program. Additionally, we pinpointed 24 long intergenic-non-coding RNA (lincRNA) differentially expressed through commitment and further identified seven novel forms. Collectively, our approach provides a comprehensive landscape of coding and non-coding transcriptomes expressed during lymphoid commitment.

This study describes concentrations of Pregnancy Associated Glycoproteins (PAG), progesterone (P4), estrone (E1) and estrone-sulfate (E1S) in American Bison sera. In 2 ranches, mature American Bison were sampled once a year for 2 yr. Subsequent American Bison cows calving days were reported. PAG concentration was determined by Radio-Immuno Assay, whereas P4, E1 and E1S were assayed using Liquid Chromatography and Mass Spectrometry. Concentrations were compared between American Bison bulls (B, n = 7), Nonpregnant cows (NP, n = 32), first (1TP, n = 3), second (2TP, n = 26) and third (3TP, n = 15) trimester of pregnancy. Seven American Bison bulls and 92 cows were sampled, 51 calved during these 2 yr. Calving occurred mostly in spring (74.5%), but also in summer (13.7%) and fall (11.8%). PAG and P4 were higher in 2TP and 3TP than B and NP (P0.0001). P4 was non-basal in B and NP. E1 and E1S were correlated (P0.0001; r = 0.76) and increased in 2TP and 3TP when compared with B and NP (P0.01). Moreover, E1S was higher in 3TP than in 2TP (P0.0001) and correlated to pregnancy day (P0.0001; r = 0.60). Breeding American Bison in Belgium induces a calving seasonality loss. P4 slowly increases in 1TP and remains steady and high in 2 and 3TP. P4 non-basal and variable concentrations in B or NP disable its use as gestation marker. American Bison produce PAG in the 2 and 3TP, but Estrone-sulfate assay seems to be the best pregnancy marker during the 2 last trimesters as it could help to estimate the gestation period.

Background Fluid overload is frequent among hemodialysis (HD) patients. Dialysis therapy itself may favor sodium imbalance from sodium dialysate prescription. As on-line hemodiafiltration (OL-HDF) requires large amounts of dialysate infusion, this technique can expose to fluid accumulation in case of a positive sodium gradient between dialysate and plasma. To evaluate this risk, we have analyzed and compared the fluid status of patients treated with HD or OL-HDF in French NephroCare centers. Method This is a cross-sectional and retrospective analysis of prevalent dialysis patients. Data were extracted from the EUCLID5 data base. Patients were split in 2 groups (HD and OL-HDF) and compared as whole group or matched patients for fluid status criteria including predialysis relative fluid overload (RelFO%) status from the BCM®. Results 2242 patients (age 71 years; female: 39%; vintage: 38 months; Charlson index: 6) were studied. 58% of the cohort were prescribed post-dilution OL-HDF. Comparing the HD and OL-HDF groups, there was no difference between HD and OL-HDF patients regarding the predialysis systolic BP, the interdialytic weight gain, the dialysate-plasma sodium gradient, and the predialysis RelFO%. The stepwise logistic regression did not find dialysis modality (HD or OL-HDF) associated with fluid overload or high predialysis systolic blood pressure. In OL-HDF patients, monthly average convective or weekly infusion volumes per session were not related with the presence of fluid overload. Conclusions In this cross-sectional study we did not find association between the use of post-dilution OL-HDF and markers of fluid volume excess. Aligned dialysis fluid sodium concentrations to patient predialysis plasma sodium and regular monitoring of fluid volume status by bioimpedance spectroscopy may have been helpful to manage adequately the fluid status in both OL-HDF and HD patients.

The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo[1,5-a]quinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.

Microporous activated carbon pellets have been prepared from date stone without the use of a binder. These pellets were tested as electrodes for capacitive deionization. The activation process involved two steps. First, a pyrolysis of the date stone was conducted to a temperature of 1000 °C under nitrogen flow. Then, the obtained carbon monoliths were physically activated at 900 °C under CO2 flow. Elemental analysis, BET, SEM, mercury porosimetry, conductivity measurement and electrochemical performance testing carried out to characterize the structure and the properties of activated carbon pellets. The activated carbon exhibited predominant microporosity with a specific surface area of 896 m2 g−1 which leads to the highest specific capacitance 270.90 F/g. The performance of activated carbon electrode at 900 °C in capacitive deionization (CDI) test was also examined.

Huntington’s disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington’s disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington’s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington’s disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington’s disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington’s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

International audience; Background: Dominant theoretical models consider that attentional biases (AB) towards alcohol-related stimuli play a key role in the development and maintenance of alcohol use disorder (AUD). Their assessment has however showed high inconsistencies and has been mostly based on unreliable behavioral measures. This study evaluated the presence and extent of alcohol-related AB in recently detoxified inpatients with severe AUD by combining the visual probe task (VPT) paradigm with eye-tracking measures, known to improve the VPT reliability in subclinical populations.Methods: We recruited 24 patients and 27 matched healthy controls. They performed the VPT (measuring reaction time when processing visual targets preceded by alcoholic and matched non-alcoholic pictures) combined with eye-tracking measures (dwell time, first fixation direction/duration, second fixation direction) during two sessions. Estimates of internal consistency, split-half reliability, and test-retest reliability were measured.Results: Patients showed shorter dwell time for alcohol cues (p = .004, d=.853) and reduced number of fixations towards alcohol after a first fixation on non-alcohol cues (p = .012, d=.758) compared to controls. These findings suggest the presence of alcohol-related avoidance AB in detoxified patients with severe AUD. The VPT achieved excellent reliability for these eye-tracking measures. Reaction times and first fixation measures did not indicate any AB pattern and showed poor reliability.Conclusions: The VPT, when combined with dwell time and second fixation direction, constitutes a reliable method for assessing AB in detoxified patients. It showed the presence of an alcohol-related avoidance bias in this clinical population, in contradiction with the approach bias predicted by theoretical models.

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.

Lyl1 encodes a hematopoietic- and endothelial-specific bHLH transcription factor. Lyl1-deficient mice are viable, but they display mild hematopoietic and vascular defects. Specifically, LYL1 is required for the maturation and stabilization of blood vessel endothelial adherens junctions. Here, we report that young adult Lyl1−/− mice exhibit transient overweight associated with general expansion of adipose tissue, without signs of metabolic disorder and unrelated to food intake. The increased fat tissue development in Lyl1−/− mice resulted from earlier differentiation of adipose stem cells (ASCs) into adipocytes through noncell autonomous mechanisms. Specifically, we found that in Lyl1−/− mice, the adipose tissue vascular structures are immature, as indicated by their high permeability, reduced coverage by pericytes, lower recruitment of VE-cadherin and ZO1 at cell junctions, and more prone to angiogenesis. Together, our data show that in Lyl1−/− mice, the impaired vascular compartment of the adipose niche promotes ASC differentiation, leading to early adipocyte expansion and premature ASC depletion. Our study highlights the major structural role of the adipose tissue vascular niche in coordinating stem cell self-renewal and differentiation into adipocytes.

International audience; Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

International audience; Although vitamin D acts in various biological processes, it plays a critical role in the maintenance of bone health, and regulates calcium homeostasis. In humans and rodents, the main tissues involved in vitamin D metabolism are the liver and the kidneys, however it has been shown that the testis has strongly participated in its bioactivation. Indeed, in these different species, enzymes metabolizing vitamin D (CYP27A1, CYP27B1 and CYP2R1) have been demonstrated in this tissue. Moreover, men with hypogonadism have shown a decrease in circulating levels of vitamin D. In equine species, the castration of males is a regular practice to reduce the behavior of stallions deemed too aggressive. Castration is carried out at various ages: in foals during their growth or in adulthood once they have reached their optimum size. Although horses exhibit atypical vitamin D metabolism with low circulating levels of vitamin D, it was suggested that testis may contribute to its activation as has been described in rodents and humans; castration could therefore be likely to affect its metabolism. In this study, blood levels of bioactive form of vitamin D (1 α,25[OH] 2 vitamin D 3 ) were measured before and after castration at different ages: 1 wk, after puberty (2 yr) and at adulthood (6 yr). The gene expression of enzymes involved in vitamin D metabolism has been sought in the testis of different experimental groups. No change in bioactive vitamin D3 levels was observed after castration regardless of the age at the time of surgery. The exceptional status of equine species is confirmed with a low or a lack of testis contribution to vitamin D metabolism, regardless of testicular development. This is demonstrated by a low or a lack of signal from enzymes involved in vitamin D bioactivation. Therefore, horses constitute a unique model in comparative endocrinology.

This report describes an option to modulate the testicular function of wild horses and field methods to assess it. Non-surgical castration of a captive wild Przewalski's stallion with anti-gonadotropin-releasing hormone (GnRH) immunization was performed by sub-cutaneous injection of two doses of 450 μg (3 ml) of GnRH conjugated to diphtheria toxin, further repeated every 6 months. Semen quality was assessed after collection by electro-ejaculation under general anesthesia. Endocrine and behavioral consequences were studied during a 2-year follow-up period. The procedure of electro-ejaculation was safe and effective to collect spermatozoa. Motility was low but was improved by a significant dilution of sample (1v/4v−1v/5v) after collection. Immuno-neutering resulted in a decrease of the total spermatozoa number and motility 1 month after primary vaccination. However, infertility could not yet be guaranteed. Six months post-vaccination, serum testosterone concentrations had decreased and the treated stallion had lost his harem stallion role. Moreover, at the same time, the total spermatozoa number was near zero with no motile spermatozoa, and offspring was no longer observed. As a conclusion, electro-ejaculation under general anesthesia is suitable on wild horses to obtain spermatozoa that should be washed or largely diluted before use for artificial insemination (AI) programs. Anti-GnRH immuno-neutering protocol led to a dramatic decrease of spermatozoa number, motility, and testosterone production. This also induced deep changes in the social structure of the band. Such technique could be considered as an alternative to surgical castration in wild horses.

The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over the past decades. We described here the preparation of new compounds based on the 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions of the quinoxaline moiety were screened to introduce novel substituents in order to study their influence on the biological activity. Several alkylamino or alkyloxy groups were also considered to replace the methylamine of our first generation of Imiqualines. Imidazo[1,2-a]pyrazine derivatives were also designed as potential minimal structure. The investigation on A375 melanoma cells displayed interesting in vitro low nanomolar cytotoxic activity. Among them, 9d (EAPB02303) is particularly remarkable since it is 20 times more potent than vemurafenib, the reference clinical therapy used on BRAF mutant melanoma. Contrary to the first generation, EAPB02303 does not inhibit tubulin polymerization, as confirmed by an in vitro assay and a molecular modelisation study. The mechanism of action for EAPB02303 highlighted by a transcriptomic analysis is clearly different from a panel of 12 well-known anticancer drugs. In vivo EAPB02303 treatment reduced tumor size and weight of the A375 human melanoma xenografts in a dose-dependent manner, correlated with a low mitotic index but not with necrosis.

International audience; Physiopathology of myelodysplastic syndrome (MDS) remains poorly understood and the role of the microenvironment is increasingly highlighted. Recent studies in mouse models demonstrate that abnormalities of mesenchymal stromal cells (MSC) contribute to the physiopathology of MDS. In particular, genetic deletion of dicer1, a gene encoding a type III RNase essential for the genesis of miRNA, in murine MSC-derived osteoprogenitors led to a pathological microenvironment generating myelodysplastic features in hematopoietic progenitors and ultimately leading to acute myeloid leukemia [1]. In human, there is an increased susceptibility to senescence of the MDS mesenchymal stem cells and defects in the support properties of the growth of hematopoietic stem cells (HSC) [2]. These observations establish a causal relationship between deregulation of the hematopoietic niche and MDS pathogenesis. However, so far only few studies have addressed the mechanisms by microenvironmental MSC and HSC exchange signals that may interfere with miRNA processing, specifically in the human MDS microenvironment.

Fluorescent tools have revolutionized our capability to visualize, probe, study, and understand the biological cellular properties, processes and dynamics, enabling researchers to improve their knowledge for example in cancer field. In this paper, we use the peculiar properties of our Imiqualines derivatives to study their cellular penetration and distribution in a human melanoma cell line A375 using confocal microscopy. Preliminary results on colocalization with the potent protein target c-Kit of our lead are also described.

The discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies., Graphical abstract Image 1, Highlights • TLRs7/8 dysregulation is involved in autoimmune, malignant and inflammatory diseases. • TLRs 7/8 agonists or antagonists are small synthetic compounds or macromolecules. • Combining TLRs7/8 modulators with other therapies could be the key for success. • Recently described specific agonist/antagonist sites will boost research insights.

Background PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds low‐density lipoprotein receptor, preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis. The PCSK9‐rs562556 variant has been reported as a gain‐of‐function mutation. The aim of this study was to determine whether the PCSK9–low‐density lipoprotein receptor–rs562556 axis is associated with carotid artery plaques between 2 visits separated by almost 20 years in a longitudinal population cohort. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non‐Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal familial cohort from the Lorraine region of France. Participants attending 2 visits (visit 1 and visit 4) separated by 18.5 years (mean) were included (n=997). Carotid artery plaques were determined with standardized vascular echography. The mean age of the adult population at visit 1 was 42±5 years. At visit 4, 203 (20.4%) participants had arterial plaques. Participants who developed arterial plaques were older (42.7±5.4 versus 41.7±4.7 years), more often male (60% versus 49%), smokers (29% versus 18%), with diabetes mellitus (6% versus 3%), and higher cholesterol levels (low‐density lipoprotein cholesterol, 1.6±0.4 versus 1.5±0.3 g/L) (all P Conclusions Higher PCSK9 concentration was associated with the development of arterial plaques almost 20 years in advance in a healthy middle‐aged population. Mutations of the single‐nucleotide polymorphism rs562556 associated with both PCSK9 levels and arterial plaques reinforce the potential causality of our findings. PCSK9 inhibitors could be useful for primary cardiovascular prevention.

By whipping air into a solution containing the pulp processing by-product black liquor, crosslinker and surfactant, stable air-in-black liquor froths were produced. The air volume in the froths was controlled by tuning the viscosity of the black liquor and the whipping time. By the selectively crosslinking the renewable lignin and hemicellulose content in the black liquor froths, lignin foams possessing a porosity of up to 88% have been produced. The porosity, pore and pore throat sizes decreased with increasing viscosity of the continuous liquid phase of the black liquor froths. The resulting lignin foams were pyrolysed to produce renewable carbon foams, which retained the shape and macropore structure of the lignin foam precursor well, opening the door to structurally designable carbon foams from lignin. The work demonstrated that froth templating using an industrial by-product is a viable low-cost method to produce both stable lignin and carbon foams.

The thermal decomposition kinetics of allyl methyl amine, allyl methyl ether, and allyl methyl sulfide in the gas phase has been studied theoretically using the M06-2x/aug-cc-pVTZ quantum chemical approach. The observed activation parameters are consistent with a concerted unimolecular mechanism involving a non-planar cyclic six-membered transition state. Based on the optimized ground state geometries, a natural bond orbital analysis of donor–acceptor interactions reveals that the stabilization energies corresponding to the electronic delocalization from the lone-pair (LP) non-bonding orbitals on the heteroatom to the neighboring $$\sigma_{{{\text{C2}} - {\text{C3}}}}^{*}$$ antibonding orbitals decrease from allyl methyl amine to allyl methyl sulfide. This delocalization fairly explains the increase of occupancies of LP orbitals on the heteroatom from allyl methyl sulfide to allyl methyl amine. The results also suggest that the kinetics of the thermolysis of the studied compounds are dominated by $${\text{LP}}\, \to \,\sigma^{*}$$ electronic delocalization effects. Analysis of bond order, bond indices, and synchronicity parameters demonstrates that these reactions proceed through a concerted and slightly asynchronous mechanism.

The Suzuki–Miyaura cross coupling is a versatile and powerful reaction for carbon–carbon bond formation which nevertheless requires optimization of conditions. While the coupling of arylboron derivatives with aryl or alkenyl halides has been widely explored, alkylation has attracted less attention. We describe herein the methylation of bromo derivatives of imidazopyrazine, imidazoquinoxaline, and pyrazoloquinoxaline having biologically interesting structures. As the challenging Suzuki–Miyaura reaction is highly substratedependent, the choices of the base, solvent, and additive are also discussed.

Imidazoquinoxaline derivatives (imiqualines) are a new series of anticancer compounds. Two lead compounds (EAPB0203 and EAPB0503) with remarkable in vitro and in vivo activity on melanoma and T-cell lymphomas have been previously identified. The modulation of the chemical structure of the most active compound, EAPB0503, has led to the synthesis of two compounds, EAPB02302 and EAPB02303, 7 and 40 times more active than EAPB0503 against A375 human melanoma cancer cell line, respectively. The aim of this study was to develop and validate a sensitive and accurate liquid chromatography-electrospray ionization-tandem mass spectrometry method to simultaneously quantify EAPB02303 and its potential active metabolite, EAPB02302, in rat and mouse plasma. Analytes were detected in multiple reaction monitoring acquisition mode using an electrospray ionization detector in positive ion mode. Following a liquid-liquid extraction with ethyl acetate, analytes and internal standard were separated by HPLC reversed-phase on a C18 RP18 Nucleoshell column (2.7μm, 4.6×100mm). The method was validated according to FDA and EMA Bioanalytical Method Validation guidelines. The robustness of the method was assessed by introducing small variations in nine nominal analytical parameters. Statistical interpretation was performed by mean of the Student's t-test. Standard curves were generated via unweighted quadratic regression of calibrators (EAPB02303: 1.95-1000ng/mL, EAPB02302: 7.81-1000ng/mL in rat plasma; EAPB02303: 0.98-1000ng/mL, EAPB02302: 1.95-1000ng/mL in mouse plasma). From the analysis of QC samples, intra- and inter-assay precision and accuracy studies demonstrated %R.S.Ds.12.5% and percent deviation from nominal concentration7%. Matrix effects (mean matrix factors from 91.8-108.5% in rat plasma; and from 90.4-102.4% in mouse plasma) and stability assays (recoveries87%) were acceptable and in accordance with the guidelines. No quantifiable carryover effect was observed. The LLOQs were 1.95ng/mL for EAPB02303 and 7.81ng/mL for EAPB02302 in rat plasma, and 0.98ng/mL and 1.95ng/mL for the two compounds in mouse plasma, respectively. This method was successfully implemented to support a mouse pharmacokinetic study following a single intraperitoneal administration of EAPB02303 in male C57Bl/6 mice. The obtained pharmacokinetic parameters of EAPB02303 would be useful to optimize the dosing and the rhythm of administration for subsequent preclinical in vivo activity studies.

A new class of emulsion-templated macroporous polymers (polyHIPEs) was prepared by step-growth polymerization involving a low molecular weight triol and a commercially available diisocyanate. Several water-in-oil High Internal Phase Emulsions (HIPEs) were formulated by varying the nature of the monomer and the volume fraction of the inner phase. The addition of particles in the continuous phase to obtain composites was studied. The preparation of Pickering emulsions and non-aqueous emulsions was also investigated. The addition of a catalyst to the HIPE and subsequent polymerization followed by solvent elimination led to the corresponding polyurethane polyHIPEs. These materials were characterized by Scanning Electron Microscopy (SEM), FT-IR, 13C solid NMR, mercury intrusion porosimetry, nitrogen adsorption and thermal analysis. The materials obtained shows porosities up to 80% and a thermal stability comparable to commercial polyurethane foams.

The cheletropic elimination process of N2 from (2,5-dihydro-1H-pyrrol-1-ium-1-ylidene) amide (C4H6N2) has been studied computationally using density functional theory, along with the M06-2X/aug-cc-pVTZ level of theory. The calculated energy profile has been supplemented with calculations of kinetic rate constants using transition state theory (TST) and statistical Rice–Ramsperger–Kassel–Marcus (RRKM) theory. This elimination process takes place spontaneously with an activation energy around 33 kJ/mol. Pressure dependence of the rate constants revealed that the TST approximation breaks down and fall-off expression is necessary for the kinetic modeling. At temperatures ranging from 240 to 360 K and atmospheric pressure, the unimolecular rate constant is evaluated from RRKM theory as $$k_{{(240 - 360\,{\text{K}})}}^{{1.0{\text{atm}}}} = 1.0249 \times 10^{12} \times {\text{e}}^{{ - \frac{{33.11\;{\text{kJ}}/{\text{mol}}}}{RT}}} \,{\text{s}}^{ - 1}$$ . Bonding changes along the reaction coordinate have been studied using bonding evolution theory. Electron localization function topological analysis reveals that the cheletropic elimination is characterized topologically by four successive structural stability domains (SSDs). Breaking of C–N bonds (Rx = 0.1992 amu1/2 Bohr) and the other selected points separating the SSDs along the reaction coordinate occur in the vicinity of the transition state.

Activated carbons were prepared from a new lignocellulosic biomass source: date palm petioles. The activation process comprise the pyrolysis to 1000 °C under nitrogen flow and then the activation at 750, 850 and 900 °C under CO2 flow. The samples were characterized by N2 adsorption, scanning electron microscopy and mercury porosimetry. The activated carbons exhibited a predominant microporosity with specific surface area from 225 m2·g−1 to 546 m2·g−1, and micropore volumes from 0.09 cm3·g−1 to 0.23 cm3·g−1.

The fluorescence properties of eleven novel derivatives based on the imidazo[1,2-a]quinoxaline structures have been studied. The absorption and emission spectra of these compounds have been recorded in dimethylsulfoxide solution. The phenyl substituting group on position 1 gives them particular properties thanks to the diverse hydroxy or methoxy decorating moieties, especially when they are multiplied or mixed. The investigated fluorescence auto-quenching revealed that the decreasing fluorescence intensity correlated only with the chemical structures of the aromatic compounds.

The thermal decomposition kinetics of 2-chloroethylsilane and derivatives in the gas phase has been studied computationally using density functional theory, along with various exchange-correlation functionals (UM06-2x and ωB97XD) and the aug-cc-pVTZ basis set. The calculated energy profile has been supplemented with calculations of kinetic rate constants under atmospheric pressure and in the fall-off regime, using transition state theory (TST) and statistical Rice–Ramsperger–Kassel–Marcus (RRKM) theory. Activation energies and rate constants obtained using the UM06-2x/aug-cc-pVTZ approach are in good agreement with the experimental data. The decomposition of 2-chloroethyltriethylsilane species into the related products [C2H4 + Et3SiCl] is characterized by 6 successive structural stability domains associated to the sequence of catastrophes C8H19SiCl: 6-C†FCC†[FF]-0: C6H15SiCl + C2H4. Breaking of Si–C bonds and formation of Si–Cl bonds occur in the vicinity of the transition state. All calculations presented in this work have been performed at the Flemish Supercomputer Center (Vlaams Supercomputer Centrum). This cluster has been financed by budgets obtained from the Katholieke Universiteit Leuven, as well as from individual contributions by users, and funding obtained from the Hercules foundation and the Flemish government.

Calcium (Ca(2+) ) is a physiological key factor, and the precise modulation of free cytosolic Ca(2+) levels regulates multiple cellular functions. Store-operated Ca(2+) entry (SOCE) is a major mechanism controlling Ca(2+) homeostasis, and is mediated by the concerted activity of the Ca(2+) sensor STIM1 and the Ca(2+) channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, while recessive loss-of-function mutations are associated with immunodeficiency. Here we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI channels, while T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggest that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca(2+) homeostasis and leading to muscle dysfunction. This article is protected by copyright. All rights reserved.

The kinetics and mechanisms of pyrolysis of 1,3-dihydroisothianaphthene-2,2-dioxide toward benzocyclobutene have been theoretically studied using canonical transition state theory (CTST), statistical Rice–Ramsperger–Kassel–Marcus (RRKM) theory, and bonding evolution theory (BET) in conjugation with M06-2X/aug-cc-pVTZ calculations. The CTST slightly breaks down to estimate the reaction rate of the cheletropic extrusion. RRKM results indicated that the cheletropic extrusion and electrocyclic reaction require energy barriers of 171.3 and 122.2 kJ/mol to be overcome; and can be characterized respectively by 7 and 3 phases associated to the sequence of catastrophes C 8 H 8 SO 2 ( 1 ): 7-[FF]C † C † FFF-0: C 8 H 8 + SO 2 and C 8 H 8 ( 2 ): 3-[F † F † ]C-0: C 8 H 8 ( 3 ). For the cheletropic extrusion, breaking of the C 7 –S and C 8 –S bonds begins respectively at Rx = −2.7434 amu 1/2 Bohr and Rx = −1.7458 amu 1/2 Bohr, and formation of the sulfur dioxide is completed at Rx = −0.2494 amu 1/2 Bohr. For the electrocyclic reaction, formation of new C 7 –C 8 bond occurs at Rx = 1.6214 amu 1/2 Bohr from C- to C- coupling between the generated pseudoradical centers at Rx = 0.1474 amu 1/2 Bohr on the terminal carbon atoms.

Heterocyclic compounds hold a huge and recognized place in the field of medicinal chemistry thanks to their multiple biological activities. Their synthetic pathways allow their easy and rapid access due to different bond-forming methodologies and provide a huge amount of multi-functionalized compounds for drug delivery. The syntheses of heterocyclic compounds are today well known for the majority, described and reviewed in an extensive literature. In this review, we choose to gather and classify available information concerning the biological activities of quinoxaline-based compounds annulated at bond a containing one and more nitrogen atoms in the fused azole ring.

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory-evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer 2/3 PNs elicited strong feed-forward perisomatic inhibition (FFI) onto layer 5 PNs. We found that FFI involving PV cells was strongly potentiated by postsynaptic PN burst firing. FFI plasticity modified PN excitation-to-inhibition (E/I) ratio, strongly modulated PN gain and altered information transfer across cortical layers. Moreover, our LTPi-inducing protocol modified the firing of layer 5 PNs and altered the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All these effects were captured by unbalancing the E/I ratio in a feed-forward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognitive-relevant network activity.Impact StatementLong-term potentiation of feed-forward perisomatic inhibition effectively alters the computational properties of single layer 5 pyramidal neurons and their association to network activity.

Density functional theory calculations are performed to study the out-of-plane polarisation in BaTiO3 (BTO) thin films epitaxially grown on platinum. Prior to any polarisation calculation, the stability of the Pt(001)/BaTiO3(001) structure is thoroughly discussed. In particular, the nature of the Pt/BTO and BTO/vacuum interfaces is characterised. The growth of BTO is shown to start with a TiO2 layer while the nature of the surface termination does not broadly modify the stability. Therefore both upper terminations are considered when describing the ferroelectric behaviour in Pt/BTO interfaces. The geometric and electronic effects of the substrate on the polarisation are investigated. To isolate the electronic influence of platinum, the out-of-plane polarisation in Pt/BTO systems is compared to the one in isolated BTO slabs constrained to the same lattice mismatch induced by the epitaxial growth on platinum. The ferroelectric phase is favoured as soon as the thickness is larger than 23 A, both for isolated and deposited BTO, for the smallest width. The Pt substrate will modify the size of polarisation domains, while an upper BaO layer through the use of asymmetric [TiO2/BaO] systems will induce an increase of the polarisation. One could take advantage of this experimentally.

Non-thermal atmospheric plasma of the gliding arc type was used as a tool for goethite-on-biochar hybrid material preparation. Biochars were first prepared by carbonizing raffia bamboo (the leafstalk of raffia palm) pith at 300 °C (BC3), 500 °C (BC5) and 700 °C (BC7). A suspension of each biochar in Fe2+ aqueous solution was then exposed to a plasma discharge burning in humid air. α-FeOOH particles were thus formed and spontaneously deposited on the biochar surface. In order to investigate the effect of plasma species on the support during goethite deposition, biochars were also treated with plasma in the absence of Fe2+ ions and then characterized. Results revealed a substantial hydroxylation and slight N-doping of biochar after plasma treatment. The prepared composite materials were tested in oxidative degradation of nitroresorcinol. The catalytic performances were in the order Fe-BC3 < Fe-BC7 < Fe-BC5 according to the abatement efficiency and half-time values obtained for each catalyst. This study establishes that waste biomass and atmospheric air can be simultaneously valorised for green production of heterogeneous catalysts.

ADORA2A has been shown to be responsible for the wakefulness-promoting effect of caffeine and the 1976T&gt, C genotype (SNP rs5751876, formerly 1083T&gt, C) to contribute to individual sensitivity to caffeine effects on sleep. We investigate the association between six single nucleotide polymorphisms (SNP) from ADORA2A and self-reported sleep characteristics and caffeine consumption in 1023 active workers of European ancestry aged 18&ndash, 60 years. Three groups of caffeine consumers were delineated: low (0&ndash, 50 mg/day, less than one expresso per day), moderate (51&ndash, 300 mg/day), and high (&gt, 300 mg/day). We found that at caffeine levels higher than 300 mg/day, total sleep time (TST) decreased (F = 13.9, p &lt, 0.01), with an increase of insomnia (ORa [95%CI] = 1.5 [1.1&ndash, 1.9]) and sleep complaints (ORa [95%CI] = 1.9 [1.1&ndash, 3.3]), whatever the ADORA2A polymorphism. Odds ratios were adjusted (ORa) for sex, age, and tobacco. However, in low caffeine consumers, lower TST was observed in the T allele compared to homozygote rs5751876 and rs3761422 C carriers. Conversely, higher TST was observed in rs2298383 T allele compared to C and in rs4822492G allele compared to the homozygote C (p &lt, 0.05). These 4 SNPs are in strong linkage disequilibrium. Haplotype analysis confirmed the influence of multiple ADORA2a SNPs on TST. In addition, the rs2298383 T and rs4822492 G alleles were associated with higher risk of sleep complaints (Ora = 1.9 [1.2&ndash, 3.1] and Ora = 1.5 [1.1&ndash, 2.1]) and insomnia (Ora = 1.5 [1.3&ndash, 2.5] and Ora = 1.9 [1.3&ndash, 3.2). The rs5751876 T allele was associated with a decreased risk of sleep complaints (Ora = 0.7 [0.3&ndash, 0.9]) and insomnia (Ora = 0.5 [0.3&ndash, 0.9]). Our results identified ADORA2A polymorphism influences in the less-than-300-mg-per-day caffeine consumers. This opens perspectives on the diagnosis and pharmacology of sleep complaints and caffeine chronic consumption.

Density functional theory, along with the ωB97XD and UM06-2x exchange-correlation functional, has been used to study the reaction mechanisms and kinetics of the atmospheric oxidation of the main (kinetically dominant) thiophene-OH adduct [C4H4S-OH]• (R1) by molecular oxygen in its triplet electronic ground state. Kinetic rate constants and branching ratios under atmospheric pressure and in the fall-off regime have been calculated by means of transition state theory (TST), variational transition state theory (VTST) and statistical Rice−Ramsperger−Kassel−Marcus (RRKM) theory. In line with the computed energy profiles, the dominant process under both the thermodynamic and kinetic control of the reaction is O2 addition at the C5 position in syn mode. The computed branching ratios indicate that the regioselectivity of the reaction decreases with increasing temperature and decreasing pressure. All calculations presented in this work have been performed at the Flemish Supercomputer Center (Vlaams Supercomputer Centrum). This cluster has been financed by budgets obtained from the Katholieke Universiteit Leuven, as well as from individual contributions by users, and funding obtained from the Hercules foundation and the Flemish government.

To the Editor: Enhanced- ice -COLD-PCR allows the detection of mutations in a single mutation hotspot down to 0.05% of mutant alleles without prior knowledge of the mutated base, and their identification by subsequent (pyro)sequencing experiments (1). This approach is useful for diagnosis, choice of a personalized treatment, prediction, or the monitoring of treatment response, and has been successfully performed on fresh frozen and formalin-fixed, paraffin-embedded tissue, and circulating cell-free DNA (1, 2). The method is a further development of ice -COLD-PCR (3) and based on the incorporation of locked–nucleic acid nucleotides in the blocker probe complementary to the wild-type (WT)1 sequence (1). During each PCR cycle, denaturation is followed by hybridization at 70 °C, where WT-blocker and mutant-blocker heteroduplexes are formed, mutant-blocker heteroduplexes are denatured at a critical temperature (Tc) higher than 75 °C, and primers are hybridized at the annealing temperature and elongated at 72 °C, leading to the enrichment of mutations underlying the blocker sequence (1). Enhanced- ice -COLD-PCR can enrich all types of mutations, allows stronger mutation enrichment, and is less sensitive to variations of the Tc (±5 °C) compared to full -, fast -, or ice -COLD-PCR, for which a slight variation (0.2 °C) can abolish mutation enrichment (1, 3, 4). Therefore, different full -, fast …

The inhibition of the NF-κB-dependent pathways by IKK inhibitors plays an important role in immunity, inflammation, and cancer. New imidazoquinoxalines tricyclic derivatives are prepared using microwave assistance and their biological activities as IKK inhibitors are described. Compounds 6a present a potent inhibition activity and selectivity for IKK2. Docking studies in the IKK2 binding site allowed identification of residues most likely to interact with theses inhibitors and explain their potent IKK2 inhibition activity and selectivity.

Macroporous polymeric materials were prepared using mixtures of polyphenol:hydrolysable tannins, condensed tannins and lignosulfonate, from pulp industry, as the main raw source. The process used is simple, green and low energy consuming. It consists of a mechanical foaming of aqueous solutions constituted with different proportions of two types of tannins, the lignosulfonate and a hardener in the presence of a surfactant, which maintain the mixture stable before curing.The final formulations, with tannins and lignin were characterized by Scanning Electronic Microscopy, mercury intrusion porosimetry, nitrogen sorption, mechanical and thermal measurements. Then, to determine whether the components react with hexamine but also between them, mixtures were made, first with one polyphenol at a time and then with polyphenols in pairs. Those formulations were characterized through thermal and mechanical properties.Solid, self-standing foams with an average porosity of 89%, an average cell diameter of 105 μm with interconnections of about 7 μm were obtained. The structure of the foams is close to that of phenolic, tannin, lignin and biobased polyurethanes foams already reported in the literature. Concerning mechanical properties, compression modulus between 0.65 MPa and 22.9 MPa were obtained. The thermal conductivity varies between 0035 and 0055 W. m−1.K−1. Keywords: Biobased porous materials, Frothing, Tannins, Lignin

The isomerization processes of naphthalene peroxy radicals [C10H8–OH] –O2 into bicyclic peroxy or oxy hydroperoxide radicals via ring closure and intramolecular hydrogen transfers have been studied computationally using density functional theory, along with various exchange–correlation functionals and an extremely large basis set. The calculated energy profiles have been supplemented with calculations of kinetic rate constants under atmospheric pressure and in the fall-off regime, using transition state theory (TST) and statistical Rice–Ramsperger–Kassel–Marcus (RRKM) theory. The cyclization of the R1-2OO-syn peroxy radical into the R1-2,9OO-syn bicyclic peroxy radical through formation of an O–O bridge is endothermic and reversible. Both from a thermodynamic and kinetic view points, the two most favorable processes for the R1-2OO-syn peroxy radical are ring closure into the R1-2,9OO-syn bicyclic peroxy radical species, and conversion through hydrogen transfer into the R1-P2O1-syn oxy hydroperoxide radical. Among all studied reaction channels, the latter process is the kinetically most competitive one. Also, in view of the computed rate constants, the R1-2OO-syn peroxy radical appears to be chemically much more reactive than the R1-4OO-syn species. All in all, the atmospheric oxidation mechanisms of naphthalene appear at this reaction stage to be quite different from that of benzene and its derivatives.

Transvinylation of aromatic and aliphatic diacids w ith vinyl acetate using several catalytic systems have been studied under conventional heatin g and microwave activation. In any case, a single addition of catalyst gave only low conversio n into diester, due to a rapid deactivation of the catalysts, the best results being obtained with [pyridine] 2·Pd(OAc) 2. Successive additions of Pd(OAc) 2 as catalyst gave better results with a 65% yield in is olated pure divinyl dodecanedioate after the successive addition of three catalyst por tions. Kinetics and catalytic mechanism considerations helped to discuss these results.

SummaryParvalbumin (PV) positive interneurons modulate cortical activity through highly specialized connectivity patterns onto excitatory pyramidal neurons (PNs) and other inhibitory cells. PV cells are auto-connected through powerful autapses, but the contribution of this form of fast disinhibition to cortical function is unknown. We found that autaptic transmission represents the most powerful input of PV cells in neocortical Layer V. Autaptic strength was greater than synaptic strength onto PNs as result of a larger quantal size, whereas autaptic and heterosynaptic PV-PV synapses differed in the number of release sites. Overall, single-axon autaptic transmission contributed to ~40% of the total perisomatic inhibition that PV interneurons received. The strength of autaptic transmission modulated the coupling of PV-cell firing with optogenetically-induced γ-oscillations preventing high frequency bursts of spikes. Autaptic self-inhibition represents an exceptionally large and fast disinhibitory mechanism to synchronize the output of PV cells during cognitive-relevant cortical network activity.