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Summary Objective A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. Methods Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently-labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants, and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. Results GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and 5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 μM and 10 μM, respectively). In DMM mice, GLPG1972/S201086 (30–120 mg/kg b.i.d) versus vehicle reduced femorotibial cartilage proteoglycan loss (23–37%), cartilage structural damage (23–39%) and subchondral bone sclerosis (21–36%). In MNX rats, GLPG1972/S201086 (10–50 mg/kg b.i.d) versus vehicle reduced cartilage damage (OARSI score reduction, 6–23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77–110%). Conclusions GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

Purpose Antibiotics are frequently used in patients receiving intermittent or continuous renal replacement therapy (RRT). RRT may alter the pharmacokinetics (PK), as well as the ability to achieve PK/pharmacodynamic (PD) targets. Therapeutic drug monitoring (TDM) could help evaluatedrug exposure and guide antibiotic dosage adjustment. The present review describes recent TDM data on antibiotic exposure and PK/PD target attainment in patients receiving intermittent or continuous RRT, proposing practical guidelines for performing TDM. Methods Studies on antibiotic TDM performed in patients receiving intermittent or continuous RRT published between 2000 and 2020 were searched and assessed. The authors focused on studies that reported data on PK/PD target attainment. TDM recommendations were based on clinically relevant PK/PD relationships and previously published guidelines. Results In total, 2383 reports were retrieved. After excluding non-relevant publications, 139 articles were selected. Overall, 107 studies reported PK/PD target attainment for 24 agents. Data were available for various intermittent and continuous RRT techniques. The study design, TDM practice, and definition of PK/PD targets were inconsistent across studies. Drug exposure and target attainment rates were highly variable. TDM appears necessary to control drug exposure in patients receiving intermittent and continuous RRT techniques, especially for antibiotics with narrow therapeutic margins and in critically ill patients. Practical recommendations can provide insights on relevant PK/PD targets, sampling, and timing of TDM for various antibiotic classes. Conclusion Highly variable antibiotic exposure and target attainment have been reported in patients receiving intermittent or continuous RRT. TDM for aminoglycosides, beta-lactams, glycopeptides, linezolid, and colistin is recommended in patients receiving RRT and suggested for daptomycin, fluoroquinolones, and tigecycline in critically ill patients on RRT.

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A general anti-Baldwin radical 4-exo-dig cyclization from nitrogen-substituted alkynes is reported. Upon reaction with a heteroleptic copper complex in the presence of an amine and under visible light irradiation, a range of ynamides were shown to smoothly cyclize to the corresponding azetidines, useful building blocks in natural product synthesis and medicinal chemistry, with full control of the regioselectivity of the cyclization resulting from a unique and underrated radical 4-exo-dig pathway., The construction of four-membered rings via a 4-exo-dig cyclization was originally theorized to be unfavourable and only recently shown in sparse examples. Here the authors present a photochemical, radical 4-exo-dig cyclization of ynamides to form azetidines, promoted by copper photoredox catalysis.

Based on supporting stoichiometric organometallic syntheses, structural analyses, reaction monitoring, radical-clock experiments, and kinetic investigations, a comparative mechanistic study between two related systems that are competent in the Ni-catalyzed Kumada cross-coupling reaction between enol phosphates and vinyl magnesium bromide is reported. We demonstrate that the two bisphosphine–nickel complexes operate via Ni(0)/Ni(II) catalytic manifolds for this type of C(sp2)–O electrophiles. The first complex of generic structure [(dppe)NiBr2] is reduced in situ upstream from the productive catalytic cycle, which itself follows a classical mechanistic scenario composed of an oxidative addition/transmetalation/reductive elimination sequence. A rapid phosphate/bromide ion exchange prior to transmetalation constitutes a key feature of this system. The related [(dmpe)NiBr2] complex follows a much less conventional pathway. Kinetic analyses distinguish themselves by an unusual apparent second order in the catalyst, which is attributed to an interplay between vinyl nickel species formed during precatalyst activation and styrenyl nickel intermediates generated downstream in the sequence of elementary steps. This hypothesis is corroborated by independent supporting organometallic investigations.

Uranium (U) contamination in groundwater from geogenic sources affects water quality globally. Here, we use a multifaceted isotopic and geochemical approach to elucidate U sources and controls on g...

Excited-state intramolecular proton transfer (ESIPT) dyes typically show strong solid-state emission, but faint fluorescence intensity is observed in the solution state owing to detrimental molecular motions. This article investigates the influence of direct (hetero)arylation on the optical properties of 2-(2'-hydroxyphenyl)benzoxazole ESIPT emitters. The synthesis of two series of ESIPT emitters bearing substituted neutral or charged aryl, thiophene, or pyridine rings is reported herein along with full photophysical studies in solution and solid states, demonstrating the dual solution-/solid-state emission behavior. Depending on the nature of substitution, several excited-state dynamics are observed: quantitative or partially frustrated ESIPT process or deprotonation of the excited species. Protonation studies revealed that pyridine substitution triggered a strong increase of quantum yield in the solution state for the protonated species owing to favorable quinoidal stabilization. These attractive features led to the development of a second series of dyes with alkyl or aryl pyridinium moieties showing strong tunable solution/solid fluorescence intensity. For each series, ab initio calculations helped rationalize and ascertain their behavior in the excited state and the nature of the emission observed by the experimental results.

The bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel antibiotics. We report a structure-activity relationship study of a new series of peptides interacting within the Escherichia coli SC (EcSC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus. In each category, single modifications were identified that increased affinity to EcSC. A combination of such modifications yielded in several cases to a substantially increased affinity compared to the parent peptides with Kd in the range of 30-80 nM. X-ray structure analysis of 11 peptide/EcSC co-crystals revealed new interactions at the peptide-protein interface (i.e., stacking interactions, hydrogen bonds, and hydrophobic contacts) that can account for the improved binding. Several compounds among the best binders were also found to be more effective in inhibiting SC-dependent DNA synthesis.

Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility.

1. Soil nutrient availability and functional traits interact in complex ways during the assembly of tree communities hindering our understanding of the implications that this may have for their phylogenetic and functional diversity. 2. We combined abundance, taxonomic, phylogenetic and functional trait data of 222 tree species distributed along nutrient concentration gradients at twenty-four plots in two tropical forest study sites. We analysed micro and macronutrient concentration in organic and topsoil horizons and tested for: (1) nutrient-based species sorting due to contrasting trait-environment relationships; (2) whether nutrient filtering has consequences for phylogenetic and functional diversity, and functional space size and occupancy; and (3) we mapped trait distributions across the phylogeny of tree species to track the evolutionary signature of nutrient availability. 3. We found that total nitrogen (N), available phosphorus and total potassium in soil accounted for 68% of the variation in tropical tree species community composition, with strong associations with nutrient concentration for 89% of the tree species included in the analysis. This nutrient-based species selection was mediated by interactions between the three soil nutrient concentrations with leaf nitrogen, leaf thickness and wood density. Soil N concentration was positively associated with the functional space at site level. At a plot level soil N concentration positively correlated with functional evenness and it was negatively associated with the functional space not occupied by any species in the tree community. Despite the phylogenetic conservatism of leaf N across tree lineages even when not considering legumes, many sister-species pairs show contrasting values which match with their habitat preferences thus indicating the evolutionary lability of this trait, particularly within recently diversified clades. 4. Synthesis. Our results demonstrate that soil nutrient-based species selection is a prevalent driver of community assembly in tropical forests, a process mediated by key functional traits within the leaf and wood economics spectrum. Functional space size and its filling increase with soil nutrient concentration, whereas niche vacancy decreases. This selection process has likely influenced tropical tree species diversification patterns via habitat specialization.

Anilines selectively arylated at their ortho, meta or para positions are useful building blocks in synthesis and have found applications in many areas. The most straightforward method for their synthesis relies on the direct arylation of a C(sp2)–H bond of anilines, an attractive strategy avoiding the prefunctionalization of the starting anilines provided that such arylations proceed with high levels of regioselectivity. Such reactions are presented and discussed, in a comprehensive manner, in this review article, with an emphasis on the regioselectivity of the processes and factors governing both the reactivity and selectivity.

Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. In male and female meiotic cells, DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, but only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity by integrating specific chromosomal features.

Through the preparation and characterization of five new derivatives, the regioselective mono and di, homo and hetero, halogenation of the benzothioxanthene (BTXI) core is demonstrated herein. All structurally solved by X-ray crystallography, these complementary functionalized building blocks open doors to the design of new symmetrical and asymmetrical π-conjugated systems based on this promising but still under-explored rylene.

Despite recent progress in our understanding of graft union formation, we still know little about the cellular events underlying the grafting process. This is partially due to the difficulty of reliably targeting the graft interface in electron microscopy to study its ultrastructure and three-dimensional architecture. To overcome this technological bottleneck, we developed a correlative light electron microscopy (CLEM) approach to study the graft interface with high ultrastructural resolution. Grafting hypocotyls of Arabidopsis thaliana lines expressing yellow FP or monomeric red FP in the endoplasmic reticulum (ER) allowed efficient targeting of the grafting interface for examination under light and electron microscopy. To explore the potential of our method to study sub-cellular events at the graft interface, we focused on the formation of secondary plasmodesmata (PD) between the grafted partners. We showed that four classes of PD were formed at the interface and that PD introgression into the cell wall was initiated equally by both partners. Moreover, the success of PD formation appeared not systematic with a third of PD not spanning the cell wall entirely. Characterizing the ultrastructural characteristics of these incomplete PD gives us insights into the process of secondary PD biogenesis. We found that the establishment of successful symplastic connections between the scion and rootstock occurred predominantly in the presence of thin cell walls and ER–plasma membrane tethering. The resolution reached in this work shows that our CLEM method advances the study of biological processes requiring the combination of light and electron microscopy.

Made available in DSpace on 2022-04-28T19:46:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-09 Background and ObjectivesPeople with multiple sclerosis MS are a vulnerable group for severe coronavirus disease 2019 COVID-19, particularly those taking immunosuppressive disease-modifying therapies DMTs. We examined the characteristics of COVID-19 severity in an international sample of people with MS.MethodsData from 12 data sources in 28 countries were aggregated sources could include patients from 1-12 countries. Demographic age, sex, clinical MS phenotype, disability, and DMT untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit ICU admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale EDSS score.ResultsSix hundred fifty-seven 28.1% with suspected and 1,683 61.9% with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02 and ICU admission aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89, although only rituximab was associated with higher risk of artificial ventilation aOR 4.00, 95% CI 1.54-10.39. Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07 and ICU admission aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23, but only rituximab was associated with artificial ventilation aOR 6.15, 95% CI 3.09-12.27. Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92 and ICU admission aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91, but only rituximab was associated with ventilation aOR 5.52, 95% CI 1.71-17.84. Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.DiscussionUsing the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19. CORe Department of Medicine and Neuroepidemiology Unit Melbourne School of Population and Global Health Menzies Institute for Medical Research University of Tasmania ESAT-STADIUS KU Leuven Department of Neurology Melbourne MS Centre Royal Melbourne Hospital MS International Federation Department of Clinical Neuroscience Swedish MS Registry Department of Neurology CHU Pontchaillou Karolinska Institutet Biomedical Research Institute-Data Science Institute Hasselt University Department of Medical Informatics University Medical Center Department of Computer Science and AI KU Leuven QMENTA Medpace Reference Laboratories Molecular Unit IConquerMS People-Powered Research Network Accelerated Cure Project for MS NeuroTransData Study Group NeuroTransData German MS-Register by the National MS Society MS Forschungs- und Projektentwicklungs-gGmbH MS Register Swansea University COViMS Division of Biostatistics Washington University in St. Louis Mellen Center for Multiple Sclerosis Cleveland Clinic Department of Neuroscience Central Clinical School Monash University Al-Amiri Hospital Kuwait City Dokuz Eylul University Neurology Department Hospital Universitario de CEMIC RELACOEM Australian MS Longitudinal Study Menzies Institute for Medical Research University of Tasmania Bulgarian SmartMS COVID-19 Dataset ABEM-Brazilian MS Patients Association Danish Multiple Sclerosis Registry Department of Neurology University Hospital Rigshospitalet Universidade Estadual Paulista Unesp Faculdade de Medicina REDONE.br-Brazilian Registry of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders Irmandade da Santa Casa de Misericórdia de São Paulo Multiple Sclerosis University Center Ramos Mejia Hospital-EMA Imperial College Swansea University Mental Health Area MS and Demyelinating Diseases Hospital Británico de Buenos Aires EMA Servei de Neurologia-Neuroimmunologia Centre d'Esclerosi Múltiple de Catalunya Cemcat Vall d'Hebron Institut de Recerca Vall d'Hebron Hospital Universitari Universitat Autònoma de Barcelona Institute of Experimental Neurology Ospedale San Raffaele Universidade Estadual Paulista Unesp Faculdade de Medicina

An original and straightforward entry to polysubstituted indenes from readily available ynamides is reported. Upon reaction with a NHC-gold complex under mild conditions, activated keteniminium ions are generated whose unique electrophilicity triggers a [1,5]-hydride shift and a subsequent cyclization. The presence of an endocyclic enamide in the densely functionalized resulting indenes was shown to be especially useful and versatile, offering a range of opportunities for their further post-functionalization., info:eu-repo/semantics/published

The mycotoxins are toxic composites frequently found in foodstuffs causing some damages to consumers. This current study has been realised in order to estimate the content of Aflatoxin B1 and Ochratoxin A in dry okra and cassava chips frequently consumed by the population of Daloa. The analysis by chromatography in the liquid phase at high performance has shown that these foodstuffs contain Aflatoxin B1 and Ochratoxin A. These results reveal an average content of : 2.58 ± 3.65 µg/Kg and 3.08 ± 5.04 µg/Kg for the Aflatoxin B1 ; 1.06 ± 0.86 µg/Kg and 0.61±0.24 µg/Kg for the Ochratoxin A respectively in the flour of cassava chips and the powder of dry okra. These concentrations are somewhat to higher than those allowed by the norm of Codex Alimentarius. Under this form, the consumption of these foodstuffs by the population expose them at risk of diseases.

Filamentous fungi are frequent contaminants of many plant substrates and certain animal products. Their presence can improve the organoleptic quality of the product or alter it and lead to the accumulation of toxic secondary metabolites, such as mycotoxins. The objective of this work is to characterize the filamentous fungi isolated from the rice "deni kachia" stored and sold on public markets in the city of Daloa. A count and isolation of filamentous fungi, followed by macroscopic and microscopic identification was carried out. Several genera of filamentous fungi was identified. These are the genera Aspergillus, Penicillium and others. The different species of molds identified by conventional biochemical techniques were confirmed by the API 50 CH freezer.The genera Aspergillus and Penicillium are the most predominant in the samples analyzed. The presence of these species with their ability to produce mycotoxins suggests that contaminated rice poses a risk to the health of consumers.

BACKGROUND/OBJECTIVES Platelet-activating factor receptor (PAFR) activation controls adipose tissue (AT) expansion in animal models. Our objective was twofold: (i) to check whether PAFR signaling is involved in human obesity and (ii) investigate the PAF pathway role in hematopoietic or non-hematopoietic cells to control adipocyte size. MATERIALS/SUBJECTS AND METHODS Clinical parameters and adipose tissue gene expression were evaluated in subjects with obesity. Bone marrow (BM) transplantation from wild-type (WT) or PAFR-/- mice was performed to obtain chimeric PAFR-deficient mice predominantly in hematopoietic or non-hematopoietic-derived cells. A high carbohydrate diet (HC) was used to induce AT remodeling and evaluate in which cell compartment PAFR signaling modulates it. Also, 3T3-L1 cells were treated with PAF to evaluate fat accumulation and the expression of genes related to it. RESULTS PAFR expression in omental AT from humans with obesity was negatively correlated to different corpulence parameters and more expressed in the stromal vascular fraction than adipocytes. Total PAFR-/- increased adiposity compared with WT independent of diet-induced obesity. Differently, WT mice receiving PAFR-/--BM exhibited similar adiposity gain as WT chimeras. PAFR-/- mice receiving WT-BM showed comparable augmentation in adiposity as total PAFR-/- mice, demonstrating that PAFR signaling modulates adipose tissue expansion through non-hematopoietic cells. Indeed, the PAF treatment in 3T3-L1 adipocytes reduced fat accumulation and expression of adipogenic genes. CONCLUSIONS Therefore, decreased PAFR signaling may favor an AT accumulation in humans and animal models. Importantly, PAFR signaling, mainly in non-hematopoietic cells, especially in adipocytes, appears to play a significant role in regulating diet-induced AT expansion.

The structure and complete nuclear magnetic resonance (NMR) assignments of orbifomitellic acid, a novel lanostane triterpene isolated from the fruiting bodies of a Gabonese Ganoderma orbiforme (Polyporaceae), are reported. Within the vast catalogue of lanostanes documented from Ganoderma spp., orbifomitellic acid is the first disclosing a -COOH group at C-4.

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI., Blood coagulation is started by contact to surfaces and this is the principle for a commonly used diagnostic clotting test, aPTT. Here, the authors identify the structure in coagulation factor XII that initiates surface-driven coagulation and use the information to develop improved aPTT assays.

Objective: Critical limb ischemia is a major complication of diabetes characterized by insufficient collateral vessel development and proper growth factor signaling unresponsiveness. Although mainly deactivated by hypoxia, phosphatases are important players in the deregulation of proangiogenetic pathways. Previously, SHP-1 (Scr homology 2-containing phosphatase-1) was found to be associated with the downregulation of growth factor actions in the diabetic muscle. Thus, we aimed to gain further understanding of the impact of SHP-1 on smooth muscle cell (SMC) function under hypoxic and diabetic conditions. Approach and Results: Despite being inactivated under hypoxic conditions, high glucose level exposure sustained SHP-1 phosphatase activity in SMC and increased its interaction with PDGFR (platelet-derived growth factor receptor)-β, thus reducing PDGF proangiogenic actions. Overexpression of an inactive form of SHP-1 fully restored PDGF-induced proliferation, migration, and signaling pathways in SMC exposed to high glucose and hypoxia. Nondiabetic and diabetic mice with deletion of SHP-1 specifically in SMC were generated. Ligation of the femoral artery was performed, and blood flow was measured for 4 weeks. Blood flow reperfusion, vascular density and maturation, and limb survival were all improved while vascular apoptosis was attenuated in diabetic SMC-specific SHP-1 null mice as compared to diabetic mice. Conclusions: Diabetes and high glucose level exposure maintained SHP-1 activity preventing hypoxia-induced PDGF actions in SMC. Specific deletion of SHP-1 in SMC partially restored blood flow reperfusion in the diabetic ischemic limb. Therefore, local modulation of SHP-1 activity in SMC could represent a potential therapeutic avenue to improve the proangiogenic properties of SMC under ischemia and diabetes.

The treatment of [IrCl(cod)]2 with (Z)-1-phenyl-2-(4′,4′-dimethyl-2′-oxazolin-2′-yl)-eth-1-en-1-ol (HL) in the presence of base yields the first Ir complex of this ligand class: Ir(κ2-N,O-L)(cod) (...

A [Ni/Mg]-catalyzed orthogonal tandem polymerization has been developed starting from enol phosphates. Initial investigations conducted on branched 1,3-dienes as monomers enabled identification of a Mg-initiated polymerization process leading to 1,4-cis-polydienes. When aryl enol phosphates are used as monomers, the [Ni/Mg]-catalyzed tandem polymerization affords 1,4-cis-polydienes with selectivities up to 99%. Elastomeric or crystalline materials were obtained by simple structural modifications of the monomeric unit. This tandem approach appears as a straightforward and efficient way to enforce diversity and selectivity in diene polymerization while retaining a fair degree of control, just as observed for stepwise systems that are accessible through established time- and manpower-consuming synthetic procedures.

Recent studies concluded that the use of ammonia in SI engines is possible thanks to an ignition booster or promoter. In this paper, the improvement of premixed ammonia/air combustion for internal combustion engines is studied as a function of performance and exhaust pollutants in a Spark-Assisted Compression Ignition single-cylinder engine, which supports a higher compression ratio (CR). For the first time, pure NH3 combustion was performed over a large range of engine operating conditions. The study concludes that neat ammonia can be used over a large operating range, here driven by the intake pressure, using a classical ignition device with a CR of 14–17 at 1000 rpm. The comparison with previous data obtained in a current single-cylinder SI engine clearly shows the potential of this engine mode, even for very low loads and various engine speeds (650, 1000, 2000 rpm), in spite of an initial aerodynamic that is not optimized to enhance flame-turbulence interaction. Kinetic simulations provide some explanations about exhaust emission behaviour, especially unburnt NH3, H2, NOx and N2O.

Disordered rocksalt (DRX) cathodes have attracted interest due to their high capacity and compositional flexibility (e.g., Co-free chemistries). However, the sloping voltage profile and gradual capacity fade during cycling have hindered the widespread adoption of these materials. Simulations predict that fluorine substitution in DRX cathodes will improve their capacity, rate performance, and cyclability. In this study, we use a fluidized bed reactor to fluorinate a model Li-rich DRX composition (Li1.15Ni0.375Ti0.375Mo0.1O2, NTMO) to investigate how fluorine content impacts the cathode's structure and electrochemical performance. Instead of substituting O with F to form oxyfluoride phases, direct fluorination of DRX cathodes leads to the formation of LiF surface films, which improves the specific energy and capacity retention. This study demonstrates the feasibility of direct fluorination to improve the electrochemical performance of high-voltage cathodes by tuning the material's surface chemistry.

While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective., Chemistry - A European Journal, 27 (47), ISSN:0947-6539, ISSN:1521-3765

La tomate est l’un des légumes les plus consommés au monde et au Bénin. Il est largement établi que la salinité agit négativement sur la germination et la croissance et modifie considérablement la concentration des composés bioactives des légumes. Au Bénin, la tomate est cultivée partiellement sur les terres cultivables des régions côtières où la salinité du sol et de l’eau d’irrigation est une réalité. Cette étude visait à évaluer l’effet de la salinité sur la floraison, la fructification et la composition nutritionnelle des fruits de tomate du cultivar local Akikon. Les plantes de trois semaines ont été arrosées jusqu’à la maturité des fruits avec diverses concentrations de NaCl de 0, 30, 60 et 120 mM. La date d’apparition des premières fleurs, la date de maturation des fruits ainsi que les teneurs en protéines des fruits n’ont pas été significativement affectées par la salinité alors que le nombre de fruits par plante, le poids des fruits, les teneurs en sucres solubles totaux et en sucres réducteurs subissent une réduction significative sous l’effet du NaCl. Par contre, les teneurs en lycopène, en vitamines B6, B12 et C ont connu une augmentation significative avec l’augmentation de la concentration de NaCl. La salinité a donc réduit la production de tomate et amélioré la qualité nutritionnelle des fruits en augmentant notamment ses teneurs en vitamines et en lycopène.Mots clés: Salinité, teneur en nutriments, sucres, lycopène, vitamines. English title:Effect of salt stress on flowering, fructification and fruit nutritional quality of Benin local tomato (Lycopersicon esculentum Mill.) cultivar AkikonTomato (Lycopersicon esculentum) is one of the most important consumable vegetable in the world and in Benin. It is widely established that salinity acts negatively on germination and growth and considerably modifies the concentration of bioactive compounds in vegetables. In Benin, tomato is partially cultivated on arable lands in coastal regions where soil and irrigation water salinity is a reality. This study investigated the impact of salinity on flowering, fructification, and fruit nutrient contents of a local cultivar of tomato Akikon. Three weeks old plants were irrigated with four NaCl concentrations: 0; 30; 60 and 120 mM NaCl till fruit ripening. The date of first flower appearance, the date of fruit ripening and fruit protein content were not affected by salinity; whereas fruit number, fruit fresh mass, fruit soluble sugars and reducing sugars contents were significantly decreased by increasing salinity. Moreover, lycopen and vitamins B6, B12 and C contents increased significantly when salinity concentration increased. Thus, salinity reduced tomato productivity but improved fruit nutritional quality by mainly increasing vitamins and lycopen contents.Keywords: Salinity, nutrients content, lycopen, sugars, vitamins.

Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of

The contamination of grape berries by Botrytis cinerea can drastically damage wine quality, in particular causing colour degradation. In musts obtained from botrytised grapes, SO2 addition is the main means of avoiding oxidation damage due to laccases excreted by the pathogen. However, consumers are becoming increasingly reluctant to accept SO2 addition to wine. Oenological tannins are used for fining wines because of their colloidal properties, and for wine colour stabilisation due to their ability to condense with anthocyanins. They are also known for their antioxidant and antioxidasic properties. They were thus investigated in the present study for their potential as an alternative to SO2 against laccase oxidation.The impact of various types of oenological tannins on musts and wines was studied once added to musts obtained from the Merlot cultivar, comprising 20 % and 50 % botrytised grapes. Laccase activity, antioxidant capacity, composition of phenolic compounds, spectrophotometric and CIELAB colour parameters were assessed in the musts and wines. Sensory analyses were also performed on 3-month-old wines to evaluate the visual, olfactory and gustative consequences of tannin addition. At a 50 % botrytisation rate, the addition of any type of oenological tannins (at a concentration of 100 g/hL) had no effect on laccase activity and did not protect phenolic compounds. However, at the same concentration and at a 20 % botrytisation rate, proanthocyanidin tannins from grape skin were found to be the most promising tannins with simultaneous protective effects, such as an inhibitory effect on laccase enzymes, protection of colour from complete degradation and preservation of some procyanidin compounds.Oenological tannins are promising candidates for protecting wines from Botrytis damage and they induce a differential effect according to their origin and structure. They could be used to reduce the amount of SO2 that is added during vatting. More research is needed to confirm and better understand the mode of action of various tannins at levels lower than the 20 % botrytised rate tested in the present study.

This study aimed to identify predictors and estimate time to teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS).Post-hoc analysis was performed on individual patient data from teduglutide-treated patients in the phase III teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs. late responders.A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p = 0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p = 0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p = 0.047), and female sex (HR: 0.3; 95% CI: 0.1-1.0; p = 0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p 0.05). The mean times to response were 3.6 (standard deviation (SD): 1.1) months for early responders (n = 27) and 10.0 (SD: 6.1) months for late responders (n = 7). Fewer early responders had colon-in-continuity (51.9%) and ileocecal valve (0.0%) compared to late responders (100% and 28.6%, respectively; both p 0.05). Early responders had a lower mean percentage of colon remaining compared to late responders (24.6% vs. 57.1%, respectively; p = 0.016).Time to response to teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings.

Background Boar taint is an unpleasant smell found in the meat of some uncastrated male pigs. This taint is often prevented by surgical castration without anesthesia or analgesia. However, this practice is an animal welfare concern. Production of entire males and immunocastration were suggested as alternatives. Ensuring that meat is untainted remains a priority for slaughterhouses. This has initiated research about the development of new boar taint detection methods. Most focus on detecting skatole and androstenone, two major contributors to boar taint. Scope and approach This review aims to describe past methods and recent advances made in rapid boar taint detection, and provide leads for future research. The main findings of past methods such as the use of insect behavior-based sensors, e-noses, and gas chromatography–mass spectrometry, are presented. Recently developed methods based on mass spectrometry, Raman spectroscopy, and sensors are also discussed. Finally, biosensors showing promising results and potential for boar taint detection are presented. The advantages and drawbacks of these techniques, cost analysis, and possible challenges encountered during their application to on-line detection are addressed. Key findings and conclusions This review presents numerous techniques that were developed for boar taint detection. Some methods, such as laser diode thermal desorption combined with tandem mass spectrometry, proved their on-line/at-line efficiency as they are fast and accurate. However, initial investment and difficulty of implementation could lead to reluctance in applying these. Further research could focus on testing new sensor materials whereas sensory evaluation remains the most practical method used in slaughterhouses.

With the rise of two-dimensional (2D) transition-metal dichalcogenide (TMD) semiconductors and their prospective use in commercial (opto)electronic applications, it has become key to develop scalable and reliable TMD synthesis methods with well-monitored and controlled levels of impurities. While metal-organic chemical vapor deposition (MOCVD) has emerged as the method of choice for large-scale TMD fabrication, carbon (C) incorporation arising during MOCVD growth of TMDs has been a persistent concern-especially in instances where organic chalcogen precursors are desired as a less hazardous alternative to more toxic chalcogen hydrides. However, the underlying mechanisms of such unintentional C incorporation and the effects on film growth and properties are still elusive. Here, we report on the role of C-containing side products of organosulfur precursor pyrolysis in MoS2 thin films grown from molybdenum hexacarbonyl Mo(CO)6 and diethyl sulfide (CH3CH2)2S (DES). By combining in situ gas-phase monitoring with ex situ microscopy and spectroscopy analyses, we systematically investigate the effect of temperature and Mo(CO)6/DES/H2 gas mixture ratios on film morphology, chemical composition, and stoichiometry. Aiming at high-quality TMD growth that typically requires elevated growth temperatures and high DES/Mo(CO)6 precursor ratios, we observed that temperatures above DES pyrolysis onset (â 600 °C) and excessive DES flow result in the formation of nanographitic carbon, competing with MoS2 growth. We found that by introducing H2 gas to the process, DES pyrolysis is significantly hindered, which reduces carbon incorporation. The C content in the MoS2 films is shown to quench the MoS2 photoluminescence and influence the trion-To-exciton ratio via charge transfer. This finding is fundamental for understanding process-induced C impurity doping in MOCVD-grown 2D semiconductors and might have important implications for the functionality and performance of (opto)electronic devices., This work was funded by the European Union’s Horizon 2020 research and innovation programme (BrainCom, grant no. 732032, Nanosmart, grant no. 825430 and Graphene Flagship Core 3, grant no. 881603). We also acknowledge funding from Generalitat de Catalunya (2017 SGR 1426), and the 2DTecBio (FIS2017-85787-R) funded by the Spanish Ministry of Science, Innovation and Universities, the Spanish Research Agency (AEI), and the European Regional Development Fund (FEDER/UE). The ICN2 is funded by the CERCA programme/Generalitat de Catalunya and supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706). C.M.S. acknowledges that this work has been done within the framework of the Ph.D. program in Materials Science of the Autonomous University of Barcelona. Furthermore, C.M.S. wants to thank Anh Tuan Hoang for fruitful discussions.

The objective of this study is to assess the presence of harmful microorganisms and to characterize some physicochemical parameters in the soya flour sold in Daloa. To carry out the work, sixty (60) samples of soybean flour were collected by purchase in PMI (20), supermarkets (20) and in certain markets (20) made up of grains that will be transformed into flour according to the defined conditions. by ourselves. His samples will be transferred to the microbiology laboratory for analysis. A count to assess the microbiological quality was carried out. The assay of some chemical parameters and the determination of some physical parameters were performed. The different pH values ​​obtained are all alkaline. Microbiological analysis revealed compliance of average microbial loads of fungi (yeasts and molds) below 103 CFU / g and aerobic mesophilic bacteria below 105 CFU / g. On the other hand, the average microbial loads of total coliforms do not comply with the defined microbiological criteria. Furthermore, with regard to the potentially pathogenic germs in Bacillus cereus occurrences, there is no conformity of the average loads of the three types of flour. The defined criterion being 10 CFU / g. As for E. coli and S. aureus, only F1 flour complies with microbiological criteria. There is a presence of Salmonella in 60% of the samples of the F1 flour. Good practices should be observed in the processing of grains into flour in order to avoid possible contamination of the flour.

Polystyrene was synthesized and applied as a template for fabricating hollow silica nanoparticles. Organic solvent and water were used as a solvent and an anti-solvent, respectively, to produce the polystyrene nanoparticles via. nanoprecipitation technique. The influence of precipitation method (one-shot or drop), solvent for dissolution of polystyrene, and concentration of polystyrene or CTAB linker on the diameter of polystyrene nanoparticles was investigated. The hollow silica nanoparticles were fabricated using the as-made polystyrene nanoparticles as a template with the help of CTAB linker. Polystyrene was recovered by the extraction of polystyrene@SiO2 composite with the tetrahydrofuran solvent, and the recovered polystyrene was re-used to make the polystyrene nanoparticles as a template for fabricating hollow silica nanoparticles. Our study can be applied for other types of polymeric materials as long as those polymeric materials form nanoparticles via. nanoprecipitation technique. In comparison with the polystyrene hard template prepared by emulsion polymerization, the size of polystyrene nanoparticles produced by the nanoprecipitation technique can be well-tuned by changing the polystyrene and linker concentrations.

BackgroundGabonese flora abounds in a significant reserve of plants in medical matter. Thus, medicinal plants occupy a significant place in African pharmacopeia. Aim of this work was to evaluate the antimicrobial, antioxidant, anti-inflammatory and cytotoxic properties of extracts ofGuibourtia tessmanii(Harms) J. Léonard.MethodsThe test for sensitivity to microorganisms was performed by the diffusion method, while the MICs and MBCs were evaluated by the microdilution technique. Antioxidant tests were performed by scavenging the DPPH and ABTS radicals. Anti-inflammatory activity was determined by protein denaturing and membrane stabilization methods. The cytotoxicity was evaluated on the tadpoles of the green frog.ResultsThe antibacterial activity shows that the Gt F2 fraction and the water-acetone extract produced the greatest inhibitions. The water, water-ethanol and water-acetone extracts exhibited bactericidal effects on the majority of bacteria. In the case of trapping of the DPPH radical, the IC50values varied from 6.92 ± 0.48 to 16.64 ± 0.20 μg/mL. For the decolouration of ABTS, oxidation was mainly inhibited by the water-acetetone, water-ethanol extracts and some fractions. The water and water-acetone extracts showed good inhibition of denaturation. The hemolysis test confirmed the good activities of the extracts. The lethal test showed that the LC50drops from 171.37 ± 9.25 to 58.25 ± 7.21 μg/mL after 24 and 96 h of exposure. In tadpoles exposed to 7.81 μg / mL of extracts, the first mortalities (12.5%) were observed on the second day of exposure. From the ninth day, the mortality rate increased (25%) until the 16th day.ConclusionOur results show thatGuibourtia tessmaniimay be a promising product for the isolations of molecules responsible for biological activities.

Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. Using single protein tracking, super-resolution microscopy and functional assays, we link the molecular behavior and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs. We show that immobilization of integrins in FAs depends on interaction with kindlin. Unlike talin, kindlin displays free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation, cell spreading and FAs formation. Thus, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation., Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Here, authors combine single protein tracking, super-resolution microscopy and functional assays, which allow correlating the molecular behaviour and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs.

Photoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8‐Naphthalimides with their extended π system can behave as light‐harvesting groups, fluorescent probes and DNA intercalators. We conjugated N‐(carboxymethyl)‐1,8‐naphthalimide (gly‐R‐Nap) with an R substituent on the naphthyl group to photoactive diazido PtIV complexes to form t,t,t‐[Pt(py)2(N3)2(OH)(gly‐R‐Nap)], R=H (1), 3‐NO2 (2) or 4‐NMe2 (3). They show enhanced photo‐oxidation, cellular accumulation and promising photo‐cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre‐intercalation into DNA, resulting in enhanced photo‐induced DNA crosslinking. Complex 3 has a red‐shifted absorption band at 450 nm, allowing photoactivation and photo‐cytotoxicity with green light., Green to go: Photoactive all‐trans diazido PtIV complexes with an axial 1,8‐naphthalimide ligand that can pre‐intercalate into DNA have been synthesised. They can be photoactivated with visible light to generate PtII DNA interstrand crosslinks and cytotoxic ROS, and are thus promising photo‐chemotherapeutic agents. Notably, a 4‐NMe2 substituent red‐shifted absorption of the naphthalimide ring, giving rise to its green‐light photo‐cytotoxicity.

Summary Galdieria sulphuraria is a cosmopolitan microalga found in volcanic hot springs and calderas. It grows at low pH in photoautotrophic (use of light as a source of energy) or heterotrophic (respiration as a source of energy) conditions, using an unusually broad range of organic carbon sources. Previous data suggested that G. sulphuraria cannot grow mixotrophically (simultaneously exploiting light and organic carbon as energy sources), its photosynthetic machinery being repressed by organic carbon.Here, we show that G. sulphuraria SAG21.92 thrives in photoautotrophy, heterotrophy and mixotrophy. By comparing growth, biomass production, photosynthetic and respiratory performances in these three trophic modes, we show that addition of organic carbon to cultures (mixotrophy) relieves inorganic carbon limitation of photosynthesis thanks to increased CO2 supply through respiration. This synergistic effect is lost when inorganic carbon limitation is artificially overcome by saturating photosynthesis with added external CO2.Proteomic and metabolic profiling corroborates this conclusion suggesting that mixotrophy is an opportunistic mechanism to increase intracellular CO2 concentration under physiological conditions, boosting photosynthesis by enhancing the carboxylation activity of Ribulose‐1,5‐bisphosphate carboxylase‐oxygenase (Rubisco) and decreasing photorespiration.We discuss possible implications of these findings for the ecological success of Galdieria in extreme environments and for biotechnological applications.