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Two new polyisoprenylated benzophenones, planchoniones A (1) and B (2), together with two known benzophenones (3, 4) and six known xanthones (5-10), were isolated from an ethyl acetate extract of t...

Three undescribed labdane diterpenoids, 15,16-epoxy-13,15-dihydroxylabd-8-ene-7-one (1), 15,16-epoxy-13-hydroxy-15-methoxylabd-8-ene-7-one (2) and 15-hydroxyleoheteronin B (3), along with eight known compounds, were isolated from an ethyl acetate extract of Leonurus japonicus. Their structures were elucidated using spectroscopic methods, mainly 1-D and 2-D NMR. Compound 1 showed the strongest cytotoxic activity against MCF-7 cells with IC50 values of 26.8 μM, using the sulforhodamine B assay.

HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8., Epitopes formed by fusion of more than one self peptide, such as proinsulin and other β cell proteins, can result in the formation of non-self hybrid peptides that can potentially trigger autoimmune responses. Here the authors show how TRBV5 + T cell receptors are geared towards recognition of HLA-DQ8 bound hybrid peptides in patients with type 1 diabetes.

A nickel-catalyzed 1,2-diarylation of alkenyl ketones with aryl iodides and arylboronic esters is reported. Ketones with a variety of substituents serve as effective directing groups, offering high levels of regiocontrol. A representative product is diversified into a wide range of useful products that are not readily accessible via existing 1,2-diarylation reactions. Preliminary mechanistic studies shed light on the binding mode of the substrate, and Hammett analysis reveals the effect of electronic factors on initial rates.

Polymer chain-extenders with one (AE, i.e., aminoethanol), two (APD, i.e., 2-amino-1,3-propanediol), and three (tris, i.e., 2-amino-2-(hydroxymethyl)-1,3-propanediol) pendant ethanol groups were us...

In this work, a close correlation between variations of critical temperature (Tc) and the hole concentration of (Bi1.6Pb0.4Sr2Ca2Cu3O10+δ)1-x(Fe3O4)x systems was studied. The (Bi1.6Pb0.4Sr2Ca2Cu3O10+δ)1-x(Fe3O4)x samples were fabricated using the solid-state reaction method, where x ranged from 0 to 0.2. The Tc values of the samples deduced from magnetization versus temperature measurement gradually decreased with increasing the Fe3O4 content (x). To investigate a possible reason for the observed decrease in the values of Tc in the samples, the valence state of copper (V) and the hole concentration (p) in all samples were examined by analyzing the Cu K-edge and Cu L2,3-edge X-ray absorption near edge structure (XANES) spectra. The values of V and p monotonously decreased with the increase in Fe3O4 doping content (x) and agreed with the behavior of Tc. The existence of Fe3+ was confirmed by analyzing Fe L2,3-edge XANES. Hence, Fe3+ ions possibly entered the lattice structure of the samples and filled the holes in CuO2 planes. The degradation of superconductivity in Fe3O4 doped samples was then explained.

Abstract The iridium-catalyzed C-H borylation of diethyl phenylphosphonate results in nonselective mono and bisborylation to afford a near statistical mixture of 3-, 3,5- and 4-boryl substituted aryl phosphonates whereas 3-substituted aryl phosphonates undergo highly regioselective C-H borylation to afford the corresponding meta-phosphonate substituted arylboronic esters as the sole product; the resulting boronic esters were used as nucleophilic reagents in a subsequent palladium-catalyzed Suzuki–Miyaura cross-coupling to generate a range of biarylmonophosphonates. Gratifyingly, the Suzuki–Miyaura cross-coupling can be conducted without purifying the boronic ester which greatly simplifies the synthetic procedure. Graphical Abstract

Resting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

The hexosamine biosynthetic pathway (HBP) is a glucose metabolism pathway that results in the synthesis of a nucleotide sugar UDP-GlcNAc, which is subsequently used for the post-translational modification (O-GlcNAcylation) of intracellular proteins that regulate nutrient sensing and stress response. The HBP is carried out by a series of enzymes, many of which have been extensively implicated in cancer pathophysiology. Increasing evidence suggests that elevated activation of the HBP may act as a cancer biomarker. Inhibition of HBP enzymes could suppress tumor cell growth, modulate the immune response, reduce resistance, and sensitize tumor cells to conventional cancer therapy. Therefore, targeting the HBP may serve as a novel strategy for treating cancer patients. Here, we review the current findings on the significance of HBP enzymes in various cancers and discuss future approaches for exploiting HBP inhibition for cancer treatment.

Cellulose microfibers were successfully fabricated from Vietnamese Nipa palm by mechanical and chemical treatments. The Nipa palm petioles were simply rolled, pressed, and separated. They were then pretreated with an alkaline solution and submitted to acid hydrolysis to remove the impurities (tCell). The microfibers were reinforced with reduced graphene oxide to form a hybrid that was reduced with hydrazine hydrate in the last stage (tCell-rGO). The structure and properties of tCell and tCell-rGO were evaluated by FTIR, XRD, DSC, TGA, SEM, BET, and the sheet resistance. It was observed that the treated cellulose microfibers exhibited a diameter of 10–20 μm and had good crystallinity in the structure. Both tCell and tCell-rGO exhibited low-density values of 1.52 kg/m3 and 0.58 kg/m3, respectively, and had good specific surface area values of 11.2 m2/g and 13.0 m2/g, respectively. These results supported the decrease in the density and the increase in the specific surface area of the tCell-rGO samples in comparison with the tCell. The existence of rGO sheets in the cellulose microfiber matrix resulted in changes in the structure, arrangement, and crystallization of pristine microfibers. The thermal property and electrical conductivity of the reinforced GO cellulose microfibers were significantly improved. rGO not only showed its role as a surface modification agent that helps the cellulose microfibers disperse better in the non-polar substrate, but also contributed to the increase of the heat-stable and mechanical properties of polymer. The thermal stability of tCell-rGO/PMMA composite was notably improved more than 40°C in maximum decomposition temperature by an emulsion polymerization technique. The material based on cellulose microfibers from the Vietnamese Nipa palm tree and reduced graphene oxide overcame some disadvantages such as the poor heat resistance, poor dispersion of the original fibers in the non-polar polymer and displayed great potential for environmentally friendly future applications.

ispartof: BLOOD vol:137 issue:8 pages:1117-1120 ispartof: location:United States status: published

Doped conjugated polymers can present high electrical conductivity, but their stability against external stimuli such as heat, moisture, and solvent is often limited. Here, we report a design appro...

Electron-deficient olefin (EDO) ligands are known to promote a variety of nickel-catalyzed cross-coupling reactions, presumably by accelerating the reductive elimination step and preventing undesired β-hydride elimination. While there is a growing body of experimental and computational evidence elucidating the beneficial effects of EDO ligands, significant gaps remain in our understanding of the underlying coordination chemistry of the Ni–EDO species involved. In particular, most procedures rely on in situ assembly of the active catalyst, and there is a paucity of preligated Ni–EDO precatalysts. Herein, we investigate the 16-electron, heteroleptic nickel complex, Ni(COD)(DMFU), and examine the performance of this complex as a precatalyst in 1,2-diarylation of alkenes.

An effective adsorbent of methylene blue was synthesized from coal fly ash (FA; waste material from a coal power plant) by a denaturing process with an alkaline solution at 90 °C. The denatured fly ash (D-FA) has a surface area and pore volume of 66.39 m2 g−1 and 15.33 cm3 g−1, respectively, whereas the values of the original FA are negligible, i.e., 3.55 m2 g−1 and 0.02 cm3 g−1. The removal of methylene blue (MB) in aqueous solution by D-FA was increased in the range of initial MB concentration (10–20 mg L−1); contact time (0–120 min); pH (2–8); D-FA dosage (1–4 g L−1). However, a larger value of those operational parameters would not improve the removal activity. Furthermore, the methylene blue adsorption on the denatured FA was fitted with the Langmuir model with R2 = 0.9991; the maximum adsorption capacity was determined as 28.65 mg g−1 from the model. Overall, the highest removal efficiency of MB using D-FA with the dosage of 4 g L−1 was 97.1% in 30 mg L−1 solution of methylene blue at pH = 7. The alkaline hydrothermal denaturation of waste FA is a promising approach to produce an adsorbent with beneficial environmental engineering applications.

The decomposition of primary sodium alkoxide salts under ambient storage conditions and the effects of this phenomenon on commonly employed transition-metal-catalyzed cross-coupling reactions are described. By utilizing NMR, IR, and Raman spectroscopy, along with a modified Karl Fischer analysis, the main inorganic degradants were characterized, and CO2 in the air was found to be a critical reactant within the decomposition process. The effects of storage conditions on decomposition were evaluated, and the preliminary experiments to understand the kinetics of this process were performed.

Microdosimetry provides measurements of stochastic lineal energy deposition in a micrometric sensitive volume (SV) that are comparable to human cell dimensions, typically in the order of 10–15 $\mu \text{m}$ in diameter. Silicon-based microdosimeters have been fabricated using “3-D technology,” providing true cell-like SVs that are fully encapsulated by a 3-D through substrate electrode. The unique geometry has been made feasible using modern microelectromechanical systems (MEMS). The combination of MEMS techniques and radiation detector fabrication brings forth challenges in achieving reliability, consistency, and high yield. This article reviews the technological challenges encountered in several prototype runs completed at SINTEF. The technological review and prototype iterations aim to deliver a future technology plan at the manufacture level with a high yield throughput.

1,2-Diarylation of alkenyl sulfonamides with aryl iodides and aryl boronic esters under nickel catalysis is reported. The developed method tolerates coupling partners with disparate electronic prop...

Polymers formed by ring-opening metathesis polymerization (ROMP) such as poly(dicyclopentadiene) (pDCPD) exhibit a technologically desirable combination of high toughness, high glass transition temperature, and outstanding low-temperature performance. However, because of their nonpolar molecular structure, they tend to suffer from relatively low elastic moduli and poor adhesion to common fillers, fibers, and substrates, limiting their utility as adhesives and composite binders without specialized bonding agents. Here, we investigate the mechanical properties of a pDCPD-based copolymer filled with well-defined spherical microparticles having four distinct surface chemistries capable of strong, moderate, or weak bonding to the matrix with surfaces ranging from polar to nonpolar. Measurements in uniaxial tension, quasi-static fracture, and high-velocity impact are complemented by digital image correlation (DIC), scanning electron microscopy (SEM) fractography, and X-ray computed tomography (X-μCT) of subcritically loaded crack tips, yielding insight into the complex roles played by interfacial bonding in strength, stiffness, and toughening mechanisms of an already tough polymer. Analysis using quantitative fracture and impact mechanism models provided valuable guidelines for designing heterogeneous systems that combine structural and tough performance.

Objectives: Acyclovir (ACV) is an antiviral drug, which requires frequent dosing regimen because of poor oral bioavailability and short half-life. In this study, ACV nanoparticles were formulated using ammonium methacrylates copolymers such as Eudragit RS 100 (Eud RS) and Eudragit RL 100 (Eud RL) to prolong release drug, and increase bioavailability. Methods: ACV loaded nanoparticles were prepared by the solvent replacement technique and then were characterized by particle size, distribution, entrapment efficiency, differential scanning calorimeter, transmission electron microscope, and in-vitro drug release. Results: It was found that as drug:polymer ratio changed from 1:2 to1:5, particle size and drug entrapment efficiency increased significantly. ACV– Eud RS loaded nanoparticles had a larger mean diameter of 363 nm in comparison to 200 nm of ACV- Eud RL nanoparticles. DSC results showed that in the prepared ACV-Eud RS nanoparticles, the drug was presented in the amorphous phase and may have been molecularly dispersed in the polymer matrix, but in the ACV-Eud RL nanoparticles, the drug was presented in the particles and homogeneously dispersed in the polymeric matrix. The entrapment efficiency of AVC-Eud RS nanoparticles was higher than that of ACV-Eud RL nanoparticles. In vitro drug release study showed that the ratios of released drug from ACV-Eud RS nanoparticles in the range from 58±3.8 to 62.9±4.6%, which was lower than those from ACV-Eud RL nanoparticles, in the range from 73.3±4.9 to 77.9±2.9%. The release was found to follow the Weibull model with a Fickian diffusion mechanism for both ACVEud RS and ACV- Eud RL nanoparticles. Conclusion: These results suggest that ACV nanoparticles based on Eud RS100 and Eud RL100 could prolong the release of the drug.

HIV infection is a global health epidemic with current FDA-approved HIV-1 Protease inhibitors (PIs) designed against subtype B protease, yet they are used in HIV treatment world-wide regardless of patient HIV classification. In this study, double electron-electron resonance (DEER) electron paramagnetic resonance (EPR) spectroscopy was utilized to gain insights in how natural polymorphisms in several African and Brazilian protease (PR) variants affect the conformational landscape both in the absence and presence of inhibitors. Findings show that Subtypes F and H HIV-1 PR adopt a primarily closed conformation in the unbound state with two secondary mutations, D60E and I62V, postulated to be responsible for the increased probability for closed conformation. In contrast, subtype D, CRF_AG, and CRF_BF HIV-1 PR adopt a primarily semi-open conformation, as observed for PI-naive-subtype B when unbound by substrate or inhibitor. The impact that inhibitor binding has on shifting the conformational land scape of these variants is also characterized, where analysis provides classification of inhibitor induced shifts away from the semi-open state into weak, moderate and strong effects. The findings are compared to those for prior studies of inhibitor induced conformational shifts in PI-naive Subtype B, C and CRF_AE.

Purpose Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. Methods and Materials A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. Results At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. Conclusions At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.

Pineapple leaf and cotton waste fibers known as abundant by-products in the agriculture and textile industry are combined for the first time to produce thermal insulating and flexible cellulose-based aerogel composites via an environmentally friendly and cost-effective freeze-drying process. The effect of total fiber content and the ratio of pineapple leaf fibers (PF) to cotton waste fibers (CF) on the density, porosity, morphology, durability, and thermal properties of aerogel composites are comprehensively investigated. The as-fabricated aerogel composites show an exceedingly low density of 0.019–0.046 g cm−3 with high porosity of more than 96%. Because of the porous structure inside, our aerogel composites exhibit outstanding heat insulation with extraordinarily low thermal conductivity of 0.039–0.043 W m−1 K−1 that is comparable to commercial insulation materials (mineral wool, fiberglass, polystyrene) and previous cellulose-based aerogels from recycled cellulose fibers, sugarcane bagasse, and rice straw. Interestingly, the combination of those fibers has remarkably improved the flexibility of our previous aerogels from pineapple leaf fibers only, in particular, the compressive modulus of aerogel composites (11.33–44.63 kPa) is 6 times higher than that of PF aerogels (5.73 kPa). The sheet of aerogel composite with a dimension of 28 × 28 cm which is rolled up shows no crack on its surface, demonstrating its excellent mechanical strength. The research results increase the possibility of applying the developed aerogel composites from biomass into practical insulation.

A nickel-catalyzed regiodivergent hydroarylation and hydroalkenylation of unactivated alkenyl carboxylic acids is reported, whereby the ligand environment around the metal center dictates the regiochemical outcome. Markovnikov hydrofunctionalization products are obtained under mild ligand-free conditions, with up to 99% yield and >20:1 selectivity. Alternatively, anti-Markovnikov products can be accessed with a novel 4,4-disubstituted Pyrox ligand in excellent yield and >20:1 selectivity. Both electronic and steric effects on the ligand contribute to the high yield and selectivity. Mechanistic studies suggest a change in the turnover-limiting and selectivity-determining step induced by the optimal ligand. DFT calculations reveal that in the anti-Markovnikov pathway, repulsion between the ligand and the alkyl group is minimized (by virtue of it being 1° versus 2°) in the rate- and regioselectivity-determining transmetalation transition state.

The ecological relationships between heterotrophic bacteria and marine phytoplankton are complex and multifaceted, and in some instances include the bacteria-mediated aggregation of phytoplankton cells. It is not known to what extent bacteria stimulate aggregation of marine phytoplankton, the variability in aggregation capacity across different bacterial taxa or the potential role of algogenic exopolymers in this process. Here we screened twenty bacterial isolates, spanning nine orders, for their capacity to stimulate aggregation of two marine phytoplankters, Thalassiosira weissflogii and Nannochloropsis oceanica. In addition to phytoplankton aggregation efficiency, the production of exopolymers was measured using Alcian Blue. Bacterial isolates from the Rhodobacterales, Flavobacteriales and Sphingomonadales orders stimulated the highest levels of cell aggregation in phytoplankton cultures. When co-cultured with bacteria, exopolymer concentration accounted for 34.1% of the aggregation observed in T. weissflogii and 27.7% of the aggregation observed in N. oceanica. Bacteria-mediated aggregation of phytoplankton has potentially important implications for mediating vertical carbon flux in the ocean and in extracting phytoplankton cells from suspension for biotechnological applications.

Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop’s N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.

Significance Eukaryotic gelsolin superfamily proteins generally comprise three or more related domains. Here we characterize single- and double-domain gelsolins from Thorarchaeota (Thor). Similar domain architectures are present in Heimdall-, Loki-, and Odinarchaeota. Thor gelsolins are functional in regulating rabbit actin in in vitro assays, showing a range of activities including actin filament severing and bundling. These gelsolins bind to the eukaryotic gelsolin/cofilin-binding site on actin. Two-domain, but not one-domain, gelsolins are calcium regulated. Thor gelsolins appear to have the characteristics and structure consistent with primitive gelsolins/cofilins, suggesting that these single- and double-domain gelsolins are a record of a nascent preeukaryotic actin-regulation machinery., Asgard archaea genomes contain potential eukaryotic-like genes that provide intriguing insight for the evolution of eukaryotes. The eukaryotic actin polymerization/depolymerization cycle is critical for providing force and structure in many processes, including membrane remodeling. In general, Asgard genomes encode two classes of actin-regulating proteins from sequence analysis, profilins and gelsolins. Asgard profilins were demonstrated to regulate actin filament nucleation. Here, we identify actin filament severing, capping, annealing and bundling, and monomer sequestration activities by gelsolin proteins from Thorarchaeota (Thor), which complete a eukaryotic-like actin depolymerization cycle, and indicate complex actin cytoskeleton regulation in Asgard organisms. Thor gelsolins have homologs in other Asgard archaea and comprise one or two copies of the prototypical gelsolin domain. This appears to be a record of an initial preeukaryotic gene duplication event, since eukaryotic gelsolins are generally comprise three to six domains. X-ray structures of these proteins in complex with mammalian actin revealed similar interactions to the first domain of human gelsolin or cofilin with actin. Asgard two-domain, but not one-domain, gelsolins contain calcium-binding sites, which is manifested in calcium-controlled activities. Expression of two-domain gelsolins in mammalian cells enhanced actin filament disassembly on ionomycin-triggered calcium release. This functional demonstration, at the cellular level, provides evidence for a calcium-controlled Asgard actin cytoskeleton, indicating that the calcium-regulated actin cytoskeleton predates eukaryotes. In eukaryotes, dynamic bundled actin filaments are responsible for shaping filopodia and microvilli. By correlation, we hypothesize that the formation of the protrusions observed from Lokiarchaeota cell bodies may involve the gelsolin-regulated actin structures.

Organic field-effect transistors (OFETs) are usually unstable at high temperature (above 150 °C), reportedly due to the disrupting charge transport pathways in the channel. Here, we demonstrate tha...

The need for active and stable oxidation catalysts is driven by the demands in production of valuable chemicals, remediation of hydrocarbon pollutants and energy sustainability. Traditional approaches focus on oxygen-activating oxides as support which provides the oxygen activation at the catalyst-support peripheral interface. Here we report a new approach to oxidation catalysts for total oxidation of hydrocarbons (e.g., propane) by surface oxygenation of platinum (Pt)-alloyed multicomponent nanoparticles (e.g., platinum-nickel cobalt (Pt–NiCo)). The in-situ/operando time-resolved studies, including high-energy synchrotron X-ray diffraction and diffuse reflectance infrared Fourier transform spectroscopy, demonstrate the formation of oxygenated Pt–NiOCoO surface layer and disordered ternary alloy core. The results reveal largely-irregular oscillatory kinetics associated with the dynamic lattice expansion/shrinking, ordering/disordering, and formation of surface-oxygenated sites and intermediates. The catalytic synergy is responsible for reduction of the oxidation temperature by ~100 °C and the high stability under 800 °C hydrothermal aging in comparison with Pt, and may represent a paradigm shift in the design of self-supported catalysts., Traditional approach to oxidation catalysts relies on metal/oxide supported peripheral interfacial oxygen activity. Here the authors show surface oxygenation of platinum-alloyed multicomponent nanoparticles, and reveals irregular oscillatory kinetics associated with the surface oxygenated sites.

The Centre for Medical Radiation Physics (CMRP) has designed and produced novel n-type silicon single strip detectors (SSDs) for use in dosimetry of synchrotron-based microbeam radiation therapy (MRT). In order to address the challenges of dosimetry and quality assurance of these beams, a detector is required with micron-scale spatial resolution, real-time read-out, large dynamic range, and significant radiation hardness. The CMRP first-generation 3-D-Mesa SSD is fabricated in n-SOI technology and involves plasma etching to produce a 10 $\times $ 36 $\times $ 250 $\mu \text{m}^{3}$ sensitive volume (SV) or a 10 $\times $ 22.5 $\times $ 250 ${\mu }\text{m}^{3}$ SV with all surrounding silicon above the insulating layer removed. The 3-D-Mesa has undergone full electrical characterization and a charge collection study, supported by TCAD simulations to model electric field in the device. The optimal operating bias was found to be −2 V, which produces a dark current of less than 1 nA and 100% charge collection efficiency within the SV. Charge collection is observed at greater biases from the silicon bridge under the Al bus that electrically connects the SV of the SSD to the readout pad. The reasons for this are discussed and will be addressed in the next generation of the 3-D-Mesa SSD.

In this study, we present a novel approach to prepare of a colorimetric chemical sensor for H2O2 and a glucose biosensor basing on the use of peroxidase-like activity of silver nanoparticles decorated on reduced graphene oxide sheets (AgNPs@rGO) nanocomposite. Herein, AgNPs@rGO nanocomposite was synthesized by a one-step hydrothermal reducing method and its physico-chemical properties were characterized by X-ray diffraction (XRD), Transmission Electron Microscopy (TEM), Ultraviolet–visible spectroscopy (UV–Vis), Fourier-Transform Infrared spectroscopy (FT-IR) and Energy Dispersive X-ray spectroscopy (EDX). Obtained evaluation results shown that the synthesized AgNPs/rGO nanocomposite has performed an efficient peroxidase-like activity for the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMBred) by H2O2, leading to the oxidized form (TMBox) which presents a typical blue color (maximum of absorbance at λmax = 655 nm). A colorimetric assay for H2O2 detection was designed and fabricated with a limit of detection of 20 μM. Moreover, we have used of AgNPs/rGO nanocomposite combining with glucose oxidase (GOx) to develop of a colorimetric glucose biosensor with a low limit of detection of 40 μM and a linear dynamic range from 125 μM to 1 mM. This glucose test was applied to the detection of glucose in human serum samples.

In this study, cellulose extracted from straw was modified using N(4)-morpholinothiosemicarbazide to generate a novel adsorbent as a chelate-complex-based material. The effects of pH, time, temperature, and mass ratios of KIO4: cellulose on the yield of the oxidation were analyzed using iodometric titration and photometric methods. The accuracy and precision of the above two methods were evaluated using Student and Fisher statistical distribution. The structure of the material was characterized by Fourier-transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, scanning electron microscopy, and Brunauer–Emmett–Teller surface area analysis. The kinetic order of Ni(II) adsorption was dependent on the concentration of Ni(II). The surface response design enabled to optimize the condition for Ni(II) adsorption at 58 °C, pH of 4.98, within 106 min. The maximum Ni(II) adsorption capacity was 90 mg g–1. This kind of adsorbent can be reused at least five times without a significant decrease in its adsorption efficiency.

The fungal indole alkaloids are a unique class of complex molecules that have a characteristic bicyclo[2.2.2]diazaoctane ring and frequently contain a spiro-oxindole moiety. While various strains produce these compounds, an intriguing case involves the formation of individual antipodes by two unique species of fungi in the generation of the potent anticancer agents (+)- and (-)-notoamide A. NotI and NotI' have been characterized as flavin-dependent monooxygenases that catalyze epoxidation and semi-pinacol rearrangement to form the spiro-oxindole center within these molecules. This work elucidates a key step in the biosynthesis of the notoamides and provides an evolutionary hypothesis regarding a common ancestor for production of enantiopure notoamides.

Ring-opening metathesis polymerization (ROMP) produced homopolymers and copolymers of 5-ethylidene-2-norbornene (ENB) and 5-methanol-2-norbornene (NBOH), and this provided a platform to explore the...

Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.

In this study, we synthesized high-performance Carbon Fiber/ Gold/ Copper (CF/Au/Cu) composite wires by using a 2-step deposition method via sputtering and electrodeposition. After Au was sputtered on PAN-based CFs as a pre-treatment, the wettability and surface reactivity of the CFs were improved, resulting in a homogeneous deposition of Cu on their surface. At different Cu electrodeposition time, the resulting CF/Au/Cu composite wires could possess a high strength of up to 3.27 GPa ( ∼ 10 times stronger than copper wires) while their electrical conductivity could be as high as 4.4 × 10 5 S/cm ( ∼ 75 % of that for copper). More importantly, since the composite wires were lightweight (up to 70 % lower than Cu mass density), they are a promising candidate to substitute conventional heavy metal wires in the future electrical applications.

Huwentoxin-IV (HwTx-IV) is a gating modifier peptide toxin from spiders that has weak affinity for the lipid bilayer. As some gating modifier toxins have affinity for model lipid bilayers, a tripartite relationship among gating modifier toxins, voltage-gated ion channels, and the lipid membrane surrounding the channels has been proposed. We previously designed an HwTx-IV analogue (gHwTx-IV) with reduced negative charge and increased hydrophobic surface profile, which displays increased lipid bilayer affinity and in vitro activity at the voltage-gated sodium channel subtype 1.7 (Na(V)1.7), a channel targeted in pain management. Here, we show that replacements of the positively-charged residues that contribute to the activity of the peptide can improve gHwTx-IV's potency and selectivity for Na(V)1.7. Using HwTx-IV, gHwTx-IV, [R26A]gHwTx-IV, [K27A]gHwTx-IV, and [R29A]gHwTx-IV variants, we examined their potency and selectivity at human Na(V)1.7 and their affinity for the lipid bilayer. [R26A]gHwTx-IV consistently displayed the most improved potency and selectivity for Na(V)1.7, examined alongside off-target Na(V)s, compared with HwTx-IV and gHwTx-IV. The lipid affinity of each of the three novel analogues was weaker than that of gHwTx-IV, but stronger than that of HwTx-IV, suggesting a possible relationship between in vitro potency at Na(V)1.7 and affinity for lipid bilayers. In a murine Na(V)1.7 engagement model, [R26A]gHwTx-IV exhibited an efficacy comparable with that of native HwTx-IV. In summary, this study reports the development of an HwTx-IV analogue with improved in vitro selectivity for the pain target Na(V)1.7 and with an in vivo efficacy similar to that of native HwTx-IV.

We report that Ni(COD)(DQ) (COD=1,5-cyclooctadiene, DQ=duroquinone), an air-stable 18-electron complex originally described by Schrauzer in 1962, is a competent precatalyst for a variety of nickel-catalyzed synthetic methods from the literature. Due to its apparent stability, use of Ni(COD)(DQ) as a precatalyst allows reactions to be conveniently performed without use of an inert-atmosphere glovebox, as demonstrated across several case studies.

Chronic inflammation that affects primarily metabolic organs, such as white adipose tissue (WAT), is considered as a major cause of human obesity-associated co-morbidities. However, the molecular mechanisms initiating this inflammation in WAT are poorly understood. By combining transcriptomics, ChIP-seq and modeling approaches, we studied the global early and late responses to a high-fat diet (HFD) in visceral (vWAT) and subcutaneous (scWAT) AT, the first being more prone to obesity-induced inflammation. HFD rapidly triggers proliferation of adipocyte precursors within vWAT. However, concomitant antiadipogenic signals limit vWAT hyperplastic expansion by interfering with the differentiation of proliferating adipocyte precursors. Conversely, in scWAT, residing beige adipocytes lose their oxidizing properties and allow storage of excessive fatty acids. This phase is followed by tissue hyperplastic growth and increased angiogenic signals, which further enable scWAT expansion without generating inflammation. Our data indicate that scWAT and vWAT differential ability to modulate adipocyte number and differentiation in response to obesogenic stimuli has a crucial impact on the different susceptibility to obesity-related inflammation of these adipose tissue depots. Electronic supplementary material The online version of this article (10.1007/s00018-020-03485-z) contains supplementary material, which is available to authorized users.

Cerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signalling in this phenomenon. Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation; a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses was observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognisedin vivoafter whisker stimulation, were significantly attenuated in mice with altered endothelial gap junctional signalling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability, after stroke. Our findings establish the integral role of intercellular electrical signalling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.SignificanceNeurovascular responses are viewed as a one step process whereby stimuli derived from neural cells focally diffuse to a neighboring vessel, altering its contractile state. While focal changes in tone can subtly tune flow distribution, they can’t substantively change “perfusion magnitude” as vascular resistance is broadly distributed along the cerebral arterial tree. We report that nature overcomes this biophysical constraint by conducting electrical signals among coupled vascular cells, along vessels, and across branch points. Our quantitative exploration of intercellular conduction illustrates how network coordination optimizes blood flow delivery in support of brain function. Diminishing the ability of vascular cells to electrically communicate, mitigates the brain’s ability to regulate perfusion during functional hyperemia and after stroke, the latter advancing tissue injury.

Nickel-catalyzed three-component alkene difunctionalization has rapidly emerged as a powerful tool for forging two C–C bonds in a single reaction. Building upon the powerful modes of bond construction in traditional two-component cross-coupling, various research groups have demonstrated the versatility of nickel in enabling catalytic 1,2-dicarbofunctionalization using a wide range of carbon-based electrophiles and nucleophiles and in a fully intermolecular fashion. Though this area has emerged only recently, the last few years have witnessed a proliferation of publications on this topic, underscoring the potential of this strategy to develop into a general platform that offers high regio- and stereoselectivity. This minireview highlights the recent progress in the area of intermolecular 1,2-dicarbofunctionalization of alkenes via nickel catalysis and discusses lingering challenges within this reactivity paradigm., Nickel-catalyzed three-component alkene difunctionalization has rapidly emerged as a powerful tool for forging multiple C–C bonds in a single step.

Three new compounds comprising two coumarins, paramicoumarins A (1) and B (2), and an acridone alkaloid, paramiacridone (3), together with seven known compounds, were isolated from the n-hexane extract of the roots of Paramignya trimera (Rutaceae). Their structures were elucidated using spectroscopic methods, mainly 1D and 2D NMR. α-Glucosidase inhibition and DPPH radical scavenging activity of the compounds and fifteen other compounds previously isolated from the roots of this plant were evaluated. Most of the compounds exhibited stronger α-glucosidase inhibitory activity than acarbose, the positive control (IC50 = 223.0 μM), and the new compounds paramiacridone (3) and paramicoumarin B (2) showed good inhibitory effect (IC50 = 62.5 and 65.5 μM, respectively). In the DPPH test for radical scavenging activity, the acridone alkaloid glycocitrin III (17) exhibited the highest antioxidant activity (IC50 = 84.2 μM) (compared with the positive control, ascorbic acid, IC50 = 152.7 μM).

Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

Fused thieno[3,2-d]thiazoles were synthesized via a coupling of acetophenone ketoximes, arylacetic acids, and elemental sulfur in the presence of Li2CO3 base. Functionalities including chloro, bromo, fluoro, trifluoromethyl, and pyridyl groups were compatible with reaction conditions. High yields and excellent regioselectivities were obtained even if meta-substituted ketoxime acetates were used. Ethyl esters of heteroarylacetic acids were competent substrates, which is very rare in the literature. Our method would offer a convenient protocol to afford polyheterocyclic structures from simple substrates.

Metabolic glycan engineering (MGE) coupled with nitroxide spin-labeling (SL) was utilized to investigate the heterogeneous environment of cell surface glycans in select cancer and normal cells. This approach exploited the incorporation of azides into cell surface glycans followed by a click reaction with a new nitroxide spin label. Both sialic acid and N-acetylglucosamine (GlcNAc) were targeted for spin labelling. Although each of these moieties experiences a diverse and heterogeneous glycan environment, their EPR spectra and hence mobility are both characterized as a linear combination of two distinct spectra where one component reflects a highly mobile or uncrowded micro-environment with the second component reflecting more restricted motion, reflective of increased crowding and packing within the glycocalyx. What differs among the spectra of the targeted glycans is the relative percentage of each component, with sialic acid moieties experiencing on average an ∼80% less crowded environment, where conversely GlcNAc/GalNAz labeled sites reported on average a ∼50% more crowded environment. These distinct environments are consistent with the organization of sugar moieties within cellular glycans where some residues occur close to the cell membrane/protein backbone (i.e. more restricted) and others are more terminal in the glycan (i.e. more mobile). Strikingly, different cell lines displayed varied relative populations of these two components, suggesting distinctive glycan packing, organization, and composition of different cells. This work demonstrates the capability of SDSL EPR to be a broadly useful tool for studying glycans on cells, and interpretation of the results provides insights for distinguishing the differences and changes in the local organization and heterogeneity of the cellular glycocalyx., Metabolic glycan engineering (MGE) coupled with nitroxide spin-labeling (SL) was utilized to investigate the heterogeneous environment of cell surface glycans in select cancer and normal cells.

Bleeding is a common adverse event following ibrutinib monotherapy. However, it remains unclear how hemostasis is affected by venetoclax in combination with ibrutinib. Here we investigated hemostasis in patients with chronic lymphocytic leukemia (CLL) at baseline, during ibrutinib monotherapy, and during venetoclax and ibrutinib combination therapy or venetoclax monotherapy. Primary hemostasis, assessed by Multiplate using adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor agonist peptide (TRAP-6), was impaired in all CLL patients at baseline, remained unchanged upon ibrutinib monotherapy, and improved significantly following venetoclax added to ibrutinib or as monotherapy. Secondary hemostasis assessed by thromboelastography (TEG) was normal and unchanged throughout treatment. The frequency of clinical bleeding events was the highest during ibrutinib monotherapy, in line with the demonstrated improved primary hemostasis upon addition of venetoclax, thus pointing toward a treatment option for CLL patients with increased bleeding risk.