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Many enzymes work as homodimers with two distant catalytic sites, but the reason for this choice is often not clear. For the main protease Mpro of SARS-CoV-2, dimerization is essential for function and plays a regulatory role during the coronaviral replication process. Here, to analyze a possible allosteric mechanism, we use X-ray crystallography, native mass spectrometry, isothermal titration calorimetry, and activity assays to study the interaction of Mpro with three peptide substrates. Crystal structures show how the plasticity of Mpro is exploited to face differences in the sequences of the natural substrates. Importantly, unlike in the free form, the Mpro dimer in complex with these peptides is asymmetric and the structures of the substrates nsp5/6 and nsp14/15 bound to a single subunit show allosteric communications between active sites. We identified arginines 4 and 298 as key elements in the transition from symmetric to asymmetric dimers. Kinetic data allowed the identification of positive cooperativity based on the increase in the processing efficiency (kinetic allostery) and not on the better binding of the substrates (thermodynamic allostery). At the physiological level, this allosteric behavior may be justified by the need to regulate the processing of viral polyproteins in time and space. Structural, biophysical, and kinetic analyses of the interaction of SARS-CoV-2 Mpro with peptide substrates shed light on the allosteric properties of the enzyme, which is based on kinetics rather than thermodynamics. [ABSTRACT FROM AUTHOR]

The biological clock in eukaryotes controls daily rhythms in physiology and behavior. It displays a complex organization that involves the molecular transcriptional clock and the redox oscillator which may coordinately work to control cellular rhythms. The redox oscillator has emerged very early in evolution in adaptation to the environmental changes in O2 levels and has been shown to regulate daily rhythms in glycerolipid (GL) metabolism in different eukaryotic cells. GLs are key components of lipid droplets (LDs), intracellular storage organelles, present in all living organisms, and essential for energy and lipid homeostasis regulation and survival; however, the cell bioenergetics status is not constant across time and depends on energy demands. Thus, the formation and degradation of LDs may reflect a time-dependent process following energy requirements. This work investigated the presence of metabolic rhythms in LD content along evolution by studying prokaryotic and eukaryotic cells and organisms. We found sustained temporal oscillations in LD content in Pseudomonas aeruginosa bacteria and Caenorhabditis elegans synchronized by temperature cycles, in serum-shock synchronized human embryonic kidney cells (HEK 293 cells) and brain tumor cells (T98G and GL26) after a dexamethasone pulse. Moreover, in synchronized T98G cells, LD oscillations were altered by glycogen synthase kinase-3 (GSK-3) inhibition that affects the cytosolic activity of the metabolic oscillator or by knocking down LIPIN-1, a key GL synthesizing enzyme. Overall, our findings reveal the existence of metabolic oscillations in terms of LD content highly conserved across evolutionary scales notwithstanding variations in complexity, regulation, and cell organization. [ABSTRACT FROM AUTHOR]

The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12–15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology. [ABSTRACT FROM AUTHOR]

A study of the influence of farming practices in the Middle Ages (X–XV AD) on the activities of 11 hydrolytic enzymes involved in the biogeochemical cycles of major elements in soils has been carried out. Agrostratozems of Medieval agricultural terraces in Dagestan mountains (Plaggic and Hortic Anthrosols) were chosen as objects of study. In all cases, the enzymatic activity of the studied soils decreased in all soil layers in the following sequence: alkaline phosphatase > phosphodiesterase > acid phosphatase > pyrophosphatase ≥ leucine aminopeptidase > arylsulfatase > chitinase > β-glucosidase > xylanase > α-glucosidase > cellobiohydrolase. The enzymatic activity of the studied soils was primarily determined by the amount of microbial biomass (Cmic). Thus, the activity of enzymes of various groups depended on Cmic by 61–94%. Agricultural practices associated with ploughing, manuring, and irrigation induce the convergence in the activity of nitrogen cycle enzymes in soils of the mountain zone, which is associated with similar features of the nitrogen cycle in agrogenic soils, regardless of bioclimatic conditions. The addition of organic materials has led to an increase in the physiological efficiency of microbial communities and the rate of enzyme production, and high levels of biological activity can persist in soil for about 1000 years. Ploughing with the application of organic fertilizers in the past led to an increase in enzymatic activity expressed per unit of microbial biomass (specific activity), therefore, this indicator can be used as an indicator of agrogenic transformation of soils in the past. [ABSTRACT FROM AUTHOR]

The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By screening AlphaFold-modeled vitamin B6-dependent enzymes, we find that a metric based on catalytically favorable conformations at the enzyme active site performs best (AUROC Score=0.84) in identifying genes associated with known reactions. Applying this procedure, we identify the mammalian gene encoding hydroxytrimethyllysine aldolase (HTMLA), the second enzyme of carnitine biosynthesis. Upon experimental validation, we find that the top-ranked candidates, serine hydroxymethyl transferase (SHMT) 1 and 2, catalyze the HTMLA reaction. However, a mouse protein absent in humans (threonine aldolase; Tha1) catalyzes the reaction more efficiently. Tha1 did not rank highest based on the AlphaFold model, but its rank improved to second place using the experimental crystal structure we determined at 2.26 Å resolution. Our findings suggest that humans have lost a gene involved in carnitine biosynthesis, with HTMLA activity of SHMT partially compensating for its function. With structural models now available on a proteome scale, Malatesta et al. show that structure-based screening can help identify proteins catalyzing orphan reactions in metabolic pathways, offering functional insights beyond sequence-based approaches. [ABSTRACT FROM AUTHOR]

The relationship between the concentration of soil DNA and microbial biomass determined by the method of substrate-induced respiration was studied in a wide range of soils differing in particle size distribution, acidity, organic carbon content, microbial biomass, and type of human activity in antiquity and at the present time. Calcaric Leptosols and Leptic Phaeozems of medieval agricultural lands in the Central Caucasus, Stratozems of agricultural terraces of the late Middle Ages—Modern times in the middle mountain zone of the Eastern Caucasus, as well as Kastanozems and Solonetzes with different grazing intensity in the dry steppe zone (Rostov region) were chosen as the key sites. It was shown that the determination of soil double-stranded DNA concentration is a reliable and simple method for determining microbial biomass in soils with a loamy texture, the organic carbon content < 2%, and the microbial biomass <700 µg C/g dry soil. The conversion factor FDNA in such soils varied in a narrow range from 5.24 to 5.41. In soils with a high content of organic carbon, an increase in FDNA (6.56 and 10.56) was observed due to the presence of recalcitrant extracellular DNA. Agristratified soil of sandy loamy texture was characterized by a lower degree of double-stranded DNA preservation, which resulted in a decrease in the determined microbial biomass (FDNA = 4.22). A reduced conversion factor FDNA (4.78) was also found in the soils of pastures in the dry steppe zone, which confirms the known limitations of using the substrate-induced respiration method in alkaline soils. Human activity did not significantly affect the relationship between the amount of soil DNA and microbial biomass. [ABSTRACT FROM AUTHOR]

Redesigning organic vegetable systems through the introduction of agroecological service crops (ASCs) terminated by the in-line roller crimper (RC) has attracted great interest, although the effects on soil quality are poorly known. In a two-year field experiment in Southern Italy, two ASCs winter cereal/legume-based mixtures were terminated by RC (ASC–RC treatment) and as green manure before organic tomato (Solanum lycopersicum L.) and compared with two tilled controls without ASCs, one of which with Mater-Bi mulch (six treatments: two ASCs, two terminations, two controls). Soil chemical and biological attributes and yields were compared to assess whether ASCs and ASC–RC can enhance the soil functioning in semi-arid environment. Tomato yield showed no differences in 2017, while in 2016 it decreased by 67% in ASC treatments compared to the controls. The ASCs didn't significantly increase soil P and N availability until midpoint of the tomato cycle. Soil mineral N increased by 200% in the ASC with higher legume presence at harvest in 2017. In the distance-based redundancy analysis, total soil organic carbon significantly predicted distribution pattern between ASCs and controls of enzyme activities, fostered by the ASCs (+ 159% for nonanoate-esterase in ASC–RC, compared to controls), although microbial biomass didn't show differences. The ASC–RC effect in improving soil biological attributes was enzyme- and ASC species-specific. Despite the results on tomato yield, agroecological management seems a promising strategy to improve soil quality in a long-term perspective, supporting soil metabolic activity and improving its self-regulating capacity. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a disease characterized by the production of viscous mucoid secretions in multiple organs, particularly the airways. The pathological increase of proteins, mucin and biological polymers determines their arrangement into a three-dimensional polymeric network, affecting the whole mucus and impairing the muco-ciliary clearance which promotes inflammation and bacterial infection. Thus, to improve the efficacy of the drugs usually applied in CF therapy (e.g., mucolytics, anti-inflammatory and antibiotics), an in-depth understanding of the mucus nanostructure is of utmost importance. Drug diffusivity inside a gel-like system depends on the ratio between the diffusing drug molecule radius and the mesh size of the network. Based on our previous findings, we propose the combined use of rheology and low field NMR to study the mesh size distribution of the sputum from CF patients. Specifically, we herein explore the effects of chest physiotherapy on CF sputum characteristic as evaluated by rheology, low field NMR and the drug penetration through the mucus via mathematical simulation. These data show that chest physiotherapy has beneficial effects on patients, as it favourably modifies sputum and enhances drug penetration through the respiratory mucus. [ABSTRACT FROM AUTHOR]

We address the structure identification and the uniform approximation of two fully nonlinear layer neural networks of the type f (x) = 1 T h (B T g (A T x)) on R d , where g = (g 1 , ⋯ , g m 0) , h = (h 1 , ⋯ , h m 1) , A = (a 1 | ⋯ | a m 0 ) ∈ R d × m 0 and B = (b 1 | ⋯ | b m 1 ) ∈ R m 0 × m 1 , from a small number of query samples. The solution of the case of two hidden layers presented in this paper is crucial as it can be further generalized to deeper neural networks. We approach the problem by sampling actively finite difference approximations to Hessians of the network. Gathering several approximate Hessians allows reliably to approximate the matrix subspace W spanned by symmetric tensors a 1 ⊗ a 1 , ⋯ , a m 0 ⊗ a m 0 formed by weights of the first layer together with the entangled symmetric tensors v 1 ⊗ v 1 , ⋯ , v m 1 ⊗ v m 1 , formed by suitable combinations of the weights of the first and second layer as v ℓ = A G 0 b ℓ / ‖ A G 0 b ℓ ‖ 2 , ℓ ∈ [ m 1 ] , for a diagonal matrix G 0 depending on the activation functions of the first layer. The identification of the 1-rank symmetric tensors within W is then performed by the solution of a robust nonlinear program, maximizing the spectral norm of the competitors constrained over the unit Frobenius sphere. We provide guarantees of stable recovery under a posteriori verifiable conditions. Once the 1-rank symmetric tensors { a i ⊗ a i , i ∈ [ m 0 ] } ∪ { v ℓ ⊗ v ℓ , ℓ ∈ [ m 1 ] } are computed, we address their correct attribution to the first or second layer ( a i 's are attributed to the first layer). The attribution to the layers is currently based on a semi-heuristic reasoning, but it shows clear potential of reliable execution. Having the correct attribution of the a i , v ℓ to the respective layers and the consequent de-parametrization of the network, by using a suitably adapted gradient descent iteration, it is possible to estimate, up to intrinsic symmetries, the shifts of the activations functions of the first layer and compute exactly the matrix G 0 . Eventually, from the vectors v ℓ = A G 0 b ℓ / ‖ A G 0 b ℓ ‖ 2 's and a i 's one can disentangle the weights b ℓ 's, by simple algebraic manipulations. Our method of identification of the weights of the network is fully constructive, with quantifiable sample complexity and therefore contributes to dwindle the black box nature of the network training phase. We corroborate our theoretical results by extensive numerical experiments, which confirm the effectiveness and feasibility of the proposed algorithmic pipeline. [ABSTRACT FROM AUTHOR]

The MMX infrared spectrometer (MIRS) is an imaging spectrometer onboard MMX JAXA mission. MMX (Martian Moon eXploration) is scheduled to be launched in 2024 with sample return to Earth in 2029. MIRS is built at LESIA-Paris Observatory in collaboration with four other French laboratories, collaboration and financial support of CNES and close collaboration with JAXA and MELCO. The instrument is designed to fully accomplish MMX's scientific and measurement objectives. MIRS will remotely provide near-infrared spectral maps of Phobos and Deimos containing compositional diagnostic spectral features that will be used to analyze the surface composition and to support the sampling site selection. MIRS will also study Mars atmosphere, in particular spatial and temporal changes such as clouds, dust and water vapor. [ABSTRACT FROM AUTHOR]

In Europe, tropospheric ozone pollution appears as a major air quality issue, and ozone concentrations remain potentially harmful to vegetation. In this study we compared the trends of two ozone metrics widely used for forests protection in Europe, the AOT40 (Accumulated Ozone over Threshold of 40 ppb) which only depends on surface air ozone concentrations, and the Phytotoxic Ozone Dose which is the accumulated ozone uptake through stomata over the growing season, and above a threshold Y of uptake (PODY). By using a chemistry transport model, we found that European-averaged ground-level ozone concentrations (− 2%) and AOT40 metric (− 26.5%) significantly declined from 2000 to 2014, due to successful control strategies to reduce the emission of ozone precursors in Europe since the early 1990s. In contrast, the stomatal ozone uptake by forests increased from 17.5 to 26.6 mmol O3 m−2 despite the reduction in ozone concentrations, leading to an increase of potential ozone damage on plants in Europe. In a climate change context, a biologically-sound stomatal flux-based standard (PODY) as new European legislative standard is needed. [ABSTRACT FROM AUTHOR]

Spectroscopy in the visible and near-infrared has been the main tool for characterising the surface properties of asteroids for decades. For a given target, the two wavelength regimes are usually acquired by different telescopes/instruments, separated by years. They are seldom obtained simultaneously. However, it is not straightforward to combine datasets from different sources because of the spectral reddening linked with phase angle. We present the first-light result of SOVAG (Spectrographe pour l'Observations dans le Visible et infrarouge proche d'Astéroïdes Géocroiseurs), a new concept of spectrograph for observing both wavelength ranges at the same time. It is compact in design and portable. We developed a prototype of this instrument between 2016 and 2018. In July 2018, we mounted SOVAG on the 1 m-telescope in Pic du Midi observatory (for which it was designed) and conducted its on-sky first light experiment. We present a spectrum of (4) Vesta which demonstrates the reliability of observations and the accuracy of the calibration. Ongoing development will allow us to push observation-limits toward fainter objects. [ABSTRACT FROM AUTHOR]

On 12 November 2014, the Philae lander descended towards comet 67P/Churyumov–Gerasimenko, bounced twice off the surface, then arrived under an overhanging cliff in the Abydos region. The landing process provided insights into the properties of a cometary nucleus1–3. Here we report an investigation of the previously undiscovered site of the second touchdown, where Philae spent almost two minutes of its cross-comet journey, producing four distinct surface contacts on two adjoining cometary boulders. It exposed primitive water ice—that is, water ice from the time of the comet's formation 4.5 billion years ago—in their interiors while travelling through a crevice between the boulders. Our multi-instrument observations made 19 months later found that this water ice, mixed with ubiquitous dark organic-rich material, has a local dust/ice mass ratio of 2.3 − 0.16 + 0.2 : 1 , matching values previously observed in freshly exposed water ice from outbursts4 and water ice in shadow5,6. At the end of the crevice, Philae made a 0.25-metre-deep impression in the boulder ice, providing in situ measurements confirming that primitive ice has a very low compressive strength (less than 12 pascals, softer than freshly fallen light snow) and allowing a key estimation to be made of the porosity (75 ± 7 per cent) of the boulders' icy interiors. Our results provide constraints for cometary landers seeking access to a volatile-rich ice sample. When the Philae lander bounced on the surface of comet 67P/Churyumov–Gerasimenko, it exposed primitive icy-dust material within cometary boulders; the intrinsic strength and porosity of this material is reported. [ABSTRACT FROM AUTHOR]

With the aim of engineering multifunctional nanoparticles useful for cancer therapy, a diketopyrrolopyrrole-porphyrin based photosensitizer was here conjugated to a block copolymer (Pluronic F108), and used to stabilize in water lipidic cubic liquid crystalline nanoparticles (cubosomes), also loaded with the antineoplastic agent docetaxel. The physicochemical characterization by SAXS, DLS, and cryo-TEM demonstrated that the formulation consisted of cubosomes, about 150 nm in size, possessing a bicontinuous cubic structure (space group Pn3m). The cellular imaging experiments proved that these nanoparticles localized in lysosomes and mitochondria, while cytotoxicity tests evidenced a slight but significant synergistic effect which, after irradiation, increased the toxicity induced by docetaxel alone, allowing further reduction of cell viability. [ABSTRACT FROM AUTHOR]

In this paper we introduce and analyze an iteratively re-weighted algorithm, that allows to approximate the weak solution of the p-Poisson problem for 1 < p ⩽ 2 by iteratively solving a sequence of linear elliptic problems. The algorithm can be interpreted as a relaxed Kačanov iteration, as so-called in the specific literature of the numerical solution of quasi-linear equations. The main contribution of the paper is proving that the algorithm converges at least with an algebraic rate. [ABSTRACT FROM AUTHOR]

During its approach to asteroid (101955) Bennu, NASA’s Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft surveyed Bennu’s immediate environment, photometric properties, and rotation state. Discovery of a dusty environment, a natural satellite, or unexpected asteroid characteristics would have had consequences for the mission’s safety and observation strategy. Here we show that spacecraft observations during this period were highly sensitive to satellites (sub-meter scale) but reveal none, although later navigational images indicate that further investigation is needed. We constrain average dust production in September 2018 from Bennu’s surface to an upper limit of 150 g s–1 averaged over 34 min. Bennu’s disk-integrated photometric phase function validates measurements from the pre-encounter astronomical campaign. We demonstrate that Bennu’s rotation rate is accelerating continuously at 3.63 ± 0.52 × 10–6 degrees day–2, likely due to the Yarkovsky–O’Keefe–Radzievskii–Paddack (YORP) effect, with evolutionary implications. [ABSTRACT FROM AUTHOR]

This paper investigated the application of Fourier transform infrared spectroscopy (FTIR) with partial least squares regression algorithms (PLS) and variable selection methods for the rapid identification of extra virgin olive oil (EVOO) adulterated with different vegetable oils. For this purpose, a unique calibration model was proposed for the identification and quantification of adulteration independent of the adulterating oil. Calibration models were developed for simultaneous determination of the concentration of oleic, linoleic and linolenic fatty acids. Robust models were also developed for quantification of the percentage of adulteration in the samples, independent of the adulterating oil. The calibration set consisted of 68 adulterated EVOO samples, prepared by the addition of vegetable oils (soybean, sunflower, corn, and canola oil) at different levels (1 to 80%, v/v), and ten commercial samples of EVOO were used to validate the models. The mid-infrared spectra were recorded in the wave number range 3200 to 650 cm−1 for all samples. Chromatographic analysis was performed to determine the fatty acid profile of the samples from the calibration and prediction sets. PLS models were developed and different strategies were investigated during the preprocessing of the IR spectra. The results of the prediction were compared with those obtained from the conventional analysis, and RMSEP values of 4.44, 1.92, and 0.62% were obtained for oleic, linoleic, and linolenic acids, respectively. The proposed methodology allowed us to quantify the acids simultaneously in the samples and also demonstrated a good predictive power to identify the adulterated samples. [ABSTRACT FROM AUTHOR]

Several methods are introduced for skin cancer treatment. An encouraging method is radionuclide skin therapy, where high-energy beta emitting radionuclides such as 32P, 90Y, 188Re and 166Ho are employed for skin irradiation. This study aimed to calculate the dose distribution for mentioned radionuclides at different layers of skin phantom through Monte Carlo simulation. Depth dose distribution, transverse dose profile and isodose curves related to the patch sources under investigation were calculated by MCNPX code. All of calculations were performed inside a developed skin phantom. Obtained results were compared with those reported by other studies to evaluate the validity of simulations. The results showed that the 166Ho and 32P have steeper dose gradient within the depth which can lead to the better normal tissue sparing. Simulated depth dose distributions were in a good agreement with other published studies and confirmed the validity of performed simulations. The obtained transverse dose profiles at 0.2 mm depth had acceptable symmetry and flatness that can improve the dose uniformity within the target area. Calculated isodose curves showed that the 90% isodose level covers a circular area with the diameter of around 8 mm for all studied beta sources. From the results, it can be concluded that 166Ho and 32P are more effective in treatment of superficial skin lesions, while, 90Y and 188Re are more rational choices in treatment of deeply distributed skin tumors. Size of employed patch source should be based on the target area to minimize the delivered dose to the adjacent tissues. [ABSTRACT FROM AUTHOR]

Litter decomposition is the main source of mineral nitrogen (N) in terrestrial ecosystem and a key step in carbon (C) cycle. Microbial community is the main decomposer, and its specialization on specific litter is considered at the basis of higher decomposition rate in its natural environment than in other forests. However, there are contrasting evidences on how the microbial community responds to a new litter input and if the mass loss is higher in natural environment. We selected leaf litter from three different plant species across three sites of different altitudinal ranges: oak (Quercus petraea (Matt.) Liebl., 530 m a.s.l), beech (Fagus sylvatica L., 1000 m a.s.l.), rhododendron (Rhododendron ferrugineum L., 1530 m a.s.l.). A complete transplantation experiment was set up within the native site and the other two altitudinal sites. Microbial community structure was analyzed via amplified ribosomal intergenic spacer analysis (ARISA) fingerprinting. Functionality was investigated by potential enzyme activities. Chemical composition of litter was recorded. Mass loss showed no faster decomposition rate on native site. Similarly, no influence of site was found on microbial structure, while there was a strong temporal variation. Potential enzymatic activities were not affected by the same temporal pattern with a general increase of activities during autumn. Our results suggested that no specialization in microbial community is present due to the lack of influence of the site in structure and in the mass loss dynamics. Finally, different temporal patterns in microbial community and potential enzymatic activities suggest the presence of functional redundancy within decomposers. [ABSTRACT FROM AUTHOR]

Production of biofuels from farm animal waste represents a promising approach to diversifying green energy production and reducing competition for cultivable lands between fuel and food-oriented crops. This work was aimed to define the technical feasibility and the specific suitability of cattle, swine and poultry manure to integrating bioethanol and biomethane production, using the biorefinery concept. Saccharification obtained by dilute acid pretreatment (3.5% H2SO4, 121 °C, 30 min) followed by enzymatic hydrolysis resulted in total sugar recovery of 230.16, 160.40, and 98.40 mg g−1 (of dry matter) for cattle, pig, and poultry manure respectively. The sugar was then fermented using free yeast co-cultures. The ethanol obtained was 56.32 mg g−1 of dry matter for cattle (about 52.59% of the theoretical ethanol yield); 27.98 mg g−1 for swine (about 88.66% of the theoretical ethanol yield); 12.69 mg g−1 for poultry (about 31.32% of the theoretical ethanol yield). Methane production from distillation waste was 72.95 mg g−1 from dry raw faeces for cattle, 126.48 mg g−1 for swine and 119.03 mg g−1 for poultry. Cattle manure showed the best energy balance in terms of ethanol production with about 824.16 kJ kg−1 of dry faeces, but the two integrated processes generated a net energy balance of 1.28 MJ kg−1 for cattle, 4.57 MJ kg−1 for swine and 4.79 MJ kg−1 for poultry. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the second most common cancer, representing 13% of all diagnosed cancers. Cetuximab is a recombinant chimeric monoclonal IgG1 antibody and epidermal growth factor receptor (EGFR) inhibitor. Cetuximab is approved for the first-line treatment in combination with chemotherapy or as a single agent in patients who have failed or are intolerant to chemotherapy in patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer. Cetuximab efficacy emerged from studies that were conducted to approve the drug. Cetuximab is well tolerated; its toxicities are caused by its mechanism of action and the most common adverse reaction is skin toxicity. The main purpose of this manuscript is to present an update on the evidence-based summary of efficacy and safety and on the cost-effectiveness of cetuximab. Furthermore, it suggests a management of adverse drug reactions to improve the tolerability of the drug. [ABSTRACT FROM AUTHOR]

The terminology used in pharmacovigilance can cause confusion, because there are similar terms that describe different phenomena (e.g. adverse reactions, adverse drug reactions, and side effects). Incorrect use of terminology can have negative effects on the reporting of adverse drug reactions and on the interpretation of these reports. To explain the most common terms used in pharmacovigilance, this article first describes the pharmacovigilance workflow process in the European Union and, as an example, in Italy. Then, the article reviews common pharmacovigilance terms. [ABSTRACT FROM AUTHOR]

An increasing number of innovative oncology monoclonal antibodies (mAbs) have been introduced into the global market, and biosimilar versions have now also been approved in Europe. Being complex to develop and difficult to manufacture, the biosimilar is a drug similar but not identical in physicochemical characteristics, efficacy, and safety to an original biological drug already approved in the European Union, for which marketing exclusivity rights have expired. Generally, the safety monitoring of biosimilars follows the same requirements that apply to all biologicals, even if specific pharmacovigilance measures exist and some of them are still being debated. The manufacturing process, immunogenicity, traceability, and extrapolation of indication are keywords which may impact on the achievement of additional knowledge about the safety of a biosimilar mAb. In this article, we aim to discuss elements that play a central role in the pharmacovigilance legislation of biosimilar mAbs. [ABSTRACT FROM AUTHOR]

Background Side effects of cancer therapy are one of the most important issues faced by cancer patients during their illness. Pharmacovigilance, namely the science and activities aimed at monitoring the safety of drugs, is particularly important in oncology, due to the intrinsic biologic toxicity of antineoplastic agents, their narrow therapeutic windows, and the high doses and rigid timing of treatment regimens. Aim of the review To identify the main issues in carrying out an effective pharmacovigilance activity in oncology. Method We searched PubMed for articles about pharmacovigilance in relation to chemotherapy, radiotherapy and targeted therapy for cancer, using MeSH terms and text words. We also searched Embase, CINAHL, Scopus, Micromedex, the Cochrane Library, two pharmacovigilance databases and the gray literature for articles published in 2012-2018. Overall, 137 articles were considered potentially relevant and were critically appraised independently by two authors, leading to the inclusion of 44 relevant studies, guidelines and reviews. Another 10 important research reports were included in the review. Results Eight critical issues of pharmacovigilance in oncology were identified. These issues pertain to: terminology; range of side effects; targeted therapy and immunotherapy; chemoradiotherapy; generic drugs and biosimilars; drug interactions, pharmacogenetics and polypharmacy; special patient categories; and under-reporting of ADRs. Conclusion The importance of pharmacovigilance in oncology must be highlighted with every effort, to improve safety and offer cancer patients every possible help to improve their quality of life during such a critical period of their lives. [ABSTRACT FROM AUTHOR]

Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio of drugs, improving patient's safety and the quality of life. In this commentary we report the milestones of pharmacovigilance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific journals, up to today's modern and ultra-structured electronic registries. The historical phases also help us to understand why pharmacovigilance helped us to achieve such important results for man's health and for pharmacology itself, and to identify the challenges that await Pharmacovigilance in future years. [ABSTRACT FROM AUTHOR]

Background The majority of adverse drug reactions (ADRs) reported in the summary of product characteristics (SPCs) are based on pivotal clinical trials, performed under controlled conditions and with selected patients. Objectives (1) to observe ADRs in the real-world setting and to evaluate if the supervision of the pharmacist impacts on the management of ADRs and on the satisfaction of patients; (2) to sensitise health professionals and patients on the need to increase the reporting of ADRs, in compliance with Pharmacovigilance. Setting CRO Aviano, Italian National Cancer Institute. Method From February 2013 to April 2015, we conducted an observational study enrolling 154 patients (≥ 18 years) undergoing treatment with at least one of ten targeted-therapies included in the study. Main outcome ADR reporting in the real-world setting. Patient satisfaction with clinical pharmacist support. Results Reported ADRs in the real setting do not always correspond with data described in the respective SPCs. Unknown ADRs were also identified such as hyperglycaemia with lenalidomide and sorafenib; and hypomagnesaemia with bevacizumab. We also observed a 124.3% increase in spontaneous reports. Conclusion This study shows the high value of active pharmacovigilance programs, and our results might be a starting point for developing a randomised trial which should aim to demonstrate the impact of the pharmacist on improving patient's adherence and in measuring the difference in ADRs reports in the different arms followed or not by the pharmacist. [ABSTRACT FROM AUTHOR]

The chemical properties and biological activities of soils were studied in the vicinity of the medieval settlement Podkumskoe-3 in the Kislovodsk basin (Northern Caucasus, Russia). Between the 5th and 8th centuries this area was ploughed regularly, but it was then abandoned up to the present day. It has been established that past human activity leads to soil undergoing significant transformations in terms of microbial communities and enzyme activity, and that such changes are maintained over long periods. Long-term manuring in the middle of the first millennium AD led to an increase in organic carbon content and the accumulation of nitrate nitrogen. Soils of ancient abandoned fields are associated with increases in microbial biomass, number of saprotrophic bacteria, urease activity, and fungal mycelium biomass. The observed changes in the microbiological and biochemical properties of soil were conditioned by secondary anthropogenically induced succession after the abandonment of arable lands. [ABSTRACT FROM AUTHOR]

Purpose: Soil enzyme activities are sensitive indicators of soil quality reflecting effects of land management. This study aims to monitor the effects of four crop rotation systems (rice-rice-rice: R-R-R, soya-rice-rice: S-R-R, fallow-rice: F-R and pea-soya-rice: P-S-R) on the activities of six important soil enzymes involved in C, N, P, and S cycling and soil properties during rice growth.Materials and methods: Four rice plots with different rotation systems were investigated before rice planting and during the phenological cycle in a paddy soil from the Veneto region, Italy; sampling of soils (0-15 cm) was carried out four times during growing season (three replicates). A total of 48 samples were air dried, for some chemical (soil pH, electrical conductivity, soil organic carbon, extractable P), physical (particle size distribution), and biochemical measurements (enzymatic assays and extraction of soil DNA). Moreover, the total concentration of trace and macro- and microelements were measured for assessing element levels and possible contamination of soils.Results and discussion: The results demonstrated that compared with field moist soil, drained soil conditions resulted in a significant increase (P < 0.05) of β-glucosidase, arylsulfatase, alkaline and acid phosphomonoesterase, leucine aminopeptidase, and chitinase activities in almost all rotations. The results obtained point to a land with high soil contamination by Li and TI. Moreover, soil DNA was negatively correlated to soil TI stress (r = − 0.41, p ˂ 0.01). The P-S-R rotation had the highest TI concentration in April and it is likely to be responsible for the lowest enzyme activities in the field-moist condition.The total concentrations of most studied elements (Al, As, Be, Cd, Co, Cr, Cu, Fe, Ni, Pb, Sb, Sn, Sr, V, Zn) in the soil samples fell within the natural geochemical background concentration levels.Conclusions: The obtained results suggest that the activity of most enzymes decreases in the different experimental conditions with the following order: drained soil > late waterlogging > early waterlogging > moist soil. However, the response of enzymes to waterlogging differed with the chemical element and the cropping pattern. The best rotation system for chitinase, leucine aminopeptidase, and β-glucosidase activity (C and N cycles) was R-R-R, while for arylsulfatase, alkaline, and acid phosphatase activities (S and P cycles), it was the S-R-R. [ABSTRACT FROM AUTHOR]

The characterization of nutrient and biostimulant effects in crops is complex and needs rigorous evaluations. In this study, we evaluated morphological and molecular responses induced by microalgae (Chlorella vulgaris and Scenedesmus quadricauda) extracts in Beta vulgaris L. The two microalgae extracts were firstly characterized by CNS, Fourier transform infrared spectroscopic analysis (FT-IR), and carbon-13 nuclear magnetic resonance (13C NMR). Seedlings were grown in Hoagland’s solution under controlled conditions. After 5 days of growth, 2 mL L−1 (1 mg Corg L−1) and 4 mL L−1 (2 mg Corg L−1) of the two microalgae extracts were added to the Hoagland solution. Roots were sampled 36 h after treatments. Inductively coupled plasma spectrometry (ICP-OES) and nanofluidic real-time PCR (OpenArray system) were used for sample profiling. Fifty-three sugar beet genes putatively involved in sulfate starvation were tested in treated and untreated samples. Root morphological traits were measured by means of a scanner-based image analysis system. Multivariate statistical analysis revealed no significant changes in the ionomic profile of Hoagland’s solutions treated with the two microalgae extracts with respect to that of the untreated solution. At the molecular level, microalgae extract supplies upregulated many of the evaluated genes. Functional categorization revealed these genes to be related to various biological pathways and processes including primary and secondary metabolism and intracellular transport. At the morphological level, the treated seedlings showed significantly higher values for root traits related to soil exploration and nutrient uptake, such as total root length, fine root length (diameter < 0.5 mm), and number of root tips, than the untreated plants. These data indicate that microalgae extracts have biostimulant effects on the expression of root traits and genes related to nutrient acquisition in sugar beet. [ABSTRACT FROM AUTHOR]

We derive a maximum principle for optimal control problems with constraints given by the coupling of a system of ordinary differential equations and a partial differential equation of Vlasov type with smooth interaction kernel. Such problems arise naturally as Gamma-limits of optimal control problems constrained by ordinary differential equations, modeling, for instance, external interventions on crowd dynamics by means of leaders. We obtain these first-order optimality conditions in the form of Hamiltonian flows in the Wasserstein space of probability measures with forward-backward boundary conditions with respect to the first and second marginals, respectively. In particular, we recover the equations and their solutions by means of a constructive procedure, which can be seen as the mean-field limit of the Pontryagin Maximum Principle applied to the optimal control problem for the discretized density, under a suitable scaling of the adjoint variables. [ABSTRACT FROM AUTHOR]

In this paper we model the role of a government of a large population as a mean field optimal control problem. Such control problems are constrained by a PDE of continuity-type, governing the dynamics of the probability distribution of the agent population. We show the existence of mean field optimal controls both in the stochastic and deterministic setting. We derive rigorously the first order optimality conditions useful for numerical computation of mean field optimal controls. We introduce a novel approximating hierarchy of sub-optimal controls based on a Boltzmann approach, whose computation requires a very moderate numerical complexity with respect to the one of the optimal control. We provide numerical experiments for models in opinion formation comparing the behavior of the control hierarchy. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease is a rare xanthomatosis that may present with characteristic radiologic and histologic features. There have been conflicting reports regarding the nature of this process, including whether it represents a reactive or neoplastic lesion. We present the clinical histories, pathologic findings, and an analysis of clonality using the HUMARA assay in two patients diagnosed with Erdheim-Chester disease. One case has previously been documented in the literature. Histologically, both cases demonstrated sheets of foamy xanthomatous histiocytes with widespread infiltration of the viscera. These regions were punctuated by variable amounts of inflammation, including lymphocytes, plasma cells, and occasional Touton-type giant cells. The histiocytes were immunoreactive for CD68 and CD163; they did not stain with S100 or CD1a. One case was found to be monoclonal; however, the second case had extensive DNA degradation; thus, clonality could not be assessed. In addition to contributing an additional report of this rare disease to the literature, we demonstrate the histiocytes to express CD163, thereby further supporting a monocyte/macrophage basis. Moreover, in confirming clonality, our observations lend additional evidence to the view that Erdheim-Chester disease represents a neoplastic process. [ABSTRACT FROM AUTHOR]

The introduction in clinical practice of pharmaceutical products known as biosimilars, as part of a more complex series of progress in the field of biological drugs, represents an excellent therapeutic resource. A biosimilar drug is a biological/biotechnological drug that is highly similar to an approved reference biologic product. Given their complexity, biosimilars require attention and a continued vigilance to ensure appropriate use, especially in cancer therapy. There is the urgent need, both at Italian and European levels, of clear and more comprehensive guidelines to elucidate the open questions. Probably, the acquisition of new data, obtained from larger samples of patients than those used in the pre-approval studies and with extremely variable clinical conditions, will allow clarifying the extent to which biosimilar drugs are similar in safety and efficacy to their biologic reference drug. The aims of this article are to provide health professionals with basic, but essential information about biosimilars, and to identify current critical points and future perspectives for clinical practice, cancer care, regulatory aspects, and pharmacovigilance. [ABSTRACT FROM AUTHOR]

Iteratively re-weighted least squares (IRLS) is a method for solving minimization problems involving non-quadratic cost functions, perhaps non-convex and non-smooth, which however can be described as the infimum over a family of quadratic functions. This transformation suggests an algorithmic scheme that solves a sequence of quadratic problems to be tackled efficiently by tools of numerical linear algebra. Its general scope and its usually simple implementation, transforming the initial non-convex and non-smooth minimization problem into a more familiar and easily solvable quadratic optimization problem, make it a versatile algorithm. However, despite its simplicity, versatility, and elegant analysis, the complexity of IRLS strongly depends on the way the solution of the successive quadratic optimizations is addressed. For the important special case of compressed sensing and sparse recovery problems in signal processing, we investigate theoretically and numerically how accurately one needs to solve the quadratic problems by means of the conjugate gradient (CG) method in each iteration in order to guarantee convergence. The use of the CG method may significantly speed-up the numerical solution of the quadratic subproblems, in particular, when fast matrix-vector multiplication (exploiting for instance the FFT) is available for the matrix involved. In addition, we study convergence rates. Our modified IRLS method outperforms state of the art first order methods such as Iterative Hard Thresholding (IHT) or Fast Iterative Soft-Thresholding Algorithm (FISTA) in many situations, especially in large dimensions. Moreover, IRLS is often able to recover sparse vectors from fewer measurements than required for IHT and FISTA. [ABSTRACT FROM AUTHOR]

This paper is concerned with the study of the consistency of a variational method for probability measure quantization, deterministically realized by means of a minimizing principle, balancing power repulsion and attraction potentials. The proof of consistency is based on the construction of a target energy functional whose unique minimizer is actually the given probability measure $$\omega $$ to be quantized. Then we show that the discrete functionals, defining the discrete quantizers as their minimizers, actually $$\Gamma $$ -converge to the target energy with respect to the narrow topology on the space of probability measures. A key ingredient is the reformulation of the target functional by means of a Fourier representation, which extends the characterization of conditionally positive semi-definite functions from points in generic position to probability measures. As a byproduct of the Fourier representation, we also obtain compactness of sublevels of the target energy in terms of uniform moment bounds, which already found applications in the asymptotic analysis of corresponding gradient flows. To model situations where the given probability is affected by noise, we further consider a modified energy, with the addition of a regularizing total variation term and we investigate again its point mass approximations in terms of $$\Gamma $$ -convergence. We show that such a discrete measure representation of the total variation can be interpreted as an additional nonlinear potential, repulsive at a short range, attractive at a medium range, and at a long range not having effect, promoting a uniform distribution of the point masses. [ABSTRACT FROM AUTHOR]

Fourteen mature female New Zealand White rabbits underwent implantation of Simplex polymethylmethacrylate (PMMA) powder or particulate (average 67 microns) ultrahigh-molecular-weight polyethylene (UHMWPE) through a drill hole in the proximal right tibia. The left tibia functioned as a prepared but nonimplanted control. Animals were killed after 16 weeks. Histological examination of the bone-implant interface in the particulate PMMA group disclosed a florid foreign-body reaction with the presence of giant cells and histiocytes. The particulate UHMWPE group demonstrated positively birefringent UHMWPE fragments, rimmed by foreign-body giant cells and histiocytes, embedded in a loose connective tissue stroma. UHMWPE interfaces were thicker and contained more histiocytes and fibrocytes; PMMA interfaces contained more marrow cells and lymphocytes. This study underscores the importance of biomaterial debris in the process of aseptic loosening of cemented joint arthroplasties. [ABSTRACT FROM AUTHOR]