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Plastics have become ubiquitous in the world’s oceans, and recent work indicates that they can transfer from the ocean to the atmosphere in sea spray aerosol (SSA). SSA is the largest contributor to annual aerosol mass load and is a significant source of plastic to the atmosphere. Plastic additives, including bisphenol-A (BPA), represent a sizable fraction of consumer plastics and have been measured consistently in air over both terrestrial and marine environments. However, the chemical lifetimes of BPA and mechanisms by which it degrades with respect to photochemical and heterogeneous oxidation processes in aerosols are unknown. The work in this dissertation utilized an extractive electrospray ionization time-of-flight mass spectrometer (EESI-TOF) to monitor changes in aerosol composition with high time resolution. In Chapter 3, the photosensitized and OH- initiated heterogeneous oxidation kinetics of BPA in the aerosol phase consisting of pure-component BPA and internal mixtures of BPA, NaCl, and dissolved photosensitizing organic matter are presented. OH-initiated degradation is enhanced in the presence of chloride, likely due to the enhanced mobility of BPA in the more liquid-like particle due to the hygroscopicity of NaCl increasing the liquid water content within the aerosol. In contrast, photosensitized reactions were limited in the presence of chloride, which was attributed to quenching of triplet state formation by dissolved Cl− in the less viscous aqueous aerosol mixtures. In Chapter 4, the composition changes in SSA during a phytoplankton bloom are determined, including the temporal variability and trends dependent on specific biological processes occurring in seawater. Through this study, it was also established that EESI-TOF sensitivity is critically dependent on the sample's relative humidity after adjusting for pressure variations at the inlet and normalization to the reagent ion. In Chapter 5, the photosensitized degradation of BPA at high and low pH is investigated. At pH 3 and pH 11, the photosensitized degradation of BPA is inhibited, and the potential causes are discussed. This dissertation highlights important heterogeneous and photosensitized reactions which BPA undergoes, as well as the role of particle viscosity. Ultimately, this work contributes to our understanding of the lifetimes of hazardous plastic pollutants in SSA with implications for pollutant transport and exposure risks in coastal marine environments.

A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin analogue pramlintide is commercially available for diabetes treatment as an adjunct to insulin therapy but requires three daily injections due to its short half-life. We report here the development of the stable, lipidated long-acting amylin analogue cagrilintide (23) and some of the structure-activity efforts that led to the selection of this analogue for clinical development with obesity as an indication. Cagrilintide is currently in clinical trial and has induced significant weight loss when dosed alone or in combination with the GLP-1 analogue semaglutide.

We report on the “one step─one pot” synthesis of chain-lengthened aliphatic amines and nitriles from CO/H2/NH3 gas feeds using potassium-promoted Co/MnOx catalysts prepared via MOF-type (metal orga...

The lone-pair…π (lp…π) (deoxy)ribose…nucleobase stacking is a recurring structural motif in Z DNA and RNAs that is characterized by sub-van der Waals lp…π contacts (

Recently, porous photocatalytically active block copolymer membranes were introduced, based on heterogenized molecular catalysts. Here, we report the integration of the photosensitizer, i. e., the light absorbing unit in an intermolecular photocatalytic system into block copolymer membranes in a covalent manner. We study the resulting structure and evaluate the orientational mobility of the photosensitizer as integral part of the photocatalytic system in such membranes. To this end we utilize transient absorption anisotropy, highlighting the temporal reorientation of the transition dipole moment probed in a femtosecond pump-probe experiment. Our findings indicate that the photosensitizer is rigidly bound to the polymer membrane and shows a large heterogeneity of absolute anisotropy values as a function of location probed within the matrix. This reflects the sample inhomogeneity arising from different protonation states of the photosensitizer and different intermolecular interactions of the photosensitizers within the block copolymer membrane scaffold.

The European Union banned the usage of antibiotic growth promoters in animal production. The probiotic microorganism of the genus Bacillus appeared to be an attractive candidate to replace antibiotics. The Bacillus subtilis DSM 29784 is one of these strains. To date, the probiotic effect has not been completely understood, but it is supposed that the effect depends on metabolites of the microorganism. Imaging high-performance thin-layer chromatography (HPTLC) is a powerful tool to visualize differences in the metabolite profile of bacteria with high genetic similarity to allow a better understanding of the probiotic effect. In comparison to other bacteria, especially these bacterial cells were more robust to harsh cultivation conditions and produced a higher level of antioxidants or bioactive substances such as surfactin. HPTLC enabled the comparison of pure cell cultures to the spore cultivation in the feed, and the results explain and support the probiotic effect.

Bio-based activated carbons with very high specific surface area of &gt, 3.000 m² g−1 (based on CO2 adsorption isotherms) and a high proportion of micropores (87% of total SSA) are produced by corncobs via pyrolysis and chemical activation with KOH. The activated carbon is further doped with different proportions of the highly pseudocapacitive transition metal oxide RuO2 to obtain enhanced electrochemical properties and tune the materials for the application in electrochemical double-layer capacitors (EDLC) (supercapacitors). The activated carbon and composites are extensively studied regarding their physico-chemical and electrochemical properties. The results show that the composite containing 40 wt.% RuO2 has an electric conductivity of 408 S m−1 and a specific capacitance of 360 Fg−1. SEM-EDX, XPS, and XRD analysis confirm the homogenous distribution of partly crystalline RuO2 particles on the carbon surface, which leads to a biobased composite material with enhanced electrochemical properties.

Ciguatoxins (CTX) are potent marine neurotoxins, which can bioaccumulate in seafood, causing a severe and prevalent human illness known as ciguatera poisoning (CP). Despite the worldwide impact of ciguatera, effective disease management is hindered by a lack of knowledge regarding the movement and biotransformation of CTX congeners in marine food webs, particularly in the Caribbean and Western Atlantic. In this study we investigated the hepatic biotransformation of C-CTX across several fish and mammalian species through a series of in vitro metabolism assays focused on phase I (CYP P450; functionalization) and phase II (UGT; conjugation) reactions. Using liquid chromatography high-resolution mass spectrometry to explore potential C-CTX metabolites, we observed two glucuronide products of C-CTX-1/-2 and provided additional evidence from high-resolution tandem mass spectrometry to support their identification. Chemical reduction experiments confirmed that the metabolites were comprised of four distinct glucuronide products with the sugar attached at two separate sites on C-CTX-1/-2 and excluded the C-56 hydroxyl group as the conjugation site. Glucuronidation is a novel biotransformation pathway not yet reported for CTX or other related polyether phycotoxins, yet its occurrence across all fish species tested suggests that it could be a prevalent and important detoxification mechanism in marine organisms. The absence of glucuronidation observed in this study for both rat and human microsomes suggests that alternate biotransformation pathways may be dominant in higher vertebrates.

Manganese (Mn) is an essential plant micronutrient that influences photosynthesis, ecosystem productivity, and soil carbon storage. Our objective was to quantify how Mn uptake by forest vegetation relates to Mn release into soil solution through mineral dissolution. A greenhouse pot experiment was conducted to quantify Mn uptake by red maple saplings as a function of mineral solubility to test whether Mn uptake was limited by the supply of Mn to soil solution. Differences in soil microbial community composition between treatments, particularly amongst Mn cycling bacteria and fungi, were also evaluated to assess potential microbial impacts on observed Mn fluxes. Plant Mn uptake was highest in systems supplied with dissolved Mn(II) because it was not kinetically limited by mineral weathering. Mn uptake was also higher in systems supplied with a fast-weathering substrate (shale containing Mn(II)-bearing pyrite) than a slow-weathering substrate (Mn(IV)-oxide). However, vegetation accumulated a decreasing proportion of available Mn with increasing solubility, indicating that uptake was tempered relative to solubility. The presence of bacterial phyla containing known Mn-oxidizing bacteria indicates the potential for Mn-oxidizing bacteria to influence Mn solubility within Mn-oxide and dissolved Mn treatments. A relatively low abundance of these bacteria points to their limited capacity to oxidize and retain Mn in the shale treatments, consistent with substantial Mn leaching. We conclude that Mn uptake was primarily controlled by dissolution rates of Mn-bearing minerals but modified by biological processes. The quantitative framework presented here can guide understanding of how biogeochemical processes control element cycling between plants and soils.

Solid oxide electrolysis cells (SOEC) recently experienced increasing attraction in the context of producing hydrogen from renewable energy. SOEC systems provide one of the highest efficiencies for hydrogen production from water and electrical power. With current cell-technology they can be operated at thermal neutral condition, which means that the cell itself generates no waste heat at all. Therefore the efficiency of the solid oxide electrolysis system is determined by the systems capability to recover heat and steam from the off-gas. The key component for heat recovery in an SOEC system is the steam generator because it is by far the largest consumer of energy beside the solid oxide electrolysis cell stack itself. In this contribution, the development of a scalable steam generator (Figure 1) and results with a prototype for a reversible solid oxide cell (rSOC) system with 40 kW of power in electrolysis mode will be presented. The steam recovery in this design is accomplished indirectly by reusing the heat of vaporization from condensation of the remaining steam in the off-gas to preheat the feed water (in HX1). The design is based on our long term experience with different types of steam generators for SOEC and a multiphase, multi-component pinch analysis. The pinch analysis shows clearly that a high degree of energy recovery requires focusing on the water preheating and steam superheating. Besides evaluating the optimal heat and steam integration, the prototype allows to investigate other design goals as stability, low steam contamination and high dynamic responsiveness. Furthermore this contribution discusses the benefits and drawbacks comparted to other approaches and the combination with off-gas recirculation. In the studied configuration a reduction in electrical energy for supplying superheated steam of about 20% is expected. That means at 70% steam utilization a reduction of about 5% of the specific energy demand of the SOEC system. Besides the cost reduction for cells and stacks, the development of a simple but highly efficient system designs is the key requirement to match the forthcoming demand for viable hydrogen production solutions based on SOEC. The steam supply is a major building block in that respect. Figure 1. Steam generator with heat and (indirect) steam recovery Figure 1

The molybdenum cofactor (Moco) is found in the active site of numerous important enzymes that are critical to biological processes. The bidentate ligand that chelates molybdenum (Mo) in Moco is the pyranopterin dithiolene (molybdopterin, MPT); however, neither the mechanism of molybdate insertion into MPT nor the structure of Moco prior to its insertion into pyranopterin molybdenum enzymes is known. Here we report this final maturation step, where adenylated MPT (MPT-AMP) and molybdate are the substrates. X-ray crystallography of the Arabidopsis thaliana Mo-insertase variant Cnx1E S269D D274S identified adenylated Moco (Moco-AMP) as an unexpected intermediate in this reaction sequence. X-ray absorption spectroscopy revealed the first coordination sphere geometry of Moco trapped in the Cnx1E active site. We have used this structural information to deduce a mechanism for molybdate insertion into MPT-AMP. Given their high degree of structural and sequence similarity, we suggest that this mechanism is employed by all eukaryotic Mo-insertases., Graphical Abstract

Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.

The high radiation field associated with spent nuclear fuel (U(IV)O 2 ) pellets produces an array of reactive radical species that impact the corrosion and formation of secondary alteration phases. Dioxygen radicals are important as radiolysis products, but the interaction between these reactive oxygen species and U(VI)O 2 2+ and its effects on the resultant alteration phases is unclear. Herein, we report the first example of a U(VI) superoxide compound and explore its reactivity in the environments relevant to the storage of spent nuclear fuel. We utilized X-ray diffraction and Raman scattering techniques to demonstrate that the uranyl superoxide reacts with CO 2 in air to afford a mixed uranyl peroxide/carbonate within 3 days, both in solution and under atmospheric conditions. An additional transformation occurs over the course of three months to form a potassium U(VI) carbonate (grimselite), which also occurs as an alteration product on Chernobyl corium. Our results demonstrate the presence and significance of the superoxide anion in the alteration of spent nuclear fuel and indicate the impact of uranyl superoxide chemistry on high prevalence of carbonate in the secondary phases of spent nuclear fuel.

The study of herbicide dynamics in the soil and their interaction with the components of the environment makes it possible to ensure the selectivity of crops and the agronomical efficiency. The aim of this research was to evaluate the influence of soil physicochemical properties on the emergence and growth of soybean, with pre-emergence application of various saflufenacil rates. An experiment was carried out in a greenhouse with a completely randomized design, testing different soil types containing “Erechim”, “Santa Maria” and “Eldorado do Sul”, at different saflufenacil rates: 0, 12.5, 25, 50, 100, 200, 400 g a.i. · ha–1. The application was performed 1 day after soybean sowing, and analyzed variables were: the phytotoxicity emergence of seedlings, dry mass and height of the soybean. The saflufenacil effective dose of 50% response in soybean (ED50) and the characteristics of the soils showed that the soil contained clay and sand which were the components most related to the saflufenacil availability to the plants. A lower ED50 by phytotoxicity to the soybean was found in soil with lower and greater content of clay and sand, respectively. The physicochemical properties of soil influenced the saflufenacil activity, having greater potential of injury to soybean in the soil from Eldorado do Sul, due to its clay and sand content.

Timely and accurate duplication of DNA prior to cell division is a prerequisite for propagation of the genetic material to both daughter cells. DNA synthesis initiates at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, a uniform method that identifies origins of replication in a comprehensive manner is still missing. Here, we present currently available and discuss new approaches to map replication origins in mammalian genomes.

Purpose Rho-associated kinase (ROCK) inhibitors have been successfully used as a rescue strategy in eyes that failed to clear after descemetorhexis without endothelial graft for treatment of Fuchs endothelial corneal dystrophy (FECD). The functional mechanisms by which ROCK inhibitors modulate corneal endothelial cell regeneration in FECD patients have, however, not been clarified. Here, we analyzed the effect of the ROCK inhibitor ripasudil on corneal endothelial cells of FECD patients and normal donors using ex vivo tissue and in vitro cellular models. Design Experimental study: laboratory investigation. Methods This institutional study used endothelial cell–Descemet membrane lamellae from FECD patients (n = 450) undergoing Descemet membrane endothelial keratoplasty (FECD ex vivo model), normal research-grade donor corneas (n = 30) after scraping off central endothelial cells (ex vivo wound healing model), normal donor corneas (n = 20) without endothelial injury, and immortalized cell lines (n = 3) generated from FECD patients (FECD in vitro model). Descemet membrane lamellae were dissected into halves and incubated for 24-72 hours in storage medium with or without a single dose of 30 μM ripasudil. The effects of ripasudil on expression of genes and proteins related to endothelial cell proliferation, migration, functionality, and endothelial-to-mesenchymal transition were analyzed and complemented by functional assays on FECD cell lines. Results A single dose of ripasudil induced significant upregulation of genes and proteins related to cell cycle progression, cell-matrix adhesion and migration, as well as endothelial barrier and pump function up to 72 hours, whereas classical markers of endothelial-to-mesenchymal transition were downregulated in both FECD and normal specimens compared to unstimulated controls ex vivo. In addition to stimulation of proliferation and migration, ripasudil-induced changes in expression of functional signature genes could be also verified in FECD cell lines in vitro. Conclusions These data support the concept that inhibition of ROCK signaling represents a potent tool in regenerative therapies in FECD patients through reactivation of cell proliferation and migration as well as restoration of endothelial pump and barrier function without inducing adverse phenotypic changes.

We present a systematic investigation of the photophysical properties of diazocines in aqueous media. The Z-E photoconversion yields of CH2CH2- and CH2S-bridged diazocines decrease with increasing water content in acetonitrile. However, there is one exception. A CH2-NAc-bridged diazocine mostly retains its photostationary state in water (85 to 72%) because of the high quantum yields for the Z → E conversion. Moreover, it is water-soluble without further substitution and is therefore ideally suited as a photoswitch in biological (aqueous) environments.

Background: Everolimus in combination with exemestane (EVE+EXE) was initially FDA approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) in patients previously treated with nonsteroidal aromatase inhibitors based on the BOLERO-2 trial. However, none of the patients in the BOLERO-2 trial received prior CDK4/6 inhibitors, which have become standard of care for mHRBC. There is limited data to support the use and clinical benefit of EVE+EXE in mHRBC patients previously treated with CDK4/6 inhibitors. Methods: We reviewed patients ≥18 years old with mHRBC treated with EVE+EXE at our institution from January 1, 2012, to April 1, 2020. Patients were excluded if they received EVE+EXE ≤30 days. Data collected included patient and tumor characteristics, prior therapies in the metastatic setting, adverse drug events, and clinical outcomes. The primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival (OS) and safety. Group comparisons were performed by two-sample t test or Wilcoxon rank sum test for continuous variables and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Log-rank test was used to compare the PFS and OS between groups. Results: One-hundred ninety two patients were included in the study; 79 patients had received prior CDK4/6 inhibitor based therapies, while 113 patients did not. Baseline patient characteristics such as histology, menopause status, de novo metastatic disease, presence of lung or liver metastases, and bone only disease were similar between groups. There was a median of 2 lines of treatment in the metastatic setting prior to receiving EVE+EXE in both groups. Fewer patients received prior chemotherapy in the metastatic setting in those who received prior CDK4/6 inhibitors (32.9% vs 49.6%, p=0.032). In patients who received a prior CDK4/6 inhibitor, median PFS was 3.9 months (95% CI: 3.5 to 4.8) compared to 5.5 months (95% CI: 4.0 to 6.3) in those who did not receive a prior CDK4/6 inhibitor (HR for progression, 1.46; 95% CI: 1.08 to 1.97, p=0.013). Overall survival between groups was not significantly different. A total of 32 (16.7%) patients discontinued EVE+EXE due to intolerance or adverse drug events. Conclusion: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not. Citation Format: Hanjie Mo, Catherine E Renna, Halle CF Moore, Jame Abraham, Megan L Kruse, Alberto J Montero, Susan B LeGrand, G Thomas Budd. Efficacy of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-18.

Cytochrome c oxidase (CcO) in its as-isolated form is known to exist in a slow and fast form, which differ drastically in their ability to bind oxygen and other ligands. While preparation methods h...

Phosphorothioates (PTs) are important chemical modifications of the RNA backbone where a single non-bridging oxygen of the phosphate is replaced with a sulphur atom. PT can stabilize RNAs by protecting them from hydrolysis and is commonly used as tool to explore their function. It is, however, unclear what basic physical effects PT has on RNA stability and electronic structure. Here, we present Molecular Dynamics (MD) simulations, quantum mechanical (QM) calculations, and NMR spectroscopy measurements, exploring the effects of PT modifications in the structural context of the Neomycin-sensing riboswitch (NSR). The NSR is the smallest biologically functional riboswitch with a well-defined structure stabilized by a U-turn motif. Three of the signature interactions of the U-turn; an H-bond, an anion-π interaction and a potassium binding site; are formed by RNA phosphates, making the NSR an ideal model for studying how PT affects RNA structure and dynamics. By comparing with high-level QM calculations, we reveal the distinct physical properties of the individual interactions facilitated by the PT. The sulphur substitution, besides weakening the direct H-bond interaction, reduces the directionality of H-bonding while increasing its dispersion and induction components. It also reduces the induction and increases dispersion component of the anion-π stacking. The sulphur force-field parameters commonly employed in the literature do not reflect these distinctions, leading to unsatisfactory description of PT in simulations of the NSR. We show that it is not possible to accurately describe the PT interactions using one universal set of van der Waals sulphur parameters and provide suggestions for improving the force-field performance.

Leaves are asymmetric, with different functions for adaxial and abaxial tissue. The bundle sheath (BS) of C3 barley (Hordeum vulgare) is dorsoventrally differentiated into three types of cells: adaxial structural, lateral S-type, and abaxial L-type BS cells. Based on plasmodesmatal connections between S-type cells and mestome sheath (parenchymatous cell layer below bundle sheath), S-type cells likely transfer assimilates toward the phloem. Here, we used single-cell RNA sequencing to investigate BS differentiation in C4 maize (Zea mays L.) plants. Abaxial BS (abBS) cells of rank-2 intermediate veins specifically expressed three SWEET sucrose uniporters (SWEET13a, b, and c) and UmamiT amino acid efflux transporters. SWEET13a, b, c mRNAs were also detected in the phloem parenchyma (PP). We show that maize has acquired a mechanism for phloem loading in which abBS cells provide the main route for apoplasmic sucrose transfer toward the phloem. This putative route predominates in veins responsible for phloem loading (rank-2 intermediate), whereas rank-1 intermediate and major veins export sucrose from the PP adjacent to the sieve element companion cell complex, as in Arabidopsis thaliana. We surmise that abBS identity is subject to dorsoventral patterning and has components of PP identity. These observations provide insights into the unique transport-specific properties of abBS cells and support a modification to the canonical phloem loading pathway in maize.

Core-shell carbon metal-oxide nanocomposites are synthesized in a well-defined counterflow burner. Benefitting from the two-nozzle configuration, the nanocomposite morphology can be controlled by adjusting the precursor loading rate and fuel mass fraction independently. In-situ laser diagnostic method and transmission electron microscopy (TEM) technique are used to investigate the formation mechanism of nanocomposites. In the presence of a 532 nm laser pulse, laser-induced incandescence, Ti atomic emissions, and C2 swan spectra that appear simultaneously can indicate the particle volume fraction, titanium component, and carbon component, respectively. By increasing the precursor loading rates, both the measured laser diagnostic signals and the TEM images demonstrate that the titania component rises proportionally with the precursor concentration while the carbonaceous layer thickness remains unchanged. As further revealed by the axial profiles of the three signals, the formation and growth of the nanocomposites is composed of two steps. The first step is the reaction, nucleation, collision, and coagulation of metal oxides in the oxidizer side of the flame sheet. The second step is the formation of carbonaceous layers surrounding the metal oxides, which can be regarded as the heterogeneous nucleation of the carbonaceous species in the fuel-rich zone. By adjusting the precursor concentration and the fuel mass fraction, we can achieve independent control of the first and the second steps, respectively, thereby actively tailoring the core size of metal oxides and the carbonaceous layer thickness.

The colloidal stability of metal nanoparticles is tremendously dependent on the thermal behavior of polymer brushes. Neat polyethylene glycol (PEG) presents an unconventional upper critical solution temperature in ethanol, where phase segregation and crystallization coexist. This thermal behavior translated to a PEG brush has serious consequences on the colloidal stability in ethanol of gold nanoparticles (AuNPs) modified with PEG brushes upon cooling. We observed that AuNPs (13 nm diameter) stabilized with conventional linear PEG brushes (Mn = 6 and 11 kg mol−1) in ethanol suffer from reversible phase separation upon a temperature drop over the course of a few hours. However, the use of a polymer brush with cyclic topology as a stabilizer prevents sedimentation, ensuring the colloidal stability in ethanol at −25 °C for, at least, four months. We postulate that temperature-driven collapse of chain brushes promotes the interpenetration of linear chains, causing progressive AuNP sedimentation, a process that is unfavorable for cyclic polymer brushes whose topology prevents chain interpenetration. This study reinforces the notion about the importance of polymer topology on the colloidal stability of AuNPs., We gratefully acknowledge support from the Spanish Ministry “Ministerio de Ciencia, Innovación y Universidades” (PGC2018-094548-B-I00, MICINN/FEDER, UE, and PID2019-111772RB-I00), Basque Government (IT-1175-19 and PIBA 2018-34) and Diputación Foral de Guipúzcoa (RED 2018).

Combining strong σ-donating N-heterocyclic carbene ligands and π-accepting pyridine ligands with a high octahedricity in rigid iron(ii) complexes increases the 3MLCT lifetime from 0.15 ps in the prototypical [Fe(tpy)2]2+ complex to 9.2 ps in [Fe(dpmi)2]2+12+. The tripodal CNN ligand dpmi (di(pyridine-2-yl)(3-methylimidazol-2-yl)methane) forms six-membered chelate rings with the iron(ii) centre leading to close to 90° bite angles and enhanced iron-ligand orbital overlap.

CD4+ T cells contribute critically to a protective immune response during intestinal infections, but have also been implicated in the aggravation of intestinal inflammatory pathology. Previous studies suggested that T helper type (Th)1 and Th17 cells depend on de novo fatty acid (FA) synthesis for their development and effector function. Here, we report that T-cell-specific targeting of the enzyme acetyl-CoA carboxylase 1 (ACC1), a major checkpoint controlling FA synthesis, impaired intestinal Th1 and Th17 responses by limiting CD4+ T-cell expansion and infiltration into the lamina propria in murine models of colitis and infection-associated intestinal inflammation. Importantly, pharmacological inhibition of ACC1 by the natural compound soraphen A mirrored the anti-inflammatory effects of T-cell-specific targeting, but also enhanced susceptibility toward infection with C. rodentium. Further analysis revealed that deletion of ACC1 in RORγt+ innate lymphoid cells (ILC), but not dendritic cells or macrophages, decreased resistance to infection by interfering with IL-22 production and intestinal barrier function. Together, our study suggests pharmacological targeting of ACC1 as an effective approach for metabolic immune modulation of T-cell-driven intestinal inflammatory responses, but also reveals an important role of ACC1-mediated lipogenesis for the function of RORγt+ ILC.

Oxygenated poly aromatic hydrocarbons (OPAH) are widely produced in biomass combustion. Recent studies suggest significantly higher toxicity for OPAH in comparison to PAH and soot. However, the pre...

Surgical stress is followed by oxidative stress, where reactive oxygene species may act as regulators of pathways related to cancer cell survival and metastatic ability. Furthermore, reactive oxygene species may cause DNA and RNA damage. The aim of this study was to examine whether laparoscopic colon cancer surgery causes oxidative stress and dysregulation of related pathways. Methods: Patients undergoing elective laparoscopic surgery for colon cancer were included. Blood and urine samples were drawn on the day prior to surgery and on day 1 and 10 after surgery. Results: Twenty-six patients were included. Out of 140 genes previously identified as sensitive to regulation by reactive oxygene species, 46 were significantly differentially expressed on day 1 after surgery (FDR < 0.05). Upregulated genes were related to cellular immune suppression, proliferation, migration and epithelial to mesenchymal transition. Downregulated genes were related to IFN pathways and cytotoxic immunological reactions. Genes related to DNA repair were primarily downregulated on day one after surgery, and urinary excretion of 8oxdG was decreased on day two after (p = 0.004), and increased on day 10 after surgery (p = 0.01). Conclusion: Laparoscopic colon cancer surgery causes oxidative stress, and impaired DNA repair. Gene expression profiling indicates that reactive oxygen species may act as regulators of pathways related to increased risk of metastasis and cellular immune suppression after surgery. Measures of intracellular oxidative stress, indicates impaired DNA repair on day two after surgery, and sustained oxidative stress on day 10 after surgery.

Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor. The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib. This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study. In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28–255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events. Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells. ClinicalTrials.gov, NCT00982865

Applications of molybdenum disulfide (MoS2) in energy storage devices, solar cells, electrocatalysts, and sensors require good electrical conductivity. However, neither of the current ways to prepa...

Chicory (Cichorium intybus var. foliosum) roots are an agricultural residue and a low cost feedstock for the production of the platform chemical 5-Hxdroxymethylfurfural (HMF). In a first step, inulin and fructose have to be extracted from the roots. The resulting aqueous extract represents the starting material for the HMF production. In the reaction to HMF, inulin has to be hydrolyzed first to fructose. For this reason, two methods to increase the fructose content in these extracts before the reaction were investigated. This was conducted within the framework of integrating acid hydrolysis into a biorefinery process for HMF production. The first method (one-step process) was acid-assisted extraction to directly hydrolyze inulin in the course of the extraction process. Chicory roots were extracted at 60 and 80 °C at pH 2 and 4 using buffer solutions. The second approach (two-step process) was aqueous extraction at neutral pH followed by nitric acid hydrolysis of the extract at 60 and 80 °C under reduced pH. It was found that in the first approach, the pH of 2 led to a fivefold increase in the fructose content of the extract, resulting from inulin hydrolysis and corresponding to 56% of theoretical fructose yield. For the second approach, it was possible to achieve complete hydrolysis at pH below 2.5 and at 80 °C. Separating extraction and hydrolysis was found to be more suitable in terms of including this process step into a biorefinery concept for HMF production. It was possible to reduce the initial inulin content by 95%.

Liquefied dimethyl ether (DME) is regarded as a promising, green solvent for biomass lipid extractions. It is non-toxic, applicable to wet feedstocks, and allows easy product separation by pressure reduction. Yet, knowledge about its usability in combination with oleaginous microalgae is limited. In the current work, four common microalgae and cyanobacteria species were used to study DME extraction characteristics: Arthrospira platensis, Nannochloropsis gaditana, Phaeodactylum tricornutum, and Scenedesmus almeriensis. Dried samples were subjected to a batch DME extraction and compared to a standard chloroform/methanol procedure. To evaluate the influence of pretreatment, particle size distributions of two different milling sequences (knife- and cryo-milling) and the resulting effects on DME extraction and oil composition were addressed. Additionally, an algae washing procedure was tested. DME extractions resulted in oil yields of 0.5–2.7% of dry mass (equal to 5–19% of total lipids) without further pretreatment. Cryo-milling reduced median particle sizes by 25–87% and simultaneously increased lipid yields to 1.7–5.6% of dry mass (17–50% of total lipids). Phaeodactylum tricornutum showed the highest extraction efficiency with DME, combined with a favorable fatty acid profile. Although being most affected by the additional milling pretreatment, Arthrospira platensis performed worst in both scenarios. DME extracted oils were generally characterized by enhanced contents of C14:0, C16:0, and C16:1 fatty acids. However, relative abundances were strongly influenced by the properties of the tested algae species. The additional cryo-milling pretreatment affected fatty acid compositions by increasing the shares of potentially valuable polyunsaturated fatty acids.

In this study, the fate of carbon and nutrient elements; nitrogen, phosphorus, and potassium was investigated during the HTC of three model solutions with different nutrient concentrations to mimic...

We demonstrate Chemical Transient Kinetics as a powerful tool for investigating catalytic reaction kinetics and mechanisms at atmospheric pressure. Quantitation of transient molecular flows while switching feed gas compositions allows key mechanistic steps of the Fischer–Tropsch reaction to be elucidated. Evidence is presented for a CO insertion mechanism operating under hydrogen-deficient reaction conditions. Consequently, formate/carboxylate-derived intermediates are likely involved in chain lengthening. This also agrees with the occurrence of characteristic time profiles when replacing CO by methyl formate or adding ammonia to a CO/H2 feed.

There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine receptor group. GPCRs are challenging targets for conventional antibody discovery methods, as many are highly conserved across species, are biochemically unstable upon purification, and possess deeply buried ligand-binding sites. Here, we describe a selection methodology to enrich for functionally modulatory antibodies using a yeast-displayed library of synthetic camelid antibody fragments called “nanobodies.” Using this platform, we discovered multiple nanobodies that act as antagonists of the angiotensin II type 1 receptor (AT1R). Following angiotensin II infusion in mice, we found that an affinity matured nanobody antagonist has comparable antihypertensive activity to the angiotensin receptor blocker (ARB) losartan. The unique pharmacology and restricted biodistribution of nanobody antagonists may provide a path for treating hypertensive disorders when small-molecule drugs targeting the AT1R are contraindicated, for example, in pregnancy.

The σ1 receptor is a transmembrane protein implicated in several pathophysiological conditions, including neurodegenerative disease (J. Pharmacol. Sci.2015127 (1), 1729), drug addiction (Behav. Pharmacol.201627 (2-3 Spec Issue), 10015), cancer (Handb. Exp. Pharmacol.2017244237308), and pain (Neural Regener. Res.201813 (5), 775778). However, there are no high-throughput functional assays for σ1 receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ1 receptor. We screened a library of over 6 million compounds using the Schrodinger Glide package, followed by experimental characterization of top-scoring candidates. 77% of tested candidates bound σ1 with high affinity (KD < 1 μM). These include compounds with high selectivity for the σ1 receptor compared to the genetically unrelated but pharmacologically similar σ2 receptor, as well as compounds with substantial crossreactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ1 receptor ligand discovery and provide compounds to prioritize in studies of σ1 biology.

The utilization of biomass and development of intensified processes are essential to establish a sustainable production of chemicals in the future. Herein, we report on a strategy that allows one to directly convert the biomass-derived platform molecule 5-(hydroxymethyl)­furfural (HMF) over Au/ZrO2 in aqueous medium to 2,5-furandicarboxylic acid (FDCA), a renewable building block for biobased polymers like polyethylene furanoate. The focus lies on identifying the influence of 5-(hydroxymethyl)­furfural synthesis byproducts, like unconverted sugars, levulinic acid, and formic acid as well as the remaining inorganics, on the synthesis of 2,5-furandicarboxylic acid to save the intermediate step of HMF purification. These components were added to the reaction mixture individually and in combination to study their effect. Although most of these substances lowered the FDCA yield, the reaction conditions could be optimized to produce FDCA quantitatively. Only the addition of levulinic acid led to a severe deterioration of the production of FDCA, which was attributed to poisoning of the catalyst. In a realistic technical scenario, the direct oxidation of impure HMF from unconcentrated sugar syrup in high FDCA yield (74%) was demonstrated. Catalyst stability was investigated in the presence of sugars. On the basis of these studies, highly needed recommendations for the HMF synthesis were developed to establish a more sustainable, technically feasible, and intensified process for direct FDCA production from sugars at industrial scales.

Integrated management practices should be recommended to avoid damage of glyphosate-resistant hairy fleabane [Conyza bonariensis (L.) Cronquist] on the soybean. This study aimed to evaluate the effect of soil cover plants and chemical control on the glyphosate-resistant hairy fleabane. Field experiment was performed in a randomized block design, with treatments arranged in a factorial scheme (3x10), using subdivided plots and four replicates. The main factor was composed by three types of soil cover (black oat, wheat and fallow), and on the subplots were evaluated the glyphosate+2,4-D amine in a tank-mix applied at 14 DBS (days before sowing) with sequential application of paraquat+diuron at 01 DBS; burndown performed at 07 DBS using glyphosate alone or applied in a tank-mix with clorimuron-ethyl, diclosulan, imazethapyr, sulfentrazone, and flumioxazine; glyphosate alone applied at the V4 phenological development stage of the soybean, and control without application on Roundup Ready® soybean. The hairy fleabane sensitivity to glyphosate was previously evaluated by the dose-response curve. Hairy fleabane demonstrated low sensibility to glyphosate, with 17,280 g a.e. ha-1 needed for a 90% reduction of dry weight. Wheat or black oat reduced the hairy fleabane population density by 95% and its plants height by 90% when compared to fallow, allowing the increased herbicide efficacy, regardless of the tank-mix. For the fallow, the tank-mix of glyphosate+2,4-D amine (1,080+1,340 g a.e. ha-1) herbicides with a sequential application of paraquat+diuron (200+100 g a.i. ha-1) provided a better control level during the evaluated period, protecting the yield potential.