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Since its outbreak in China in December 2019 a novel Coronavirus, named SARS-CoV-2, has spread worldwide causing many cases of severe pneumonia, referred to as COVID-19 disease, leading the World Health Organization to declare a pandemic emergency in March 2020. Up to now, no specific therapy against COVID-19 disease exists. This paper aims to review COVID-19 treatment options currently under investigation. We divided the studied drugs into three categories (antiviral, immunomodulatory and other drugs). For each molecule, we discussed the putative mechanisms by which the drug may act against SARS-CoV-2 or may affect COVID-19 pathogenesis and the main clinical studies performed so far. The published clinical studies suffer from methodological limitations due to the emergency setting in which they have been conducted. Nevertheless, it seems that the timing of administration of the diverse categories of drugs is crucial in determining clinical efficacy. Antiviral drugs, in particular Remdesivir, should be administered soon after symptoms onset, in the viraemic phase of the disease; whereas, immunomodulatory agents, such as tocilizumab, anakinra and steroids, may have better results if administered in pneumonia/hyperinflammatory phases. Low-molecular-weight heparin may also have a role when facing COVID-19-related coagulopathy. Up to now, treatment choices have been inferred from the experience with other coronaviruses or viral infection outbreaks. Hopefully, in the near future, new treatment strategies will be available thanks to increased knowledge on SARS-CoV2 virus and COVID-19 pathogenesis. In the meanwhile, further well-designed clinical trials are urgently needed to establish a standard of care in COVID-19 disease.

The synthesis of three new polyamine receptors based on a common 1,4,8,11-tetraazacyclododecane (cyclen) platform with appended, via a methylene linker, heteroaromatic fluorophores, a single quinoline (Q) or an 8-hydroxy-quinoline (8-OH-Q) moiety (L1 and HL2) or a Q and an 8-OH-Q unit (HL3), is reported. The proton binding features of these receptors, together with those of two similar receptors containing two equal Q moieties (L4) and two Q and two acetate groups (H2L5), have been studied by means of potentiometric, 1H NMR, UV-vis absorption and fluorescence emission measurements in aqueous solution at different pH values. While cyclen is a commonly used binding unit, Q and 8-OH-Q represent classical examples of signalling units in conjugated fluorescent chemosensors and their protonation features can strongly influence their ability in metal cations, and anion coordination and sensing. This study reveals that the structural features of these receptors are controlled by a subtle balance between hydrogen bonding and electrostatic repulsions occurring in their protonated species. At the same time, their emission properties are tuned by photoinduced electron and/or proton transfer processes taking place in the excited state.

In anion exchange membrane fuel cells, catalytic reactions occur at a well-defined three-phase interface, wherein conventional heterogeneous catalyst layer structures exacerbate problems such as low catalyst utilization and limited mass transfer. We developed a structural engineering strategy to immobilize a molecular catalyst tetrakis(4-methoxyphenyl)porphyrin cobalt(II) (TMPPCo) on the side chains of an ionomer (polyfluorene, PF) to obtain a composite material (PF-TMPPCo), thereby achieving a homogeneous catalysis environment inside ion flow channels, with greatly improved mass transfer and turnover frequency due to 100% utilization of the catalyst molecules. The unique brand-new structure of the homogeneous catalysis system comprising interconnected nanoreactors exhibits advantages of low overpotential and high fuel cell power density. This strategy of reshaping of the catalyst layer structure may serve as a new platform for applications of many molecular catalysts in fuel cells.

The effects of anthropogenic pressures in coastal areas are extensively studied in temperate but not in tropical zones, where their impact might be amplified by high water temperatures and upwelling phenomena. Sedimentary features and benthic metabolism were studied during the non upwelling (NUPW) and upwelling (UPW) seasons in Taganga Bay (Colombia). The bay is impacted by a submarine outfall of virtually untreated, organic and nutrient-rich wastewater. Samplings were performed in November 2017 (NUPW) and in January–February 2018 (UPW) at 4 stations located in the proximity and 100, 750 and 1800 m far from the outfall, respectively, at depths between 22 and 28 m. Aerobic respiration, denitrification, dissimilative nitrate reduction to ammonium (DNRA) and nutrient fluxes were measured. The influence of the outfall was detectable 750 and 1800 m away from the point pollution source, where δ13C data suggested that ~ 40 and ~ 20% of organic inputs were terrigenous, respectively. In the proximity of the outfall benthic oxygen demand peaked and the presence of Beggiatoa mats suggested reoxidation of sulphides, that were abundant in pore water. Under sulfidic conditions, DNRA was the major driver of nitrate demand, whereas at stations far from the outfall, denitrification dominated nitrate consumption. Organic matter and nitrate inputs to the bay during the UPW season enhanced the effects of the outfall by increasing aerobic respiration and DNRA. Higher N availability during the UPW season reversed fluxes of molecular nitrogen and turned the sediments of 3 out of 4 sites from net sinks to net N2 sources. Results from this study suggest that the analysis of sediments allows tracing the impact of the outfall and that such impact is enhanced during the upwelling season. In tropical areas, marine outfalls and upwelling may act in synergy and contribute to ecosystem deterioration due to high temperatures, increase of microbial respiration, sulphide toxicity and benthic biodiversity loss.

A novel Gram-negative, non-spore-forming, vibrio-shaped, anaerobic, alkaliphilic, sulfate-reducing bacterium, designated strain PAR22NT, was isolated from sediment samples collected at an alkaline crater lake in Guanajuato (Mexico). Strain PAR22NT grew at temperatures between 15 and 37 °C (optimum, 32 °C), at pH between pH 8.3 and 10.1 (optimum, pH 9.0–9.6), and in the presence of NaCl up to 10 %. Pyruvate, 2-methylbutyrate and fatty acids (4–18 carbon atoms) were used as electron donors in the presence of sulfate as a terminal electron acceptor and were incompletely oxidized to acetate and CO2. Besides sulfate, both sulfite and elemental sulfur were also used as terminal electron acceptors and were reduced to sulfide. The predominant fatty acids were summed feature 10 (C18 : 1 ω7c and/or C18 : 1 ω9t and/or C18 : 1 ω12t), C18 : 1 ω9c and C16 : 0. The genome size of strain PAR22NT was 3.8 Mb including 3391 predicted genes. The genomic DNA G+C content was 49.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that it belongs to the genus Desulfobotulus within the class Deltaproteobacteria . Its closest phylogenetic relatives are Desulfobotulus alkaliphilus (98.4 % similarity) and Desulfobotulus sapovorans (97.9 % similarity). Based on phylogenetic, phenotypic and chemotaxonomic characteristics, we propose that the isolate represents a novel species of the genus Desulfobotulus with the name Desulfobotulus mexicanus sp. nov. The type strain is PAR22NT (=DSM 105758T=JCM 32146T).

Several drugs previously tested in clinical trials and approved for different indications have been repurposed for bipolar disorder. We carried out a systematic meta-review of meta-analyses of randomized placebo-controlled trials investigating repurposed drugs as adjunctive treatments for mania and bipolar depression. We performed a critical appraisal using ‘A MeaSurement Tool to Assess systematic Reviews’ Version 2 (AMSTAR 2). We synthesized results on efficacy, tolerability, and safety, assessing evidence quality according to the ‘Grading of Recommendations, Assessment, Development and Evaluations’ (GRADE) approach. Our systematic search identified nine eligible studies investigating 12 drugs, four for mania and eight for bipolar depression. The quality of reporting was heterogeneous according to AMSTAR 2. In mania, allopurinol (for symptoms reduction and remission at 4–8 weeks) and tamoxifen (for response and symptoms reduction at 4–6 weeks) showed higher efficacy than placebo, with low and very low quality of evidence, respectively. Concerning bipolar depression, modafinil/armodafinil (for response, remission, and symptoms reduction at 6–8 weeks) and pramipexole (for response and symptoms reduction at 6 weeks) were superior to placebo, despite the low quality of evidence. Results on the efficacy of celecoxib and N-acetylcysteine were of low quality and limited to certain outcomes. Overall, the lack of evidence of high and moderate quality does not allow us to draw firm conclusions on the clinical utility of repurposed drugs as adjunctive treatments for mania and bipolar depression, highlighting the need for additional research.

In this work, novel platforms for paracetamol sensing were developed by the deposition of Bi2O3, Bi5O7NO3 and their heterostructures onto screen-printed carbon-paste electrodes. An easy and scalable solid state synthesis route was employed, and by setting the calcination temperatures at 500 °C and 525 °C we induced the formation of heterostructures of Bi2O3 and Bi5O7NO3. Cyclic voltammetry measurements highlighted that the heterostructure produced at 500 °C provided a significant enhancement in performance compared to the monophases of Bi2O and Bi5O7NO3, respectively. That heterostructure showed a mean peak-to-peak separation Ep of 411 mV and a sensitivity increment of up to 70% compared to bare electrodes. A computational study was also performed in order to evaluate the geometrical and kinetic parameters of representative clusters of bismuth oxide and subnitrate when they interact with paracetamol.

Growing evidence suggests that a dysregulation of the kynurenine pathway (KP) occurs in bipolar disorder (BD). This systematic review and meta-analysis aimed at assessing the possible differences in peripheral blood levels of KP metabolites between individuals with BD and healthy controls. We searched Medline, Embase, and PsycInfo electronic databases for articles indexed up to February 2020. We included any observational study comparing the peripheral blood levels of at least one KP metabolite between adults with BD and healthy controls. Random-effects meta-analyses were carried out generating pooled standardized mean differences (SMDs). Heterogeneity between studies was estimated using the I2 index. Meta-regression and sensitivity analyses were conducted. Sixteen studies met inclusion criteria and were included in our study. Meta-analyses showed that individuals with BD have lower peripheral blood levels of tryptophan (SMD = -0.29), kynurenine (SMD = -0.28), kynurenic acid (SMD = -0.30), and xanthurenic acid (SMD = -0.55), along with lower kynurenic acid to kynurenine (SMD = -0.60) and kynurenic acid to quinolinic acid (SMD = -0.37) ratios, than healthy controls. Individuals with a manic episode showed the greatest reductions in tryptophan levels (SMD = -0.51), whereas kynurenic acid levels were more reduced among subjects in a depressive phase (SMD = -0.70). Meta-regression and sensitivity analyses confirmed our results. The findings of the present meta-analysis support the hypothesis of an abnormality of the KP in BD. Considering the partial inconsistency of the findings and the small-to-medium magnitude of the estimated effect sizes, additional research assessing possible mediators or confounders is needed.

The fabrication of a biodegradable and fluorescent cylindrical waveguide with doped hybrid nanoparticles (silica-carbon nanodots) is reported. The fluorescent hybrids were obtained by coupling amino-functionalized fumed silica nanoparticles with the carboxylic acid surface groups of amorphous carbon nanodots obtained from the thermolysis of citric acid. The hybrid nanoparticles present diameters lower than 10 nm, maximum fluorescence at 465 nm, and excitation-wavelength-dependent behavior. They were occluded into an agarose matrix, providing a low-cost and easily scalable sensor capable of detecting pH variations with maximum sensitivity of 5.61 nm/(pH unit) when excited by a 403 nm UV light-emitting diode (LED).

Exceptional magmatic events coincided with the largest mass extinctions throughout Earth’s history. Extensive degassing from organic-rich sediments intruded by magmas is a possible driver of the catastrophic environmental changes, which triggered the biotic crises. One of Earth’s largest magmatic events is represented by the Central Atlantic Magmatic Province, which was synchronous with the end-Triassic mass extinction. Here, we show direct evidence for the presence in basaltic magmas of methane, generated or remobilized from the host sedimentary sequence during the emplacement of this Large Igneous Province. Abundant methane-rich fluid inclusions were entrapped within quartz at the end of magmatic crystallization in voluminous (about 1.0 × 106 km3) intrusions in Brazilian Amazonia, indicating a massive (about 7.2 × 103 Gt) fluxing of methane. These micrometre-sized imperfections in quartz crystals attest an extensive release of methane from magma–sediment interaction, which likely contributed to the global climate changes responsible for the end-Triassic mass extinction., Global climate changes triggered by massive output of greenhouse gases led to mass extinctions in Earth’s past. Here, the authors show that widespread release of methane at the time of the end-Triassic mass extinction was caused by interaction of a Large Igneous Province with sedimentary host-rocks.

Resistive Plate Chambers have largely been used in High Energy Physics and Cosmic Ray research. In view of using this detector for calorimetry applications it is important to know the maximum measurable particle density, or its intrinsic linearity limit, which is tightly related to the dimension of the discharge region. In this paper we report the results of measurements performed at the Beam Test Facility (INFN National Laboratory of Frascati, Italy) where the intrinsic linearity of bakelite RPCs operated in streamer mode has been tested at different impinging particle densities.

Previous research has hypothesized a role for serum uric acid as a marker of mental disorders and related behaviors, possibly due to its link with purinergic transmission and antioxidant activity. We tested the association of serum uric acid levels with specific behavioral and clinical characteristics in 99 individuals suffering from major affective disorders. Subjects were assessed and interviewed using the Kessler Psychological Distress Scale, the Columbia-Suicide Severity Rating Scale, the Modified Overt Aggression Scale, and the Barratt Impulsiveness Scale. We found that psychological distress and suicidal ideation severity were associated with lower uric acid serum levels. On the other hand, verbal aggression and history of violence were associated with higher levels of serum uric acid. However, according to linear regression analyses, there were no behavioral and clinical characteristics independently associated with serum uric acid. Serum uric acid levels were influenced by creatinine and BMI, as well as, possibly, by white blood cells count and gender. Despite some limitations, these results suggest that no behavioral / clinical features are associated with variations of serum uric acid, which rather seem attributable to specific biochemical and metabolic parameters. Nevertheless, the role of purinergic system in different mental disorders and behavioral abnormalities, deserves further research.

D-glucosamine is investigated as a non-toxic and sustainable carbon/nitrogen (C/N) source for the templated synthesis of nitrogen-containing CMK-8 ordered mesoporous carbons (NOMCs) conceived for selective CO2 uptake. Pyrolysis temperature is varied during nanocasting using the KIT-6 silica hard template to tailor microporosity and nitrogen inclusions. NOMCs exhibit large surface area (600e1000 m2 g-1) and excellent pore ordering. The CO2/adsorbent interaction energy is estimated by the isosteric enthalpy of adsorption (~33e40 kJ mol-1) and Henry's constants. The role of nitrogen content (~7 e12 at.%) and of each type of N-species on CO2 adsorption is studied by X-ray photoelectron spectroscopy, and CO2/N2 selectivity is attributed, being pyridinic functionalities the most effective ones. NOMCs are tested at different temperatures, gas flow compositions, reversibility, and so on; in all tested conditions, they outperform a homologous bare sucrose-derived carbon. Enhancing micropore volume allows achieving maximum adsorption capacity in pure CO2 (1.47 mmol g1 at 30 C/0.9 bar), whereas increasing surface N-content accounts for the highest selectivity in CO2/N2 mixtures (20/80 v/v) at 35 C/ 1 bar (maximum CO2 uptake 0.82 mmol g1 ). The combination of a suitable C/N precursor and the hard templating synthetic route is effective for obtaining high-performing, sustainable, and reusable selective CO2 sorbents, without any activation steps or N-doping post-treatments. © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Sulfamethoxazole (SMX) is a frequently used antibiotic for the treatment of urinary tract, respiratory, and intestinal infections and as a supplement in livestock or fishery farming to boost production. The release of SMX into the environment can lead to the development of antibiotic resistance among the microbial community, which can lead to frequent clinical infections. SMX removal from water is usually done through advanced treatment processes, such as adsorption, photocatalytic oxidation, and biodegradation. Among them, the advanced oxidation process using TiO2 and its composites is being widely used. TiO2 is a widely used photocatalyst; however, it has certain limitations, such as low visible light response and quick recombination of e−/h+ pairs. Integrating the biochar with TiO2 nanoparticles can overcome such limitations. The biochar-supported TiO2 composites showed a significant increase in the photocatalytic activities in the UV-visible range, which resulted in a substantial increase in the degradation of SMX in water. The present review has critically reviewed the methods of biochar TiO2 composite synthesis, the effect of biochar integration with the TiO2 on its physicochemical properties, and the chemical pathways through which the biochar/TiO2 composite degrades the SMX in water or aqueous solution. The degradation of SMX using photocatalysis can be considered a useful model, and the research studies presented in this review will allow extending this area of research on other types of similar pharmaceuticals or pollutants in general in the future.

Background Transthyretin amyloidosis (ATTR) is a rare and serious, systemic disease characterized by deposits of amyloid fibrils in various tissues and organs. Tafamidis meglumine is a potent and selective stabilizer of TTR, indicated since 2011 in the treatment of neurological forms of the disease. The French “Agence Nationale de Sécurité du Médicament et des produits de santé” (ANSM) granted a temporary recommendation for use (RTU) on November 28th 2018, based on ATTR-ACT, the pivotal trial results, and designed to enable use of tafamidis meglumine in ATTR cardiomyopathy (ATTR-CM) patients with NYHA I, II and III before marketing authorization. This RTU has been a unique opportunity in France to collect real world data of ATTR-CM patients treated by tafamidis meglumine. Objective We aimed to describe the characteristics of ATTR-CM patient treated by tafamidis in the setting of the RTU, over 2 years from November 28th 2018 to November 27th 2020. Methods Demographic and clinical data about the diagnosis pathway of patients included in the RTU were prospectively collected using questionnaires, as requested by ANSM to be completed by physicians at the time of tafamidis prescription. A second version of the inclusion form, introduced in May 2020, has allowed collection of additional clinical information. Results Overall, 1902 ATTR-CM patients have been included by 189 physicians from 107 centers. Nine centers included each at least 50 patients, accounting for 1092, or 57.4% of all patients. The median age of the patients was 82 years (IQR=9 years), 82% were male, and, 12.4%, 58.8% and 28.7% of patients had a NYHA class of I, II and III, respectively. For almost all patients, the diagnosis of restrictive/infiltrative heart failure was based on heart MRI and/or echocardiography (98.5%; among the 601 patients included from May 2020 28.8% had both exams, 69.7% echo only and 1.6% MRI only), the infiltrative nature of the cardiomyopathy had been confirmed by bone scintigraphy (99.3%), and the absence of light chains had been confirmed by protein electrophoresis or Bence Jones proteinuria (96.6%). Genetic test was performed in 1205 patients (69.4%). Out of the 884 patients who had a genetic test result available at the time of initial prescription, 762 (86.2%) were affected with the wild-type form and 122 (13.8%) with the hereditary form. Among the 601 patients included from May 2020, a hospitalization for cardiovascular condition within the 6 months preceding tafamidis initiation was reported for 22.3% of them, and tafamidis was initiated within 12 months after diagnosis for 92% of them (only 8% initiated the treatment beyond that period). Conclusion The RTU program has provided 1902 ATTR-CM patients with early access to tafamidis over 24 months, in France. Overall, as compared to patients included in ATTR-ACT, the pivotal trial, RTU patients were older, the proportion of wild-type was slightly higher, and NYHA distributions were similar. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Early access program sponsored by Pfizer

Upper dermal mast cells are markers of chronic photoexposure and they are more prominent in melasma than in unaffected adjacent skin.1 As mast cells degranulate under stimulation (e.g., heat, UV exposure), and several treatments for melasma, such as oral tranexamic acid, topical nicotinamide, and topical corticosteroids reduce them, such cells are thought to play a key role in melasma pathogenesis.2,3 To date, there are no studies exploring the stabilization of mast cells and H2 blockade as a potential therapeutic strategy in melasma.

We report on the microwave shielding efficiency of non-structural composites, where inclusions of biochar—a cost effective and eco-friendly material—are dispersed in matrices of interest for building construction. We directly measured the complex permittivity of raw materials and composites, in the frequency range 100 MHz–8 GHz. A proper permittivity mixing formula allows obtaining other combinations, to enlarge the case studies. From complex permittivity, finally, we calculated the shielding efficiency, showing that tailoring the content of biochar allows obtaining a desired value of electromagnetic shielding, potentially useful for different applications. This approach represents a quick preliminary evaluation tool to design composites with desired shielding properties starting from physical parameters.

The electrochemical reforming of ethanol to H2 is achieved at 150 °C in an autoclave electrochemical cell that allows the safe pressurization of the H2 produced as no O2 is evolved. The alkaline conditions are very aggressive to catalysts including noble metals like Pt and Pd. We report a highly active ethanol oxidation catalyst (PdCoNifoam) composed of Pd nanoparticles supported on nanostructured Co oxide structures grown on nickel foam. Treatment with phosphorous vapors at high temperature yields a thin coating of phosphate that confers enhanced stability to the electrode operating in an electrolysis cell at 150 °C. A combination of scanning electron microscopy (energy dispersive X-ray spectroscopy) and X-ray photoelectron spectroscopy reveal a 3D nano-flake surface with an external layer of phosphates that prevents Pd dissolution. The PdCoP@Nifoam catalyst was successfully used for ethanol electrochemical reforming at 150 °C with self-pressurization of the H2 produced by the electrochemical reaction.

An integrated characterization of physical, chemical, biochemical and microbiological properties of litter fractions (litter, fragmented and humified), corresponding at three decomposition phases, has been conducted in a degraded pine forest. Litter fractions were characterized in terms of C and N content, microbial communities’ structure, enzyme activities and optical properties. The objective of this approach was to give an insight of actors and mechanisms operating during decomposition process, evaluating the relationships between litter pools (organic matter and microbial communities) and activities (respiration and enzymes). The effect of different thinning treatments (traditional and selective) on litter biomass and respiration was also investigated for 2 years, to identify forest management practices aiming at increase C storage and mitigate climate change. The litter fractions showed well-distinct chemical composition, with a decrease in carbon and an increase in nitrogen as decomposition advanced. Parallelly, an increase in fungal richness and diversity, and related enzyme activities, was observed. Bacteria were similar in the three fractions but seemed to have a role in the early phase of cellulose and hemicellulose decomposition. Thinning induced a short-term increase in litter input to soil, which disappeared after the first year until determining a general decrease in litter biomass, stronger with selective thinning. Further, in the warmer months of the second year after thinning litter respiration showed an increasing trend. Overall, positive effects of thinning on C storage were evident in the short term, followed by a decrease in litter pool driven by higher litter respiration.

Philadelphia has high rates of chronic disease, including hypertension and diabetes, which can be mitigated through reduction of dietary sodium intake. To address this, the City of Philadel...

Tomato fruit ripening and postharvest display a complex net of metabolic pathways, which are controlled by different signaling molecules and hormones that coordinate this physiological process. The inhibition of the ethylene action with 1-methylcyclopropene (1-MCP) has proved to be an excellent tool for maintaining fruit quality during postharvest. Along with these findings, nitric oxide (NO) demonstrated different effects on several species in fruit postharvest. The aim of this work was to evaluate the joint effect of 1-MCP and a NO donor (S-nitrosoglutathione, GSNO) during tomato postharvest at 23 °C. Breaker tomatoes were harvested from a local grower and divided in the following treatments: untreated, 1 mM GSNO, 0.5 μL L−1 of 1-MCP, and the combination of 1 mM GSNO + 0.5 μL L−1 1-MCP. Fruit was stored at 23 °C and analyzed after 5 and 10 d. According to the results, the combination of 1-MCP and the NO donor delayed fruit softening at days 5 and 10, reduced the ethylene synthesis significantly at day 5 and elevated the respiration rate at 10 d, compared to the individual treatments of 1-MCP and GSNO alone. However, the solely application of 1-MCP, independently from the addition of GSNO, showed a strong effect in the rise of the total titratable acidity content, together with the citric acid content. 1-MCP also up-regulated the CAT, SOD and POD activities at 5 and 10 d after harvest. These findings may suggest that some fruit quality parameters in tomato postharvest are controlled by ethylene, while others need the coordination of nitric oxide as a signal molecule.

Since the early 2010s, deaths due to the use of new synthetic opioids (NSO) including fentanyl and its analogs have been increasing dramatically. As fentanyl analogs bear strong structural similarities, they can share common metabolites. In some clinical or forensic cases, it can be important to demonstrate the presence of both the metabolite and the parent product to confirm that the compound is responsible for the intoxication. Norcarfentanil is a common metabolite of carfentanil (NSO) and remifentanil (widely used in medical care). This article reported the investigation of norcarfentanil origin in three cases. Comprehensive screenings were performed using gas chromatography coupled to mass spectrometry and liquid chromatography coupled to a diode array detection, whereas targeted screening of NSO were performed using liquid chromatography coupled to tandem mass spectrometry. Norcarfentanil was detected at concentrations ranging from 0.05 to 15.8 ng/mL in plasma and from 8.8 to 1820 ng/mL in urine, but carfentanil was detected in two out of the three cases. The presence of norcarfentanil has been supposed to be due to the treatment with remifentanil during the medical care of the patient. In the first two cases, norcarfentanil was present as the metabolite of carfentanil, whereas in the last case, norcarfentanil was the metabolite of remifentanil. Without the identification of remifentanil, confusion could occur, and norcarfentanil could be attributed to carfentanil misuse.

Endothelial cells selectively release cargo stored in Weibel-Palade bodies (WPBs) to regulate vascular function, but the underlying mechanisms are poorly understood. Here we show that histamine evokes the release of the proinflammatory ligand, P-selectin, while diverting WPBs carrying non-inflammatory cargo away from the plasma membrane to the microtubule organizing center. This differential trafficking is dependent on Rab46 (CRACR2A), a newly identified Ca2+-sensing GTPase, which localizes to a subset of P-selectin–negative WPBs. After acute stimulation of the H1 receptor, GTP-bound Rab46 evokes dynein-dependent retrograde transport of a subset of WPBs along microtubules. Upon continued histamine stimulation, Rab46 senses localized elevations of intracellular calcium and evokes dispersal of microtubule organizing center–clustered WPBs. These data demonstrate for the first time that a Rab GTPase, Rab46, integrates G protein and Ca2+ signals to couple on-demand histamine signals to selective WPB trafficking.

Freshwater ecosystems are challenged by cultural eutrophication across the globe, and it is a priority for water managers to implement water quality monitoring at different spatio-temporal scales to control and mitigate the eutrophication process. Phytoplankton abundance is a key indicator of the trophic and water quality status of lakes. Phytoplankton dynamics are characterized by high spatio-temporal variation, driven by physical, chemical and biological factors, that challenge the capacity of routine monitoring with conventional sampling techniques (i.e., boat based sampling) to characterise these complex relationships. In this study, high frequency in situ measurements and multispectral satellite data were used in a synergistic way to explore temporal (diurnal and seasonal) dynamics and spatial distribution of Chlorophyll-a (Chl-a) concentration, a proxy of phytoplankton abundance, together with physico-chemical water parameters in a shallow fluvial-lake system (Mantua Lakes). A good agreement was found between Chl-a retrieved by remote sensing data and Chl-a fluorescence data recorded by multi-parameters probes (R2 = 0.94). The Chl-a maps allowed a seasonal classification of the Mantua Lakes system as eutrophic or hypertrophic. Along the Mantua lakes system an increasing gradient in Chl-a concentration was recorded following the transition from a fluvial to lacustrine system. There was significant seasonal heterogeneity among the sub-basins, probably due to different hydrodynamics, influenced also by macrophyte stands. High-frequency data revealed the importance of rainfall events in the timing and growth dynamics of phytoplankton, particularly for spring and late summer blooms. Combining temporal and spatial data at high resolution improves the understanding of complex fluvial-lake systems. This technique can allow managers to target blooms in near-real time as they move through a system and guide them to localized hot spots enabling timely management action in ecosystems of high conservation and recreational value.

(1) Background: The geothermal spring of La Crouen (New Caledonia) discharges warm (42 °C) alkaline water (pH~9) enriched in dissolved nitrogen with traces of methane, but its microbial diversity has not yet been studied. (2) Methods: Cultivation-dependent and -independent methods (e.g., Illumina sequencing and quantitative PCR based on 16S rRNA gene) were used to describe the prokaryotic diversity of this spring. (3) Results: Prokaryotes were mainly represented by Proteobacteria (57% on average), followed by Cyanobacteria, Chlorofexi, and Candidatus Gracilibacteria (GN02/BD1-5) (each &gt, 5%). Both potential aerobes and anaerobes, as well as mesophilic and thermophilic microorganisms, were identified. Some of them had previously been detected in continental hyperalkaline springs found in serpentinizing environments (The Cedars, Samail, Voltri, and Zambales ophiolites). Gammaproteobacteria, Ca. Gracilibacteria and Thermotogae were significantly more abundant in spring water than in sediments. Potential chemolithotrophs mainly included beta- and gammaproteobacterial genera of sulfate-reducers (Ca. Desulfobacillus), methylotrophs (Methyloversatilis), sulfur-oxidizers (Thiofaba, Thiovirga), or hydrogen-oxidizers (Hydrogenophaga). Methanogens (Methanobacteriales and Methanosarcinales) were the dominant Archaea, as found in serpentinization-driven and deep subsurface ecosystems. A novel alkaliphilic hydrogenotrophic methanogen (strain CAN) belonging to the genus Methanobacterium was isolated, suggesting that hydrogenotrophic methanogenesis occurs at La Crouen.

Bacteria adapt to versatile environments by modulating gene expression through a set of stress response regulators, alternative Sigma factors, or two-component systems. Among the central processes that must be finely tuned is membrane homeostasis, including synthesis of phospholipids (PL). However, few genetic regulations of this process have been reported. We have previously shown that the gene coding the first step of PL synthesis is regulated by σE and ppGpp, and that the BasRS (PmrAB) two component system controls the expression of the DgkA PL recycling enzyme. The gene coding for phosphatidylserine decarboxylase, the last step in phosphatidylethanolamine synthesis is another gene in the PL synthesis pathway susceptible of stress response regulation. Indeed, psd appears in transcriptome studies of the σE envelope stress Sigma factor and of the CpxAR two component system. Interestingly, this gene is presumably in operon with mscM coding for a miniconductance mechanosensitive channel. In this study, we dissected the promoter region of the psd-mscM operon and studied its regulation by σE and CpxR. By artificial activation of σE and CpxRA stress response pathways, using GFP transcriptional fusion and western-blot analysis of Psd and MscM enzyme production, we showed that the operon is under the control of two distinct promoters. One is activated by σE, the second is activated by CpxRA and also responsible for basal expression of the operon. The fact that the phosphatidylethanolamine synthesis pathway is controlled by envelope stress responses at both its first and last steps might be important for adaptation of the membrane to envelope perturbations.

BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked causally to the development and progression of degenerative diseases of the retina including diabetic retinopathy, age-related macular degeneration and glaucoma, leading causes of blindness worldwide. The above responses may be related directly to dysregulated retinal immunity and are potentiated by the combined actions of native retinal cells (e.g., retinal pigment epithelial (RPE) and microglial cells) and immune cells infiltrating from the periphery. Maintaining tight regulation of these cells such that effective control of pathogens is accomplished yet uncontrolled inflammation and consequent tissue damage is prevented is extremely important. However, the molecular mechanisms that control this delicate balance are poorly understood. We hypothesize that the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) may play an important role. HCAR2/GPR109A has been shown to regulate immune cell responses that potentiate anti-inflammatory signaling upon its activation in various tissues as evidenced principally by suppressed pro-inflammatory cytokine secretion in various experimental model systems. We have demonstrated HCAR2/GPR109A expression in RPE, microglia and endothelial cells and, our in vitro studies support that the receptor elicits anti-inflammatory signaling in these cell types. However, the functional relevance of HCAR2/GPR109A expression and its activation in the retina of the living animal has not been demonstrated definitively. This is the purpose of the present study.MethodsRetinal function was evaluated temporally in wildtype (Hcar2/Gpr109a +/+, WT) and knockout (Hcar2/Gpr109 -/-, KO) mice via electroretinography (ERG). Fundoscopic imaging, spectral domain-optical coherence tomography (OCT), fluorescein angiography and post-mortem histological analyses were additionally performed to evaluate retinal health. Gene microarray, RT-qPCR studies, ingenuity analyses and proteome pathway mapping were performed to evaluate potential key differences in the molecular signatures of WT and KO mouse retinas. Leukostasis and flow cytometric assays were performed to demonstrate the in vivo impact of HCAR2/GPR109A expression and its therapeutic activation on pro-inflammatory immune cell trafficking in retina.ResultsLongitudinal studies revealed progressive anomalies in retinal morphology and function in HCAR2/GPR109A knockout mice that impacted the entire retina. Gene expression and protein interactome analyses revealed differences in gene and protein expression consistent with the increased immune reactivity and infiltration of bone-marrow derived immune cells detected in KO mouse retinas. Studies conducted in an acute model of retinal (endotoxin-induced) inflammation revealed that targeting the receptor via intraperitoneal administration of agonist, beta-hydroxybutyrate, limits immune cell activation, infiltration and related inflammation in WT retinas.ConclusionsThe present studies demonstrate a central role for HCAR2/GPR109A in regulating the complex interplay between resident retinal cells and peripheral immune cells and, the potential therapeutic utility that targeting the receptor holds with respect to preventing and treating inflammatory retinal diseases.HighlightsOxidative stress and inflammation are major causative factors in degenerative retinal diseases stemming from numerous causes (e.g., aging, diabetes, sickle cell). Thus, identifying new targets and developing strategies to counter these factors to prevent and treat retinal degeneration is important. The present in vivo study demonstrates convincingly the principal role of the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) as a major regulator of retinal immune responses under normal conditions and therefore, as a target with extremely high potential for therapeutic modulation of these responses in retinal disease.

This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.

Pathophysiological mechanisms of major depressive disorder (MDD) seem to be associated with oxidative stress pathways and altered purinergic metabolism. We conducted a systematic review and meta-analysis to estimate if subjects with MDD might have reduced levels of antioxidant uric acid, considering also potential influence of antidepressant treatment. We searched the main Electronic Databases, identifying 14 studies that met our inclusion criteria. Meta-analyses were carried out generating pooled Hedges' g and mean differences (MDs), using random-effects models. Heterogeneity across studies and risk of publication bias were estimated using standard methods. Relevant sensitivity and meta-regression analyses were conducted. Subjects with MDD had levels of uric acid lower than healthy controls (Hedges' g = -0.30; p = 0.003). Overall between-study heterogeneity was high (I 2 = 76.3%). The effect was significant among studies including drug naive/free MDD individuals (Hedges' g = -0.55; p = 0.023), but not among those involving treated subjects (Hedges' g = -0.15; p = 0.062). Relevant quality- and heterogeneity-based sensitivity analyses, as well as meta-regressions, confirmed these findings. In addition, uric acid levels significantly, though inconsistently (I 2 = 79.2%), increased after treatment (MD = +0.71 mg/dL; p