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Laser-induced fluorescence spectroscopy is a useful laboratory and in situ technique for planetary exploration, with applications in biosignature detection and the search for life on Mars. However,...

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy., Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.

Background: Mediterranean diets limit red meat consumption and increase intakes of high-phytate foods, a combination that could reduce iron status. Conversely, higher intakes of fish, a good source of selenium, could increase selenium status. Objectives: A 1-y randomized controlled trial [New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE)] was carried out in older Europeans to investigate the effects of consuming a Mediterraneanstyle diet on indices of inflammation and changes in nutritional status. Methods: Selenium and iron intakes and status biomarkers were measured at baseline and after 1 y in 1294 people aged 65–79 y from 5 European countries (France, Italy, the Netherlands, Poland, and the United Kingdom) who had been randomly allocated either to a Mediterranean-style diet or to remain on their habitual, Western diet. Results: Estimated selenium intakes increased significantly with the intervention group (P < 0.01), but were not accompanied by changes in serum selenium concentrations. Iron intakes also increased (P < 0.001), but there was no change in iron status. However, when stratified by study center, there were positive effects of the intervention on iron status for serum ferritin for participants in Italy (P = 0.04) and France (P = 0.04) and on soluble transferrin receptor (sTfR) for participants in Poland (P < 0.01). Meat intake decreased and fish intake increased to a greater degree in the intervention group, relative to the controls (P < 0.01 for both), but the overall effects of the intervention on meat and fish intakes were mainly driven by data from Poland and France. Changes in serum selenium in the intervention group were associated with greater changes in serum ferritin (P = 0.01) and body iron (P = 0.01), but not sTfR (P = 0.73); there were no study center × selenium status interactions for the iron biomarkers. Conclusions: Consuming a Mediterranean-style diet for 1 y had no overall effect on iron or selenium status, although there were positive effects on biomarkers of iron status in some countries. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012. Am J Clin Nutr 2019;00:1–12.

Ligand-coordinated supported catalysts (LCSCs) are of growing interest for heterogeneous single-atom catalysis. Here, the effect of the choice of organic ligand on the activity and stability of TiO2 -supported single-atom Pt-ligand catalysts was investigated for ethylene hydrogenation. The activity of these catalysts showed a significant dependence on the choice of ligand and also correlated with coordination number for Pt-ligand and Pt-Cl- . Of the three ligands examined in this study, the one with the lowest Pt coordination number, 1,10-phenanthroline-5,6-dione (PDO), showed the lowest reaction temperature and highest reaction rate, likely due to those metal sites being more accessible to reactant adsorption. In-situ X-ray absorption spectroscopy (XAS) experiments showed that the activity also correlated with good heterolytic dissociation of hydrogen, which was supported by OH/OD exchange experiments and was the rate-determining step of the hydrogenation reaction. In these in-situ XAS experiments up to 190 °C, the supported Pt-ligand catalyst showed excellent stability against structural and chemical change. Instead of Pt, the PDO ligand could be coordinated with Ir on TiO2 to form Ir LCSCs that showed slow activation by loss of Ir-Cl bonds, then excellent stability in the hydrogenation of ethylene. These results provide the chance to engineer ligand-coordinated supported catalysts at the single-atom catalyst level by the choice of ligand and enable new applications at relatively high temperature.

Engineered epithelial cell sheets for clinical replacement of non-functional upper aerodigestive tract mucosa are regulated as medicinal products and should be manufactured to the standards of good manufacturing practice (GMP). The current gold standard for growth of epithelial cells for research utilises growth arrested murine 3T3 J2 feeder layers, which are not available for use as a GMP compliant raw material. Using porcine mucosal tissue, we demonstrate a new method for obtaining and growing non-keratinised squamous epithelial cells and fibroblast cells from a single biopsy, replacing the 3T3 J2 with a growth arrested primary fibroblast feeder layer and using pooled Human Platelet lysate (HPL) as the media serum supplement to replace foetal bovine serum (FBS). The initial isolation of the cells was semi-automated using an Octodissociator and the resultant cell suspension cryopreservation for future use. When compared to the gold standard of 3T3 J2 and FBS containing medium there was no reduction in growth, viability, stem cell population or ability to differentiate to mature epithelial cells. Furthermore, this method was replicated with Human buccal tissue, providing cells of sufficient quality and number to create a tissue engineered sheet.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

The fabrication of robust microfluidics can be tedious, often involving the use of numerous cleanroom resources and processes. We propose a process that is easy to apply yet capable of producing precision microfluidics in polymer with high yield and high fidelity at a wafer scale. The process is centered on the use of a wafer aligner-bonder implementing a one-step hot embossing process to transfer microfluidic designs from a Si master mold onto a thermoplastic deformable substrate. The approach has the additional benefit of transferring features directly to the substrate without the need for pre-annealing or other pre-processing. Additionally, the mold used to replicate the microfluidic design can be re-used numerous times. The most important process parameters, embossing temperature, embossing pressure, embossing time and demolding temperature, were optimised. We demonstrate the process by fabricating over 340 microfluidic chips per 4-inch diameter cyclic-olefin co-polymer substrate. The approach should scale to larger wafer diameters using a wafer aligner-bonder of larger diameter platens, suitable for volume manufacturing.

In this work, we present a novel series of oxide-supported Ir-ligand single-atom catalysts (SACs) for ethylene hydrogenation. The SACs were created by a metal–ligand self-assembly strategy developed by our group, using one of two ligands, either 1,10-phenanthroline-5,6-dione (PDO) or 3,6-Di-2-pyridyl-1,2,4,5-tetrazine (DPTZ), on powder supports of either CeO2 or MgO. Characterization by XAS, XPS, and CO adsorption proved that Ir exist principally as highly uniform, cationic single-atoms. Ir SACs show significantly higher durability and metal utilization efficiency than Ir nanoparticle (NP) catalysts during ethylene hydrogenation at 100 °C, as well as excellent stability, as no Ir aggregates were detected after >10 h reaction. The activity can be tuned by ligand and support effects: PDO and CeO2 are superior to DPTZ and MgO, respectively. This tunability is attributed to differences in H2 activation capability, which results from differences in support reducibility, electron density on Ir, and, potentially, the local coordination environment of Ir. The Ir SACs lose H2 activation activity either under inert gas or under H2. Through XPS and in situ XAS studies, we attributed the former to the reversible loss of Ir hydride, which is the active species for H2 activation, and the latter to irreversible over-hydrogenation and loss of Ir–O/N coordination. This work presents a new type of Ir hydrogenation SACs that are more durable, efficient, and tunable than supported Ir NPs, while more stable than homogeneous Ir complexes. It also offers fundamental understanding regarding ligand and support effects, as well as the evolution of Ir single-atoms under H2, instructing future design of stable, effective hydrogenation SACs.

Shergottite meteorites are ultramafic to mafic igneous rocks derived from partial melting of distinct regions of the martian mantle. As such, they trace magmatic processes, including fractional crystallization and mixing processes in Mars. New chalcophile (Cu, Se, Zn, Pb), siderophile (Ni, Co, W), and highly siderophile element (HSE: Au, Re, Pd, Rh, Pt, Ru, Ir, Os) abundance data are reported for sulfide assemblages in a suite of thirteen incompatible trace-element depleted, intermediate and enriched shergottites, along with new whole-rock HSE abundance and 187Os/188Os data for seven shergottites. Sulfide grains in depleted and intermediate shergottites typically have the highest absolute abundances of HSE, with broadly flat CI-chondrite normalized patterns. Enriched shergottite sulfide grains typically have highly variable Au, elevated Pd and Rh and are relatively depleted in Zn, Ir and Os. The new HSE whole-rock data for enriched (Northwest Africa [NWA] 7397, NWA 7755, NWA 11043), and intermediate shergottites (NWA 10961, NWA 11065, NWA 12241, and NWA 12536) are generally consistent with existing 187Os/188Os and HSE abundance data for these geochemical groupings. Enriched shergottites with >1 ppb bulk rock Os have measured 187Os/188Os ranging between 0.1296 and 0.1471, with variable Pd and Pt contents. Intermediate shergottites with >1 ppb bulk rock Os have chondrite-relative proportions of the HSE at ∼0.01 to 0.001 × CI chondrites and 187Os/188Os from 0.1284 and 0.1295. Sulfides are the major host of the HSE, and they control the behavior of the HSE during petrogenetic processes in shergottite magmas, enabling the determination of HSE compatibility for martian magmatism in the order: Os > Ir ≥ Ru ≥≥ Rh ≥ Pd ≥ Re ≥ Pt ≥ Au. Fractionation models of removal of an olivine-dominated cumulate recreate HSE patterns for the whole-rock shergottites. Enriched shergottites are best reproduced by 25 to 30% of fractionation from a degassed parent melt (250 ± 50 ppm of S), whereas depleted and intermediate shergottites can be explained by slightly lower fractionation (10 to 15%) from higher S content parent melts (350 ± 100 ppm of S). Sulfur contents in the melt that are ∼50% higher than these estimates yield earlier S-saturation during fractional crystallization, leading to an abrupt decrease of the more compatible HSE (Ru, Ir, Os), which is not observed. These results indicate that the martian mantle and partial melts derived from it, are probably not anomalously enriched in S, and instead are similar to slightly higher than those of the terrestrial mantle and its partial melts.

A systematic study of alluaudite, hagendorfite, and varulite was done using single-crystal X-ray diffraction, powder diffraction, and electron probe microanalysis of samples from 12 separate localities. The crystal structures of the representative alluaudite and hagendorfite samples were refined to R1 indices of 3.7 and 1.8%, respectively, using a Siemens P4 automated four-circle diffractometer equipped with a graphite monochromator and MoKα X-radiation. These samples and several others were analyzed with an electron microprobe to study variations in chemical composition. For the single-crystal analyses, the resulting unit formulae are (Na0.11□0.89)(Na0.59Mn0.27Ca0.14)Mn1.00(Fe3+1.64Al0.24Mg0.13)(PO4)3 for alluaudite, (Na0.79□0.21)(Na0.81Mn2+0.19)(Mn0.70Fe2+0.30)(Fe2+1.72Mg0.27Al0.01)(PO4)3 for hagendorfite, and (Na0.84□0.16)(Na0.71Ca0.23□0.06)Mn1.00(Fe3+0.89Fe2+0.68Mn0.42Mg0.01)(PO4)3 for varulite. Originally, a nomenclature scheme was proposed for the alluaudite-group minerals that was based on sequentially distributing the cations in the cell according to increasing polyhedron size, matching that size with increasing ionic radii of the cations. For alluaudite, the structural formula was written as X(2)4X(1)4M(1)4M(2)8(PO4)12, with the sites ordered in decreasing size of the discrete polyhedra. Later, the formula [A(2)A(2)'A(2)”2][A(1)A(1)'A(1)”2]M(1)M(2)2(PO4)3 was proposed, which takes into account the distinct crystallographic sites in the channels of the structure. More recently there has been a revision to the nomenclature of the group. The simplified structural formula for the alluaudite-type is now A(2)'A(1)M(1)M(2)2(TO4)3; the new nomenclature scheme has been adopted by the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association (IMA-CNMNC), based on the contents of the M(1) and M(2) octahedral sites, and the results are reviewed here. Compounds belonging to the alluaudite structural family have been the focus of synthetic mineral studies for decades owing to the open-framework architecture and their unique physical properties. Improvements in synthesis methods have allowed researchers to substitute a wide range of elements into the alluaudite structure.

Rice Husks (RHs) are one of the most abundant sources of biomass in the world due to rice consumption. Lignocellulose and silica are two of the main components of RHs, which allow RHs to be applied in different areas. Lignocellulose can be partially dissolved in 1-butyl-3-methylimidazolium chloride (BMIMCl), which is a simple way of competing with the traditional extraction methods that suffer from high chemical consumption. A lignocellulose freeze gel is obtained via a cyclic liquid nitrogen freeze-thaw (NFT) process. Multi-functional self-assembled lignocellulose aerogel is obtained after CO2supercritical drying. Based on the aerogel’s special properties, two routes are developed for practical applications. On one hand, the aerogel is coated to exhibit a superhydrophobic property that can be applied as an absorbent for oil spills. On the other hand, a carbon aerogel is synthesized via a pyrolysis process, resulting in a porous amorphous carbon. The residue after partially dissolving lignocellulose in BMIMCl is further calcined to obtain amorphous silica nanoparticles, achieving a comprehensive application of RHs.Graphical abstract

Online extraction of fission products, such as the medical isotope Mo-99, is a key advantage of the proposed molten salt nuclear reactor design. The chemical and structural behavior of Mo solvated in fluoride salt has been relatively unknown. Ab initio molecular dynamics simulations were employed to examine the behavior of molybdenum in the molten salt FLiNaK (LiF-NaF-KF) for oxidation states between 0 and 6+. Mo complexation was found to vary with the Mo oxidation state, with lower oxidation states tending to result in complexes with more molybdenum ions. Complexes containing multiple Mo ions were observed for all Mo oxidation states studied except 5+ and 6+. A relationship between the solubility of a complex and electronic isolation of a complex in a molten salt is explored using the Bader atoms in molecule electron density partitioning scheme, with more volatile complexes exhibiting greater electronic isolation. The impacts of UF4 and H2O on the predominant molybdenum species are also considered. While no impacts on Mo behavior by UF4 were observed, Mo-O interactions may inhibit the formation of complexes containing multiple Mo ions.

Activated carbon (AC) is widely used in water treatment, however, it has some technical disadvantages, such as its high cost and difficulty to recover. To overcome these drawbacks, AC particles have been encapsulated within a polymeric support, mainly chitosan and alginate-based. The use of these biological macromolecules results in composites with lower-cost, superior mechanical properties, and higher number of functional groups, advantages that have been attracted the attention of the scientific community. However, the number of publications is relatively low, demonstrating an important research gap yet to be investigated. Thus, this paper aims to review the recent studies concerning the use of chitosan, alginate and other macromolecules as AC immobilizing agents, describing the synthesis methods, characterization analyses and adsorption studies, focusing on the main advantages, disadvantages, gaps and future perspectives. Throughout the review it was verified that the composites were able to remove several water contaminants, mainly dyes and heavy metals, with high efficiency. Synergistic effects were detected, indicating the role of both polymers and AC, which increased the spectrum of contaminants capable of being adsorbed. Finally, it was observed a gap in column experiments, suggesting that future studies are essential to elucidate the applications in the industrial perspective.

Summary Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B‐cell malignancies. In ibrutinib clinical studies, low‐grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any‐grade bleeding were similar for single‐agent ibrutinib and ibrutinib combinations (39% and 40%). Low‐grade bleeding was more common in ibrutinib‐treated than comparator‐treated patients (35% and 15%), and early low‐grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person‐months). MH led to treatment discontinuation in 1% of all ibrutinib‐treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure‐adjusted relative risk for MH in both the total ibrutinib‐treated population (1.9; 95% confidence interval, 1.2–3.0) and RCT comparator‐treated patients (2.4; 95% confidence interval, 1.0–5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B‐cell malignancies.

Land use features can have a significant impact on the flux and stoichiometry of nutrients from the watershed to the sea along the freshwater continuum. Traditional agricultural watersheds designated as a Globally Important Agricultural Heritage System (GIAHS) may have unique features on nutrient dynamics. Here, we conducted seasonal, high-resolution spatial surveys for concentrations of dissolved inorganic phosphorus (DIP) and nitrogen (DIN) and stable isotopes of water and nitrate of the GIAHS in Japan (Kunisaki Peninsula). The highest upstream DIN concentrations (mean = 83 μM) were observed in the non-irrigation period in autumn. 17O isotopes of nitrate suggested that microbial nitrification in forest soil was the primary source (> 95%) of total nitrate. Spatial differences in DIP and DIN concentrations among the upstream, midstream, and downstream waters were small, with high DIN/DIP ratios (> 50) were exported from the watershed to coastal seas. Nutrient concentrations exhibited different dynamics during summer when irrigation was taking place with average DIP concentrations increasing from upstream (0.5 μM) to downstream (2.1 μM) waters. A generalized linear model showed that the proportion of paddy fields, cultivated land, residential area as well as forest were the primary drivers of DIP concentrations. DIN concentrations decreased moving downstream likely due to denitrification in the anaerobic irrigation ponds and paddy fields. This study showed that the traditional agricultural landscapes mitigated the excess DIN loading from forested areas while supplying the essential DIP for coastal production, suggesting an important forest-river-sea connection system that manages nutrient inputs to coastal waters.

Tree stem mediated methane emissions represent a potentially important yet poorly constrained source of atmospheric methane. Here we present the first ever quantification of tree stem methane emissions from Melaleuca quinquenervia, a widespread iconic Australian lowland tree and globally invasive species. Under two distinct hydrological conditions (wet and dry) we captured 431 tree stem flux measurements encompassing six different vertical stem heights along a 50 m topo-gradient transect, separated into three distinct hydrological zones (upper, transitional and lower). The tree stem methane fluxes closely reflected local topography/hydrology and ranged from − 30.0 to 123,227 µmol m−2 day−1, with the maximum values amongst the highest values reported to date. The highest methane emissions were observed during wet conditions, within the inundated lower zone and from near the tree stem bases and water table. The average methane flux per tree (scaled to 1 m of stem) for the transitional and lower zones was 52-fold and 46-fold higher during wet conditions compared to dry, whereas the upper zone emissions changed little between seasons. Adjacent soil fluxes followed similar trends along the hydrology gradient with the upper zone tree stem emissions offsetting the adjacent soil methane sink capacity. A clear trend of sharply decreasing methane emissions with stem-height suggests a soil methane origin. A 45-h time-series of two trees within the lower zone revealed three to fourfold diel variability, with elevated morning-time fluxes. Overall, the study revealed that seasonal hydrological conditions and topo-gradient substantially regulated the methane emissions from M. quinquenervia and that this previously overlooked pathway should be accounted for within wetland methane budgets, especially during inundated conditions.

The spotted-wing drosophila, Drosophila suzukii Matsumura, is an invasive pest causing significant damage to soft skinned fruits. Control of D. suzukii is critical since there is no tolerance for infested fruit in the market. While most insecticides control one or more D. suzukii life-stages (e.g., egg, larvae, and adult), the impact of insecticides that are toxic to immature stages is unclear on the subsequent generation of a field population. Insecticides were applied at field recommended rates on cherries and blueberries in the laboratory to determine immature D. suzukii mortality. Spinetoram, cyantraniliprole, malathion, methomyl, spinosad, and phosmet resulted in relatively high mortality of all immature life stages. Zeta-cypermethrin, cyclaniliprole, and fenpropathrin resulted in lower mortality of egg and all larval instars. Malathion was also applied to lowbush blueberries with different fruit sizes (small, medium, and large) in the laboratory and there was no statistical difference in mortality rates depending on fruit sizes. Mortality data from the laboratory experiments were used to parameterize a refined D. suzukii population model. The model revealed that the timing and order of different insecticide classes are important to control D. suzukii population. Model runs that included early applications of more effective insecticides resulted in high immature mortality and greater reduction of D. suzukii populations compared to treatments applied later.

The Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae) has a worldwide distribution and is considered of medical and veterinary importance. Its synanthropic behavior combined with the visitation of decaying organic matter allows it to mechanically transmit pathogens to human and animals. Pyrethroids are widely used pesticides, effective in low doses against a broad spectrum of insects. Our objective was to evaluate the action of K-Othrine® on the post-embryonic development of C. megacephala. First instar larvae were exposed to different concentrations of K-Othrine® (3.75 × 10−5 g a.i/mL (low), 7.5 × 10−5 g a.i/mL (intermediate low), 1.125 × 10−4 g a.i/mL (intermediate), 1.5 × 10−4 g a.i/mL (intermediate high), and 2.5 × 10−4 g a.i/mL (high)) mixed into artificial diets and a control with no pesticide. We measured weight, time of development, sex ratio, larval and pupal mortality, and esterase patterns. The mean weight values at intermediate low and intermediate concentrations were significantly lower compared with the control; additionally, the development time was delayed compared with the control. The larval and pupal mortality differed among the treatments. The larvae had six esterase regions, which altered its relative activity at 48 h and 72 h after insecticide ingestion. Further studies must investigate the effects of different insecticides on the post-embryonic development of C. megacephala.

Background Mitochondrial serine catabolism to formate induces a metabolic switch to a hypermetabolic state with high rates of glycolysis, purine synthesis and pyrimidine synthesis. While formate is a purine precursor, it is not clear how formate induces pyrimidine synthesis. Methods Here we combine phospho-proteome and metabolic profiling to determine how formate induces pyrimidine synthesis. Results We discover that formate induces phosphorylation of carbamoyl phosphate synthetase (CAD), which is known to increase CAD enzymatic activity. Mechanistically, formate induces mechanistic target of rapamycin complex 1 (mTORC1) activity as quantified by phosphorylation of its targets S6, 4E-BP1, S6K1 and CAD. Treatment with the allosteric mTORC1 inhibitor rapamycin abrogates CAD phosphorylation and pyrimidine synthesis induced by formate. Furthermore, we show that the formate-dependent induction of mTOR signalling and CAD phosphorylation is dependent on an increase in purine synthesis. Conclusions We conclude that formate activates mTORC1 and induces pyrimidine synthesis via the mTORC1-dependent phosphorylation of CAD.

Introduction Adjuvants and immunotherapies designed to activate adaptive immunity to eliminate infectious disease and tumors have become an area of interest aimed at providing a safe and effective strategy to prevent or eliminate disease. Existing approaches would benefit from the development of immunization regimens capable of inducing efficacious cell-mediated immunity directed toward CD8+ T cell-specific antigens. This goal is critically dependent upon appropriate activation of antigen-presenting cells (APCs) most notably dendritic cells (DCs). In this regard, polyanhydride particles have been shown to be effectively internalized by APCs and induce activation. Methods Here, a prophylactic vaccine regimen designed as a single-dose polyanhydride nanovaccine encapsulating antigen is evaluated for the induction of CD8+ T cell memory in a model system where antigen-specific protection is restricted to CD8+ T cells. Bone marrow-derived dendritic cells (BMDCs) are used as an in vitro model system to evaluate the magnitude and phenotype of APC activation. Primary DCs, particularly those with described ability to activate CD8+ T cells, are also evaluated for their in vitro responses to polyanhydride nanoparticles. Results Herein, polyanhydride nanoparticles are shown to induce potent in vitro upregulation of costimulatory molecules on the cell surface of BMDCs. In contrast to the classically used TLR agonists, nanoparticles did not induce large amounts of pro-inflammatory cytokines, did not induce characteristic metabolic response of DCs, nor produce innate antimicrobial effector molecules, such as nitric oxide (NO). The polyanhydride nanovaccine results in protective CD8+ T cell responses as measured by inhibition of tumor progression and survival. Discussion Together, these results suggest that the use of a polyanhydride-based nanovaccine can be an effective approach to inducing antigen-specific CD8+ T cell memory by providing antigen delivery and DC activation while avoiding overt inflammatory responses typically associated with traditional adjuvants.

Microelectronic computers have encountered challenges in meeting all of today’s demands for information processing. Meeting these demands will require the development of unconventional computers employing alternative processing models and new device physics. Neural network models have come to dominate modern machine learning algorithms, and specialized electronic hardware has been developed to implement them more efficiently. A silicon photonic integration industry promises to bring manufacturing ecosystems normally reserved for microelectronics to photonics. Photonic devices have already found simple analog signal processing niches where electronics cannot provide sufficient bandwidth and reconfigurability. In order to solve more complex information processing problems, they will have to adopt a processing model that generalizes and scales. Neuromorphic photonics aims to map physical models of optoelectronic systems to abstract models of neural networks. It represents a new opportunity for machine information processing on sub-nanosecond timescales, with application to mathematical programming, intelligent radio frequency signal processing, and real-time control. The strategy of neuromorphic engineering is to externalize the risk of developing computational theory alongside hardware. The strategy of remaining compatible with silicon photonics externalizes the risk of platform development. In this perspective article, we provide a rationale for a neuromorphic photonics processor, envisioning its architecture and a compiler. We also discuss how it can be interfaced with a general purpose computer, i.e. a CPU, as a coprocessor to target specific applications. This paper is intended for a wide audience and provides a roadmap for expanding research in the direction of transforming neuromorphic photonics into a viable and useful candidate for accelerating neuromorphic computing.

The mechanism and the nature of the species formed by molecular doping of the model polymer poly(3-hexylthiophene) (P3HT) in its regioregular (rre-) and regiorandom (rra-) forms in solution are investigated for three different dopants: the prototypical π-electron acceptor 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ), the strong Lewis acid tris(pentafluorophenyl)borane (BCF), and the strongly oxidizing complex molybdenum tris[1-(methoxycarbonyl)-2-(trifluoromethyl)ethane-1,2-dithiolene] (Mo(tfd-CO2Me)3). In a combined optical and electron paramagnetic resonance study, we show that the doping of rreP3HT in solution occurs by integer charge transfer, resulting in formation of P3HT radical cations (polarons) for all of the dopants considered here. Remarkably, despite the different chemical nature of the dopants and dopant–polymer interaction, the formed polarons exhibit essentially identical optical absorption spectra. The situation is very different for the doping of rraP3HT, where we observe formation of a charge-transfer complex with F4TCNQ and of a “localized” P3HT polaron on nonaggregated chains upon doping with BCF, while there is no indication of dopant-induced species in the case of Mo(tfd-CO2Me)3. We estimate the ionization efficiency of the respective dopants for the two polymers in solution and report the molar extinction coefficient spectra of the three different species. Finally, we observe increased spin delocalization in regioregular compared to regiorandom P3HT by electron nuclear double resonance, suggesting that the ability of the charge to delocalize on aggregates of planarized polymer backbones plays a significant role in determining the doping mechanism.

BACKGROUND: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described. METHODS: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018. RESULTS: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23–69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF. CONCLUSIONS: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.

Interfacial properties of perovskite layers and metal electrodes play a crucial role in device performance and long-term stability of perovskite solar cells. In this work, we performed a comprehensive study of the interfacial structures and ion migration at the interface of a CH3NH3PbI3 perovskite layer and an Al electrode using in situ synchrotron radiation photoemission spectroscopy measurements. It was found that the Al electrode can react with the perovskite layers, leading to the formation of aluminum iodide species and the bonding between Al and N, as well as the reduction of Pb2+ ions to metallic Pb species at the interface. Moreover, during the Al deposition, iodide ions can migrate from the CH3NH3PbI3 subsurface to the Al electrode, while the reduced Pb remains at the subsurface. The depth profile photoemission measurements, made by varying the photon energies of incident synchrotron radiation X-rays, demonstrate that the reaction occurs at the Al/CH3NH3PbI3 interface at least with a thickness of ∼3.5 nm below the perovskite surface. This study provides an atomic-level fundamental understanding of the Al/CH3NH3PbI3 interfacial structures and insight into the degradation mechanisms of perovskite solar cells when using Al metal as the electrode.

Reactive Ion Etching (RIE) of Cytop as the cladding material for optical waveguides and microfluidic channels is investigated. Different grades of Cytop (M, A and S), different mask materials including photoresist and metals, different RIE parameters, along with different substrate materials were investigated. Grass-like structure was observed at the bottom of etched channels, of height that depends on the etching process parameters. A comprehensive post-etch acid cleaning procedure was devised to effectively remove the grass structure. [2019-0232]

Tree stem methane emissions are gaining increasing attention as an overlooked atmospheric source pathway. Existing methods for measuring tree stem greenhouse gas fluxes and isotopes may provide robust integrated emission estimates, but due to their coarse resolution, the capacity to derive insights into fine-scale dynamics of tree stem emissions is limited. We demonstrate and field test an alternative method that is Small, Nimble, In situ and allows for Fine-scale Flux (‘SNIFF’) measurements, on complex and contrasting stem surfaces. It is lightweight and therefore suitable to remote field locations enabling real-time data observations allowing for field-based, data driven sampling regimes. This method facilitated novel results capturing fine-scale vertical and radial methane flux measurements (5 cm increments) and revealed: (1) 86–89% of methane emissions emanated from the lower 30 cm of sampled wetland tree species; (2) clear vertical and horizontal trends in δ13C-CH4 possibly due to fractionation associated with oxidation and/or mass-dependant fractionation during diffusive transport; and (3) the occurrence of substantial radial heterogeneity. We also compared a variety of up-scaling approaches to estimate methane flux per tree, including novel smartphone 3D photogrammetry that resulted in substantially higher stem surface area estimations (> 16 to 36%) than traditional empirical methods. Utilising small chambers with high radial and vertical resolution capabilities may therefore facilitate more robust future assessments into the drivers, pathways, oxidation sinks and magnitude of tree stem greenhouse gas emissions, and compliment previous broad-scale sampling techniques.

Avocado (Persea americana Mill.; Lauraceae) seed-derived polyhydroxylated fatty alcohols (PFAs) or polyols (i.e., avocadene and avocadyne) are metabolic modulators that selectively induce apoptosis of leukemia stem cells and reverse pathologies associated with diet-induced obesity. Delivery systems containing avocado polyols have not been described. Herein, natural surface active properties of these polyols are characterized and incorporated into self-emulsifying drug delivery systems (SEDDS) that rely on molecular self-assembly to form fine, transparent, oil-in-water (O/W) microemulsions as small as 20 nanometers in diameter. Mechanistically, a 1:1 molar ratio of avocadene and avocadyne (i.e., avocatin B or AVO was shown to be a eutectic mixture which can be employed as a novel, bioactive, co-surfactant that significantly reduces droplet size of medium-chain triglyceride O/W emulsions stabilized with polysorbate 80. In vitro cytotoxicity of avocado polyol-SEDDS in acute myeloid leukemia cell lines indicated significant increases in potency and bioactivity compared to conventional cell culture delivery systems. A pilot pharmacokinetic evaluation of AVO SEDDS in C57BL/6J mice revealed appreciable accumulation in whole blood and biodistribution in key target tissues. Lastly, incorporation of AVO in SEDDS significantly improved encapsulation of the poorly water-soluble drugs naproxen and curcumin.

The brewer's spent grain (BSG) is a byproduct of the brewing industry produced in large quantities and with few ecological disposal options. The use of this low-cost residue was investigated for the removal of methylene blue (MB) and tartrazine yellow (TY) dyes. The BSG has been extensively characterized to obtain its physicochemical characteristics. Batch experiments were conducted to investigate the effects of biosorption parameters: initial pH, kinetics, equilibrium isotherms and adsorption thermodynamics. The characterization showed high carbon content and heterogeneous morphology with the presence of meso and macropores. The best experimental conditions were obtained as pH 11 for MB and pH 2 for TY. Kinetics resulted in an equilibrium time of 240 min for MB and 300 min for TY and was best represented by the pseudo-second order model. Different interaction mechanisms were suggested, such as electrostatic interactions, electron donors and electron acceptors, hydrogen bonds, π-π dispersion interactions and the dye molecules aggregation. Equilibrium data were better represented by Langmuir isotherm. The maximum adsorbed amount of MB and TY was 284.75 and 26.18 mg/g, respectively, in each better experimental condition. Through the thermodynamic analysis, it was observed that the adsorption of the dyes was spontaneous and favourable. MB is preferentially retained through chemisorption, whereas TY followed a physical process. Considering the characteristics and results found compared to the recent literature, it was verified that BSG can be used as an effective and innovative biosorbent for removal purposes of dyeing effluent.

Propane and butane are the main constituents of liquefied petroleum gas and are used extensively for transport and domestic use. They are clean burning fuels, suitable for the development of low carbon footprint fuel and energy policies. Here, we present blueprints for the production of bio-alkane gas (propane and butane) through the conversion of waste volatile fatty acids by bacterial culture. We show that bio-propane and bio-butane can be produced photo-catalytically by bioengineered strains of E. coli and Halomonas (in non-sterile seawater) using fatty acids derived from biomass or industrialwaste, and by Synechocystis (using carbon dioxide as feedstock). Scaled production using available infrastructure is calculated to be economically feasible using Halomonas. These fuel generation routes could be deployed rapidly, in both advanced and developing countries, and contribute to energy security to meet global carbon management targets and clean air directives.

The support–metal interaction is an important element of heterogeneous catalyst design and is particularly critical for the rapidly growing field of single-atom catalysts (SACs). We investigate the impact of varying the defect density of the titania support on metal–organic Pt SACs for hydrosilylation reactions. Pt SACs are decorated on the powder titania support, employing a metal–ligand interaction with a dipyridyl-tetrazine ligand (DPTZ). The single-atom nature of Pt is verified by X-ray absorption spectroscopy (XAS) on both pristine and defective titania surfaces. These Pt species have a +2 oxidation state and are stabilized by bonding with DPTZ, surface oxygen, and residual chloride from the metal precursor. The catalytic activity is evaluated for the alkene hydrosilylation reaction and it is discovered that the activity of Pt-ligand is positively correlated with the defect density of the titania support. The turn-over number (TON) is calculated to be 12 530 for Pt SACs on a defective surface, which is significantly higher than Pt SACs on a pristine titania surface (830) for the same reaction period (10 min) under the same conditions (70 °C). We ascribe the high activity of Pt SACs on defective titania surfaces to two aspects: the coordination of Pt with more chloride than on pristine titania surfaces, which shortens the induction period of the reaction, and the preferential dispersion of Pt–DPTZ units on defective regions of titania surfaces, allowing facile contact between Pt sites and reactants. The supported Pt–DPTZ SACs show high stability through multiple cycles of batch reactions. This work demonstrates an efficient approach to improve the activity and stability of SACs by optimizing the metal–support interaction, which can also be applied to other oxide surfaces to further develop next-generation heterogeneous single-atom catalysts.

International audience; ABSTRACT Background Maintenance of high physical performance during aging might be supported by an adequate dietary intake of niacin, vitamins B-6 and B-12, and folate because these B vitamins are involved in multiple processes related to muscle functioning. However, not much is known about the association between dietary intake of these B vitamins and physical performance. Objectives The objectives of this study were to investigate the association between dietary intake of niacin, vitamins B-6 and B-12, and folate and physical performance in older adults and to explore mediation by niacin status and homocysteine concentrations. Methods We used baseline data from the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) trial, which included n = 1249 healthy older adults (aged 65–79 y) with complete data on dietary intake measured with 7-d food records and questionnaires on vitamin supplement use and physical performance measured with the short physical performance battery and handgrip dynamometry. Associations were assessed by adjusted linear mixed models. Results Intake of vitamin B-6 was related to lower chair rise test time [β: –0.033 ± 0.016 s (log); P = 0.043]. Vitamin B-6 intake was also significantly associated with handgrip strength, but for this association, a significant interaction effect between vitamin B-6 intake and physical activity level was found. In participants with the lowest level of physical activity, higher intake of vitamin B-6 tended to be associated with greater handgrip strength (β: 1.5 ± 0.8 kg; P = 0.051), whereas in participants in the highest quartile of physical activity, higher intake was associated with lower handgrip strength (β: –1.4 ± 0.7 kg; P = 0.041). No evidence was found for an association between intake of niacin, vitamin B-12, or folate and physical performance or for mediation by niacin status or homocysteine concentrations. Conclusions Vitamin B-6 intake was associated with better chair rise test time in a population of European healthy older adults and also with greater handgrip strength in participants with low physical activity only. Homocysteine concentrations did not mediate these associations. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012.

In this present work, vinasse, a by-product of sugarcane industry, was examined using combined treatment methods to purify it. Electrocoagulation/flocculation, ultrafiltration were applied as pre-treatment and post-treatment, respectively. The effectiveness of combined process was evaluated based on colour, turbidity and chemical oxygen demand (COD) removal. The efficiency of electrochemical reactor was investigated according to process variables such as retention time, electrode distance and electrolyte dose. From the results, the price to treat unit vinasse is found to be 2.5 US$/m3 under optimum conditions. FT-IR analysis of sludge obtained shows the results of electro-coagulation process. Ultrafiltration as post treatment experiments showed the enhanced removal efficiency of colour (91%), turbidity (88%) and COD (85%). The results showed that electrocoagulation followed by ultrafiltration is a suitable combined technique to reduce the colour, turbidity and COD from vinasse liquid.

Whole red raspberry polyphenols (RRW), including ellagic acid, and their gut-derived metabolite, urolithin A (UroA), attenuate inflammation and confer health benefits. Although results from recent studies indicate that polyphenols and UroA also provide neuroprotective effects, these compounds differ in their bioavailability and may, therefore, have unique effects on limiting neuroinflammation. Accordingly, we aimed to compare the neuroprotective effects of RRW and UroA on BV-2 microglia under both 3 h and 12 and 24 h inflammatory conditions. In inflammation induced by lipopolysaccharide (LPS) and ATP stimulation after 3 h, RRW and UroA suppressed pro-inflammatory cytokine gene expression and regulated the JNK/c-Jun signaling pathway. UroA also reduced inducible nitric oxide synthase gene expression and promoted M2 microglial polarization. During inflammatory conditions induced by either 12 or 24 h stimulation with LPS, UroA—but not RRW—dampened pro-inflammatory cytokine gene expression and suppressed JNK/c-Jun signaling. Taken together, these results demonstrate that RRW and its gut-derived metabolite UroA differentially regulate neuroprotective responses in microglia during 3 h versus 12 and 24 h inflammatory conditions.

Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair., Apoptosis is a cellular process that eliminates damaged or superfluous cells. Here the authors show that cells undergoing apoptotic stresss secrete the growth factor FGF2, which upregulates pro-survival BCL-2 proteins in neighbouring cells, thereby promoting their survival.

Objective To gain insight into Treg interactions with synovial tissues in early OA, an equine tri-culture model of OA was used to test the hypothesis that Tregs, in the absence of T Helper 17 ​cells, are sufficient to resolve inflammation elicited by IL-1β. Methods To model normal and OA joints, synoviocytes were co-cultured with chondrocytes in a transwell system and ± stimulated with IL-1β. Tregs were activated and enriched, then added to co-cultures, creating tri-cultures. At culture end, synoviocytes and chondrocytes were analyzed for gene expression, Treg Foxp3 expression was reexamined by flow cytometry, and conditioned media were evaluated by ELISA. Results Tregs increased IL-10 and IL-4 in tri-culture media and increased TIMP1 gene expression in synoviocytes and chondrocytes. Tregs increased IL-6 in conditioned media and Il6 gene expression in synoviocytes, which was additive with IL-1β. In chondrocytes, addition of Tregs decreased Col2b gene expression while Acan gene expression was decreased by IL-1β and addition of Tregs. IL-17A was detected in tri-cultures. CCL2 and CCL5 were increased in tri-cultures. Conclusions In a tri-culture model of OA, addition of Tregs resulted in conditions conducive to chondroprotection including increased concentration of IL-10 and IL-4 in conditioned media and increased gene expression of TIMP1 in both chondrocytes and synoviocytes. However, there was increased concentration of the catabolic cytokine IL-6, and decreased gene expression of Col2b and Acan in IL-1β-stimulated chondrocytes. These results suggest that blocking IL-6 could enhance Treg function in mitigating OA progression.

Tissino et al. demonstrate that in chronic lymphocytic leukemia, the VLA-4 (CD49d/CD29) integrin remains activable by B cell receptor stimulation also upon in vitro and in vivo ibrutinib exposure. Clinically, ibrutinib-treated CD49d-positive CLL patients experience reduced recirculation lymphocytosis and nodal response and inferior outcomes., The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Bipolar disorder is a debilitating mood disorder characterized by recurring episodes of mania and depression. It affects 2.6% of adults and has a lifetime prevalence among adults of 3.9%. Current mood stabilizers are not always effective and/or are not well tolerated by many patients; thus, there is a need to develop or identify more effective and less harmful treatments. Omega-3-fatty acids have been shown to be effective in the treatment of bipolar disorder; however, their mechanism of action is unknown. Myo-inositol depletion has been hypothesized as the mechanism by which mood stabilizers exert their therapeutic effect. Using an enzymatic assay, we determined intracellular myo-inositol levels increased more than 2-fold when cells were grown in the presence of the omega-3 fatty acid docosahexaenoic acid (DHA). RT-qPCR was used to characterize the effects of DHA on genes in the myo-inositol biosynthetic pathway. We show DHA increases relative expression and has a concentration-dependent impact on INO1 and INM1, which encode myo-inositol-1-phosphate synthase and myo-inositol monophosphate 1-phosphatase, respectively. We therefore conclude that the omega-3-fatty acid DHA exerts its therapeutic effect on bipolar disorder by increasing intracellular myo-inositol, which may be accomplished by upregulating its biosynthetic genes.

Strength, hardness, and ductility characteristics were determined for a series of palladium-copper alloys that compositionally vary from 5 to 25 weight percent copper. Alloy specimens subjected to vacuum annealing showed clear evidence of solid solution strengthening. These specimens showed, as a function of increasing copper content, increased yield strength, ultimate strength, and Vickers microhardness, while their ductility was little affected by compositional differences. Annealed alloy specimens subsequently subjected to exposure to hydrogen at 323 K and PH2 = 1 atm showed evidence of hydrogen embrittlement up to a composition of ~15 wt. % Cu. The magnitude of the hydrogen embrittlement decreased with increasing copper content in the alloy.