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Blood-feeding behavior has independently evolved in arthropods multiple times. Unlike hard ticks, soft ticks employ a rapid-feeding strategy for hematophagy, and there are comparatively limited studies on the transcriptomes of these organisms. This study investigates the soft tick Ornithodoros hermsi, conducting histopathological examinations at bitten skin sites and tick whole-body transcriptomic analyses across various developmental and feeding stages, including larvae, 1st-nymphal, and 2nd-nymphal stages. The results revealed the ability of O. hermsi to induce skin hemorrhage at the bite sites. Transcriptomic analyses identified three consistent transcriptional profiles: unfed, early-fed (6 h, 12 h, 24 h), and late-fed (5 days). The unfed profile exhibited high transcriptional activity across most of the functional classes annotated. In contrast, early-fed stages exhibited decreased expression of most functional classes, except for the unknown, which is highly expressed. Finally, transcriptional expression of most functional classes increased in the late-fed groups, resembling the baseline expression observed in the unfed groups. These findings highlight intense pre-feeding transcriptional activity in O. hermsi ticks, aligning with their rapid-feeding strategy. Moreover, besides shedding light on the temporal dynamics of key pathways during blood meal processing and tick development, this study contributes significantly to the transcriptome repertoire of a medically relevant soft tick species with relatively limited prior knowledge. [ABSTRACT FROM AUTHOR]

Background: Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment Methodology/Principal findings: Addition of L. obliqua venom to purified prekallikrein and human plasma in vitro or to vascular smooth muscle cells (VSMC) in culture, was able to generate kallikrein in a dose-dependent manner. Injected in rats, the venom induced AKI and increased kallikrein levels in plasma and kidney. Kallikrein inhibition by aprotinin prevented glomerular injury and the decrease in glomerular filtration rate, restoring fluid and electrolyte homeostasis. The mechanism underlying these effects was associated to lowering renal inflammation, with decrease in pro-inflammatory cytokines and matrix metalloproteinase expression, reduced tubular degeneration, and protection against oxidative stress. Supporting the key role of kallikrein, we demonstrated that aprotinin inhibited effects directly associated with vascular injury, such as the generation of intracellular reactive oxygen species (ROS) and migration of VSMC induced by L. obliqua venom or by diluted plasma obtained from envenomed rats. In addition, kallikrein inhibition also ameliorated venom-induced blood incoagulability and decreased kidney tissue factor expression Conclusions/Significance: These data indicated that kallikrein and consequently kinin release have a key role in kidney injury and vascular remodeling. Thus, blocking kallikrein may be a therapeutic alternative to control the progression of venom-induced AKI and vascular disturbances. [ABSTRACT FROM AUTHOR]

Due to steadily increasing resource demand and accompanying raising public awareness, a variety of assessment methodologies evaluating resource use and its consequences were published in the last years. Existing methodologies are typically developed considering the specific characteristics of one particular resource type and as consequence are not suitable for cross-cutting assessment of different resource types. This paper proposes an 3-step approach for combining different resource use assessment methodologies allowing for a consistent assessment of product systems using different resource types. The first steps evaluate if the considered dimensions, categories, indicators, indicator models and underlying data are consistent. When this is the case, they can be included in the combined methodology without further adjustments. Differences are identified simultaneously and addressed in the subsequent steps. Within the steps guidance is provided on how the dimensions, categories and indicators of the methodologies can be adjusted to fit in the combined methodology. In a case study the proposed approach is applied to two methodologies developed by the authors assessing abiotic (ESSENZ method) and biotic resources and raw materials (BIRD method). The ESSENZ method consists of four dimensions, which are quantified by overall 21 categories and indicators. The BIRD method takes into account five dimensions and 24 corresponding categories and indicators. As none of the considered dimension of the two methodologies match, comparison of the considered resource types as well as application in a case study is not possible. By applying the proposed approach all five dimensions and 25 of the overall 27 categories and indicators can be integrated in the combined approach for a consistent assessment of abiotic and biotic resources and raw materials. The obtained combined methodology is then applied to three shelves made out of metal, wood and plastic. It could be shown that the introduced approach provides meaningful guidance on how to combine different resource use assessment methodologies and increases the findings gained from a combined and consistent assessment. [ABSTRACT FROM AUTHOR]

With increasing demand of abiotic resources also the pollution of natural resources like water and soil has risen in the last decades due to global industrial and technological development. Thus, enhancing resource efficiency is a key goal of national and international strategies. For a comprehensive assessment of all related impacts of resource extraction and use all three sustainability dimensions have to be taken into account: economic, environmental and social aspects. Furthermore, to avoid burden shifting life cycle based methods should be applied. As companies need operational tools and approaches, a comprehensive method has been developed to measure resource efficiency of products, processes and services in the context of sustainable development (ESSENZ). Overall 21 categories are established to measure impacts on the environment, physical and socio-economic availability of the used resources as well as their societal acceptance. For the categories socio-economic availability and societal acceptance new approaches are developed and characterization factors are provided for a portfolio of 36 metals and four fossil raw materials. The introduced approach has been tested on several case studies, demonstrating that it enhances the applicability of resource efficiency to assess product systems significantly by providing an overall framework that can be adopted across sectors, using indicators and methods which are applicable and can be integrated into existing life cycle assessment based schemes. [ABSTRACT FROM AUTHOR]

Digital health is an umbrella term which encompasses eHealth and benefits from areas such as advanced computer sciences. eHealth includes mHealth apps, which offer the potential to redesign aspects of healthcare delivery. The capacity of apps to collect large amounts of longitudinal, real‐time, real‐world data enables the progression of biomedical knowledge. Apps for rhinitis and rhinosinusitis were searched for in the Google Play and Apple App stores, via an automatic market research tool recently developed using JavaScript. Over 1500 apps for allergic rhinitis and rhinosinusitis were identified, some dealing with multimorbidity. However, only six apps for rhinitis (AirRater, AllergyMonitor, AllerSearch, Husteblume, MASK‐air and Pollen App) and one for rhinosinusitis (Galenus Health) have so far published results in the scientific literature. These apps were reviewed for their validation, discovery of novel allergy phenotypes, optimisation of identifying the pollen season, novel approaches in diagnosis and management (pharmacotherapy and allergen immunotherapy) as well as adherence to treatment. Published evidence demonstrates the potential of mobile health apps to advance in the characterisation, diagnosis and management of rhinitis and rhinosinusitis patients. [ABSTRACT FROM AUTHOR]

The first total synthesis of the boron-containing macrodiolide antibiotic tartrolon B is reported in full detail. Two convergent approaches to the target compound are described, the first of which eventually failed, due to sensitive functionality. In the second, successful route the key step was a stereoselective boron-mediated aldol addition of a bicyclic acetonide protected ketone to a dienealdehyde. In this case the synthesis could be completed without major problems, using a Yamaguchi dimerization macrolactonization endgame. [ABSTRACT FROM AUTHOR]

N -Acetylglucosamine is a major component of complex carbohydrates. The mammalian salvage pathway of N -acetylglucosamine recruitment from glycoconjugate degradation or nutritional sources starts with phosphorylation by N -acetylglucosamine kinase. In this study we describe the identification of two active site cysteines of the sugar kinase by site-directed mutagenesis and computer-based structure prediction. Murine N -acetylglucosamine kinase contains six cysteine residues, all of which were mutated to serine residues. The strongest reduction of enzyme activity was found for the mutant C131S, followed by C143S. Determination of the kinetic properties of the cysteine mutants showed that the decreased enzyme activities were due to a strongly decreased affinity to either N -acetylglucosamine for C131S, or ATP for C143S. A secondary structure prediction of N -acetylglucosamine kinase showed a high homology to glucokinase. A model of the three-dimensional structure ofN -acetylglucosamine kinase based on the known structure of glucokinase was therefore generated. This model confirmed that both cysteines are located in the active site of N -acetylglucosamine kinase with a potential role in the binding of the transfered γ-phosphate group of ATP within the catalytic mechanism. [ABSTRACT FROM AUTHOR]

N-Acetylglucosamine is produced by the endogenous degradation of glycoconjugates and by the degradation of dietary glycoconjugates by glycosidases. It enters the pathways of aminosugar metabolism by the action of N-acetylglucosamine kinase. In this study we report the isolation and characterization of a cDNA clone encoding the murine enzyme. An open reading frame of 1029 base pairs encodes 343 amino acids with a predicted molecular mass of 37.3 kDa. The deduced amino-acid sequence contains matches of the sequences of eight peptides derived from tryptic cleavage of rat N-acetylglucosamine kinase. The recombinant murine enzyme was functionally expressed in Escherichia coli BL21 cells, where it displays N-acetylglucosamine kinase activity as well as N-acetylmannosamine kinase activity. The complete cDNA sequence of human N-acetylglucosamine kinase was derived from the nucleotide sequences of several expressed sequence tags. An open reading frame of 1032 base pairs encodes 344 amino acids and a protein with a predicted molecular mass of 37.4 kDa. Similarities between human and murine N-acetylglucosamine kinase were 86.6% on the nucleotide level and 91.6% on the amino-acid level. Amino-acid sequences of murine and human N-acetylglucosamine kinase show sequence similarities to other sugar kinases, and all five sequence motifs necessary for the binding of ATP by sugar kinases are present. Tissue distribution of murine N-acetylglucosamine kinase revealed an ubiquitous occurrence of the enzyme and a very high expression in testis. The size of the murine mRNA was 1.35 kb in all tissues investigated, with the exception of testis, where it was 1.45 kb mRNA of the murine enzyme was continuously expressed during mouse development. mRNA of the human enzyme was expressed in all investigated human tissues, as well as in cancer cell lines. In both the tissues and the cancer cell lines, the human mRNA was 1.35 kb in size. [ABSTRACT FROM AUTHOR]

• We present the first full review of research pertaining a water planetary boundary. • Initial shortcomings of the water planetary boundary have partly been resolved. • Input-output analysis may facilitate investigation into the exceedance of boundaries. • Spatiotemporal mismatches amid input-output and hydrological data pose a challenge. The water planetary boundary has been proposed to determine limits for a sustainable anthropogenic appropriation of freshwater. Aim of the present research was to summarise the water planetary boundary's development status and applications including its integration into Life Cycle Assessment and Environmentally-Extended Input-Output-Analysis. A systematic literature review was conducted for studies featuring the keywords "planetary boundary" and "water consumption". All pertinent studies were categorised as either revision, commentary, stand-alone application, the application within Life Cycle Assessment or application within Environmentally-Extended Input-Output Analysis and subsequently summarised and discussed. Overall, 35 studies from the period of 2009 until mid-2020 are subject of this review. Recent advancements such as spatially differentiated thresholds and refined sub-boundaries have addressed initial shortcomings of the concept of a water planetary boundary. Stand-alone applications of the water planetary boundary have either established local thresholds or allocated fair shares of afore-defined global thresholds. Several authors integrated the concept of a water planetary boundary into LCA e.g. via characterisation factors, weighting or normalisation, often under consideration of sharing principles. An application of the water planetary boundary into Environmentally-Extended Input-Output Analysis is less represented although some authors have demonstrated its powerfulness in investigating causes for the exceedance of local thresholds. For some of the reviewed studies, a link to the water planetary boundary remains rather vague as these studies merely investigate water availability in comparison to consumption. Although it should be applied with caution, the concept of a planetary boundary for freshwater use can contribute to understanding limits to sustainable freshwater consumption. Many studies established water use thresholds but refrained from analysing causative drivers in detail. Challenges for exploring this further include overcoming spatial and temporal mismatches of environmentally-extended economic accounts and hydrogeological data. [ABSTRACT FROM AUTHOR]

Investigates the inhibition of T cell signal transduction by polyunsaturated fatty acids (PUFA). Detergent-resistant membrane (DRM) domains involved in signal transduction; Enrichment of PUFA in T cells; Correlation of signal transduction in PUFA-enriched T cells with presence of Src family kinase Lck in DRM.

The EOS™2D/3D system is a low-dose, 3D imaging system that utilizes two perpendicular X-ray beams to create simultaneous frontal and lateral images of the body. This is a useful modality to assess spinal pathologies. However, due to the slow imaging acquisition time up to 25 s, motion artifacts (MA) frequently occur. These artifacts may not be distinguishable from pathological findings, such as scoliosis, and may impair the diagnostic process. The aim of this study was to design a method to detect MA in EOS X-ray. We retrospectively analyzed EOS imaging from 40 patients wearing a radiopaque reference device during imaging. We drew a straight vertical line along the reference device. We measured deviations from it to quantify MA, presenting these findings through descriptive statistics. For a subset of patients with high MA, acquisitions were repeated after giving specific instructions to stand still. For these patients, we compared MA between the two acquisitions. In our study, a substantial proportion of patients exhibited MA ≥ 1 mm, with 80% in frontal projections and 87.9% in lateral projections. In the subjects who received a second acquisition, MA was significantly lower in the second images. Our method allows for a precise detection of MA on EOS images through a simple, yet reliable solution. Our method may improve the reliability of spine measurements, and reduce the risk of wrong diagnosis due to low imaging quality. [ABSTRACT FROM AUTHOR]

Due to the increasing relevance of analyzing water consumption along product life cycles, the method of Water Footprinting gained rising attention in the last years. In this context the water accounting and vulnerability evaluation model (WAVE+) was developed at the TU Berlin. Based on a consumption-to-availability ratio derived from the hydrological model WaterGap3, WAVE+ currently analyzes the vulnerability of basins to freshwater depletion in more than 8.000 basins. On the accounting level the atmospheric evaporation recycling within drainage basins is considered which can reduce the water consumption volumes within specific basins significantly. However, the model does not consider evaporation recycling patterns across basin boundaries until now.This research focuses on the enhancement of the method by including the latter point. In addition to the consideration of the basin internal evaporation recycling (BIER) the basin external evaporation recycling (BEER) is included for the first time. The main outcome are monthly and basin-specific recycling patterns which are able to show in which drainage basins evaporated water will finally re-precipitate. The results were gained from the atmospheric moisture tracking model WAM-2layers which was fed with climatic input data from the ERA-Interim reanalysis on a 1.5° latitude and 1.5° longitude grid for the period of 2001-2010. With regard to evaporation data, the Era-Interim data were replaced by data of the hydrological model WaterGap3 to ensure consistency with the WAVE+ model. The import and export of water flows were aggregated according to the basin delineation of the WAVE+ method.First results for the region around Berlin show that most of the evaporated water re-precipitates over land, mainly in basins located in Eastern Germany, Poland, Czech Republic, Slovakia and the Ukraine. With regards to the region of Central Borneo most of the re-precipitation takes place on the island itself as well as over the surrounding sea and East Indonesia. In addition to presenting basin-specific recycling patterns, the research discusses methodological aspects on how those results could potentially be used within the scope of Water Footprinting. In order to enable further application purposes, the un-aggregated raw data of the fate analysis of evaporated water will be provided on a 1.5° latitude and 1.5° longitude grid and be made publicly available. [ABSTRACT FROM AUTHOR]

Various studies investigated the fate of evaporation and the origin of precipitation. The more recent studies among them were often carried out with the help of numerical moisture tracking. Many research questions could be answered within this context, such as dependencies of atmospheric moisture transfers between different regions, impacts of land cover changes on the hydrological cycle, sustainability-related questions, and questions regarding the seasonal and interannual variability of precipitation. In order to facilitate future applications, global datasets on the fate of evaporation and the sources of precipitation are needed. Since most studies are on a regional level and focus more on the sources of precipitation, the goal of this study is to provide a readily available global dataset on the fate of evaporation for a fine-meshed grid of source and receptor cells. The dataset was created through a global run of the numerical moisture tracking model Water Accounting Model-2layers (WAM-2layers) and focused on the fate of land evaporation. The tracking was conducted on a 1.5∘×1.5∘ grid and was based on reanalysis data from the ERA-Interim database. Climatic input data were incorporated in 3- to 6-hourly time steps and represent the time period from 2001 to 2018. Atmospheric moisture was tracked forward in time and the geographical borders of the model were located at ±79.5 ∘ latitude. As a result of the model run, the annual, the monthly and the interannual average fate of evaporation were determined for 8684 land grid cells (all land cells except those located within Greenland and Antarctica) and provided via source–receptor matrices. The gained dataset was complemented via an aggregation to country and basin scales in order to highlight possible usages for areas of interest larger than grid cells. This resulted in data for 265 countries and 8223 basins. Finally, five types of source–receptor matrices for average moisture transfers were chosen to build the core of the dataset: land grid cell to grid cell, country to grid cell, basin to grid cell, country to country, basin to basin. The dataset is, to our knowledge, the first ready-to-download dataset providing the overall fate of evaporation for land cells of a global fine-meshed grid in monthly resolution. At the same time, information on the sources of precipitation can be extracted from it. It could be used for investigations into average annual, seasonal, and interannual sink and source regions of atmospheric moisture from land masses for most of the regions in the world and shows various application possibilities for studying interactions between people and water, such as land cover changes or human water consumption patterns. The dataset is accessible under 10.1594/PANGAEA.908705 (Link et al., 2019a) and comes along with example scripts for reading and plotting the data. [ABSTRACT FROM AUTHOR]

The applied surface dose is a key parameter for the measurement of toxic effects of airborne particles by air liquid interface exposure of human lung cells. Besides online measurement of the deposited particle mass by quartz crystal microbalance frequently other dose metrics such as particle size distribution, surface and agglomeration state are required. These particle properties and their spatial distribution can be determined by digital processing of micrographs obtained by transmission electron microscopy (TEM). Here, we report the development and characterization of a novel holder for film coated TEM copper grids, which allows for sampling under identical geometric and ambient conditions as in a cell culture chamber. The sample holder avoids artefacts by reliable grounding of the grids and improves handling of the grids to prevent damage of the sensitive film. This sample holder is applied during exposure experiments with titanium dioxide nanoparticles. The measured dose of 0.2 µg/cm² corresponds well to the mass loading signal of the quartz crystal microbalance. Additionally, the spatial distribution of particles on the sampling surface shows a good homogeneity of deposition. This novel sampling method allows verifying other dosimetry methods and gives additional information about particle properties and homogeneity of the dose. [ABSTRACT FROM AUTHOR]

The recent outbreak of Zika virus (ZIKV) in Brazil and other countries globally demonstrated the relevance of ZIKV studies. During and after this outbreak, there was an intense increase in scientific production on ZIKV infections, especially toward alterations promoted by the infection and related to clinical outcomes. Considering this massive amount of new data, mainly thousands of genes and proteins whose expression is impacted by ZIKV infection, the ZIKA Virus Infection Database (ZIKAVID) was created. ZIKAVID is an online database that comprises all genes or proteins, and associated information, for which expression was experimentally measured and found to be altered after ZIKV infection. The database, available at https://zikavid.org, contains 16,984 entries of gene expression measurements from a total of 7348 genes. It allows users to easily perform searches for different experimental hosts (cell lines, tissues, and animal models), ZIKV strains (African, Asian, and Brazilian), and target molecules (messenger RNA [mRNA] and protein), among others, used in differential expression studies regarding ZIKV infection. In this way, the ZIKAVID will serve as an additional and important resource to improve the characterization of the molecular impact and pathogenesis associated with ZIKV infection. [ABSTRACT FROM AUTHOR]

Ticks successfully feed and transmit pathogens by injecting pharmacological compounds in saliva to thwart host defenses. We have previously used LC-MS/MS to identify proteins that are present in saliva of unfed Amblyomma americanum ticks that were exposed to different hosts. Here we show that A. americanum serine protease inhibitor (serpin) 27 (AAS27) is an immunogenic saliva protein that is injected into the host within the first day of tick feeding and is an anti-inflammatory protein that might act by blocking plasmin and trypsin functions. Although AAS27 is injected into the host throughout tick feeding, qRT-PCR and western blotting analyses indicate that the respective transcript and protein are present in high amounts within the first 24 h of tick feeding. Biochemical screening of Pichia pastoris-expressed recombinant (r) AAS27 against mammalian proteases related to host defense shows it is an inhibitor of trypsin and plasmin, with stoichiometry of inhibition indices of 3.5 and 3.8, respectively. Consistent with typical inhibitory serpins, rAAS27 formed heat- and SDS-stable irreversible complexes with both proteases. We further demonstrate that rAAS27 inhibits trypsin with ka of 6.46 ± 1.24 x 104 M-1 s-1, comparable to serpins of other tick species. We show that native AAS27 is part of the repertoire of proteins responsible for the inhibitory activity against trypsin in crude tick saliva. AAS27 is likely utilized by the tick to evade the hosts inflammation defense since rAAS27 blocks both formalin and compound 48/80-induced inflammation in rats. Tick immune sera of rabbits that had acquired resistance against tick feeding following repeated infestations with A. americanum or Ixodes scapularis ticks reacts with rAAS27. Of significant interest, antibody to rAAS27 blocks this serpin inhibitory functions. Taken together, we conclude that AAS27 is an anti-inflammatory protein secreted into the host during feeding and may represent a potential candidate for development of an anti-tick vaccine. [ABSTRACT FROM AUTHOR]

Alternaria alternata is a common fungus strongly related with severe allergic asthma, with 80% of affected individuals being sensitized solely to its major allergen Alt a 1. Here, we assessed the function of Alt a 1 as an innate defense protein binding to micronutrients, such as iron–quercetin complexes (FeQ2), and its impact on antigen presentation in vitro. Binding of Alt a 1 to FeQ2 was determined in docking calculations. Recombinant Alt a 1 was generated, and binding ability, as well as secondary and quaternary structure, assessed by UV-VIS, CD, and DLS spectroscopy. Proteolytic functions were determined by casein and gelatine zymography. Uptake of empty apo– or ligand-filled holoAlt a 1 were assessed in human monocytic THP1 cells under the presence of dynamin and clathrin-inhibitors, activation of the Arylhydrocarbon receptor (AhR) using the human reporter cellline AZ-AHR. Human PBMCs were stimulated and assessed for phenotypic changes in monocytes by flow cytometry. Alt a 1 bound strongly to FeQ2 as a tetramer with calculated Kd values reaching pico-molar levels and surpassing affinities to quercetin alone by a factor of 5000 for the tetramer. apoAlt a 1 but not holoAlta 1 showed low enzymatic activity against casein as a hexamer and gelatin as a trimer. Uptake of apo– and holo–Alt a 1 occurred partly clathrin-dependent, with apoAlt a 1 decreasing labile iron in THP1 cells and holoAlt a 1 facilitating quercetin-dependent AhR activation. In human PBMCs uptake of holoAlt a 1 but not apoAlt a 1 significantly decreased the surface expression of the costimulatory CD86, but also of HLADR, thereby reducing effective antigen presentation. We show here for the first time that the presence of nutritional iron complexes, such as FeQ2, significantly alters the function of Alt a 1 and dampens the human immune response, thereby supporting the notion that Alt a 1 only becomes immunogenic under nutritional deprivation. [ABSTRACT FROM AUTHOR]

Abstract Evaluating the impacts on biodiversity by means of the life cycle assessment (LCA) is a task researchers are currently facing. One impact assessment method that aims to do so is the recently developed biodiversity impact assessment BIA+. The aim of the present paper is to test this method and to show its applicability and feasibility. Additionally opportunities and challenges of this method shall be revealed. For this purpose, a case study for assessing the impacts of biodiesel production on freshwater biodiversity is introduced. Two substances, namely phosphorus and 1,4-dichlorobenzene (DCB), which are used for the biodiesel production for fertilization and the usage of pesticides, are being considered. The inventory data needed for the case study is gathered through the grey water footprint of the crop production that forms the basis of the European biodiesel consumption. Further, the BIA+ method is applied in order to assess the impacts of the biodiesel consumption in Europe for the year 2010 on freshwater biodiversity. The results reveal that even though assumptions have to be made and the results are highly uncertain, this method helps to identify hotspots within production processes. By including the BIA+ as an impact assessment method into LCA, impacts of products can be assessed with regard to biodiversity including genetic, species and ecosystem diversity. The main impact hotspot occurs in France with a potential loss of the biodiversity of 0.5 points. The lowest loss of the biodiversity occurs in Brazil (loss of 8.05*10–06 points). The results are mainly influenced by the impact of the toxic substance 1,4-DCB. By means of the case study, it is shown that the BIA+ method is applicable. [ABSTRACT FROM AUTHOR]

The private sector plays a crucial role in achieving the United Nations Sustainable Development Goals (SDGs). However, implementation of the SDGs into corporate strategies is low, and there are as yet no practicable methods to assess the impact of business activities on the SDGs. Therefore, this paper identifies influencing factors of industries on the official SDG indicators, and we develop a top-down method to quantify industry footprints vis-à-vis the SDGs, including the manufacturing and use phase and supply-chain effects. We apply the proposed method to case studies for 19 industries (which is the entire private sector, with the exception of services) and 28 environmental SDG indicators, covering topics such as greenhouse gas emissions, energy consumption, microplastic emissions, and land take. First, the results show that the private sector has a high impact on the SDG indicators under analysis, with a total footprint of 66% for all industries on average. Second, large industries such as agriculture, construction, and motor vehicles usually have the highest footprints. Third, a few industries cause a major part of the footprint for each indicator, which means efficient improvements are indeed possible. Finally, every industry has some impact on any given SDG indicator, at least in a small way via the supply chain. By quantifying footprints for the private sector, this paper demonstrates where responsibility for achieving the SDGs lies, it also supports companies in making decisions and implementing the SDGs in their strategy. In addition, this data-based assessment helps to avoid "SDG-picking". • Top-down method for quantifying industries impact on the SDGs developed. • Influencing factors of the private sector on 28 SDG indicators identified. • High impact of the private sector on the SDGs and relevant SDG indicators identified. • Footprints of 19 industry sectors quantified; sectors with high impacts identified. • Solid foundation for strategic implementation of the SDGs in industries. [ABSTRACT FROM AUTHOR]

The aim of this exploratory study was the assessment of the metabolic profiles of persons with complete spinal cord injury (SCI) in three region-of-interests (pons, cerebellar vermis, and cerebellar hemisphere), with magnetic resonance spectroscopy, and their correlations to clinical scores. Group differences and association between metabolic and clinical scores were examined. Fifteen people with chronic SCI (cSCI), five people with subacute SCI (sSCI) and fourteen healthy controls were included. Group comparison between cSCI and HC showed lower total N-acetyl-aspartate (tNAA) in the pons (p = 0.04) and higher glutathione (GSH) in the cerebellar vermis (p = 0.02). Choline levels in the cerebellar hemisphere were different between cSCI and HC (p = 0.02) and sSCI and HC (p = 0.02). A correlation was reported for choline containing compounds (tCho) to clinical scores in the pons (rho = − 0.55, p = 0.01). tNAA to total creatine (tNAA/tCr ratio) correlated to clinical scores in the cerebellar vermis (rho = 0.61, p = 0.004) and GSH correlated to the independence score in the cerebellar hemisphere (rho = 0.56, p = 0.01). The correlation of tNAA, tCr, tCho and GSH to clinical scores might be indicators on how well the CNS copes with the post-traumatic remodeling and might be further examined as outcome markers. [ABSTRACT FROM AUTHOR]

Water footprinting has emerged as an important approach to assess water use related effects from consumption of goods and services. Assessment methods are proposed by two different communities, the Water Footprint Network (WFN) and the Life Cycle Assessment (LCA) community. The proposed methods are broadly similar and encompass both the computation of water use and its impacts, but differ in communication of a water footprint result. In this paper, we explain the role and goal of LCA and ISO-compatible water footprinting and resolve the six issues raised by Hoekstra (2016) in “A critique on the water-scarcity weighted water footprint in LCA”. By clarifying the concerns, we identify both the overlapping goals in the WFN and LCA water footprint assessments and discrepancies between them. The main differing perspective between the WFN and LCA-based approach seems to relate to the fact that LCA aims to account for environmental impacts, while the WFN aims to account for water productivity of global fresh water as a limited resource. We conclude that there is potential to use synergies in research for the two approaches and highlight the need for proper declaration of the methods applied. [ABSTRACT FROM AUTHOR]

After spinal cord injury (SCI), reorganization processes and changes in brain connectivity occur. Besides the sensorimotor cortex, the subcortical areas are strongly involved in motion and executive control. This exploratory study focusses on the cerebellum and vermis. Resting-state functional magnetic resonance imaging (fMRI) was performed. Between-group differences were computed using analysis of covariance and post-hoc tests for the seed-based connectivity measure with vermis and cerebellum as regions of interest. Twenty participants with complete SCI (five subacute SCI, 15 with chronic SCI) and 14 healthy controls (HC) were included. Functional connectivity (FC) was lower in all subjects with SCI compared with HC in vermis IX, right superior frontal gyrus (pFDR = 0.008) and right lateral occipital cortex (pFDR = 0.036). In addition, functional connectivity was lower in participants with chronic SCI compared with subacute SCI in bilateral cerebellar crus I, left precentral- and middle frontal gyrus (pFDR = 0.001). Furthermore, higher amplitude of low-frequency fluctuations (ALFF) was found in the left thalamus in individuals with subacute SCI (pFDR = 0.002). Reduced FC in SCI indicates adaptation with associated deficit in sensory and motor function. The increased ALFF in subacute SCI might reflect reorganization processes in the subacute phase. [ABSTRACT FROM AUTHOR]

Abstract: The technical relevant Pt-catalyzed hydrosilylation of allyl chloride with trichlorosilane was investigated in a monophasic reaction system containing an ionic liquid (IL) additive. ILs screening allowed us to identify the liquid 1-decyl-3-methylimidazolium bis(trifloromethanesulfonyl)amide ([DMIM][NTf2]) as the best additive for such process. This IL combined complete miscibility with reactants as long as chemical and thermal robustness. After the reaction, the hydrosilylation product (3-chloropropyl)trichlorosilane was distilled off and the residual IL/catalyst solution could be reused. In such a way, a final TON of 14,200 was achieved over 10 reaction/distillation cycles without any loss of catalytic activity. The ability of [DMIM][NTf2] to prevent catalyst decomposition was deeper investigated and it was found that even with a Pt loading as high as 9500ppm, the IL acted as protective/stabilizing agent for the catalyst during the thermally stressing product distillation. [Copyright &y& Elsevier]

Background: Dipeptidyl peptidase IV (DPPIV) also known as the T cell activation marker CD26 is a multifunctional protein which is involved in various biological processes. The association of human-DPPIV with components of the human immunodeficiency virus type-1 (HIV1) is well documented and raised some discussions. Several reports implicated the interaction of human-DPPIV with the HIV1 transcription transactivator protein (HIV1-Tat) and the inhibition of the dipeptidyl peptidase activity of DPPIV by the HIV1-Tat protein. Furthermore, enzyme kinetic data implied another binding site for the HIV1-Tat other than the active centre of DPPIV. However, the biological significance of this interaction of the HIV1-Tat protein and human-DPPIV has not been studied, yet. Therefore, we focused on the interaction of HIV1-Tat protein with DPPIV and investigated the subsequent biological consequences of this interaction in Spodoptera frugiperda cells, using the BAC-TO-BAC baculovirus system. Results: The HIV1-Tat protein (Tat-BRU) co-localized and co-immunoprecipitated with human-DPPIV protein, following co-expression in the baculovirus-driven Sf9 cell expression system. Furthermore, tyrosine phosphorylation of DPPIV protein was up-regulated in Tat/DPPIV-co-expressing cells after 72 h culturing and also in DPPIV-expressing Sf9 cells after application of purified recombinant Tat protein. As opposed to the expression of Tat alone, serine phosphorylation of the Tat protein was decreased when co-expressed with human-DPPIV protein. Conclusions: We show for the first time that human-DPPIV and HIV1-Tat co-immunoprecipitate. Furthermore, our findings indicate that the interaction of HIV1-Tat and human-DPPIV may be involved in signalling platforms that regulate the biological function of both human-DPPIV and HIV1-Tat. [ABSTRACT FROM AUTHOR]

Background: Online pollen diaries and mobile applications nowadays allow easy and fast documentation of pollen allergy symptoms. Such crowd-sourced symptom data provides insights into the development and the onset of a pollen allergy. Hitherto studies of the symptom load index (SLI) showed a discrepancy between the SLI and the total pollen amount of a season, but did not analyze the daily data. Methods: The Patient's Hayfever Diary (PHD) was used as data pool for symptom data. Symptom data of Vienna (Austria) was chosen as a large and local sample size within the study period of 2013 until 2017. The city was divided into three different areas based on equal population densities and different environmental factors. Correlation factors, regression lines, locally weighted smoothing (LOESS) curves and line plots were calculated to examine the data. Results: Daily SLI and pollen concentration data correlates well and the progress of the SLI within a pollen season is mirrored by the pollen concentrations. The LOESS curves do not deviate much from the regression line and support the linearity of the symptom-pollen correlation on a daily basis. Seasonal SLI data does not follow the same pattern as the respective seasonal pollen indices. Results did not vary in the three areas within Vienna or when compared with the Eastern region of Austria showing no significant spatial variation of the SLI. Discussion: Results indicate a linear relationship of the SLI and pollen concentrations/seasonal polllen index (SPIn) on a daily basis for both in general and throughout the season, but not on a seasonal basis. These findings clarify the frequent misinterpretation of the SLI as index that is tightly connected to pollen concentrations, but reflects as well the seasonal variation of the burden of pollen allergy sufferers. Conclusion: More than just the seasonal pollen index has to be considered when the SLI of a selected pollen season has to be explained. Cross-reactivity to other pollen types, allergen content and air pollution could play a considerable role. The similar behavior of the SLI in Vienna and a whole region indicate the feasibility of a possible symptom forecast in future and justifies the use of a single pollen monitoring station within a city of the size of Vienna. [ABSTRACT FROM AUTHOR]

Envenomation caused by human contact with the caterpillar Lonomia is characterized by deleterious effects on coagulation and patency of blood vessels. The cellular effects induced by Lonomia obliqua venom highlights its capacity to activate endothelial cells, leading to a proinflammatory phenotype. Having more knowledge about the mechanisms involved in envenomation may contribute to better treatment. We aimed to evaluate the effects of Lonomia obliqua caterpillar bristle extract (LOCBE) on vascular smooth muscle cells (VSMC).We observed that LOCBE induced VSMC migration, which was preceded by alterations in actin cytoskeleton dynamics and Focal Adhesion Kinase activation. LOCBE also induced Extracellular Signal-Regulated Kinase (ERK) phosphorylation in VSMC, and the inhibition of this pathway impaired cell proliferation. Stimulation of VSMC with LOCBE triggered reactive oxygen species (ROS) production through the activation of NADPH oxidase. The rapid increase in these ROS further induced mitochondrial ROS production, however only NADPH oxidase-derived ROS were involved in ERK activation in VSMC. We that demonstrated the chemotactic and proliferative effects of LOCBE on VSMC were dependent on ROS production, mainly through NADPH oxidase. Together, the data show that Lonomia obliqua venom can interact with and activate VSMC. These effects rely on ROS production, suggesting new potential targets for treatment against vascular damage during envenomation. [ABSTRACT FROM AUTHOR]

Alterations in glycosylation have been observed in many human diseases and specific changes in glycosylation have been proposed as relevant diagnostic information. Capillary electrophoresis coupled with laser-induced fluorescence (CE-LIF) is a robust method to quantify desialylated N-glycans that are labeled with 8-aminopyrene-1,3,6-trisulfonic acid prior to analysis. To date, only a maximum of 12 glycan structures, the most abundant ones, have been identified by CE-LIF to characterize glycome modulations of total serum in the course of the diseases. In most forms of cancer, findings using CE-LIF were limited to the increase of triantennary structures carrying a Lewis epitope. In this work, we identified 32 linkage and positional glycan isomers in healthy human serum using exoglycosidase digestions as well as standard glycoproteins, for which we report the assignment of novel structures. It was possible to identify and quantify 34 glycan isomers in the serum of primary epithelial ovarian cancer patients (EOC). Reduced levels of diantennary structures and of high-mannose 5 were statistically significant in the EOC samples, and also, elevated branching as well as increased antennary fucosylation were observed. For the first time, we could demonstrate that not only antennary fucosylation was of relevance in tetraantennary structures but also core-fucosylated tetraantennary N-glycans were statistically increased in EOC patients. The results of the current study provide an improved dataset to be used in glycan biomarker discovery. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Antigen-specific Abs are able to enhance or suppress immune responses depending on the receptors that they bind on immune cells. Recent studies have shown that pro- or antiinflammatory effector functions of IgG Abs are also regulated through their Fc N-linked glycosylation patterns. IgG Abs that are agalactosylated (non-galactosylated) and asialylated are proinflammatory and induced by the combination of T cell-dependent (TD) protein antigens and proinflammatory costimulation. Sialylated IgG Abs, which are immunosuppressive, and Tregs are produced in the presence of TD antigens under tolerance conditions. T cell-independent (TI) B cell activation via B cell receptor (BCR) crosslinking through polysaccharides or via BCR and TLR costimulation also induces IgG Abs, but the Fc glycosylation state of these Abs is unknown. We found in mouse experiments that TI immune responses induced suppressive sialylated IgGs, in contrast to TD proinflammatory Th1 and Th17 immune responses, which induced agalactosylated and asialylated IgGs. Transfer of low amounts of antigen-specific sialylated IgG Abs was sufficient to inhibit B cell activation and pathogenic immune reactions. These findings suggest an immune regulatory function for TI immune responses through the generation of immunosuppressive sialylated IgGs and may provide insight on the role of TI immune responses during infection, vaccination, and autoimmunity. [ABSTRACT FROM AUTHOR]

The significant incidence of deforestation in South America culminates in the contact of humans with typical forests species. Among these species, one may highlight Lonomia obliqua caterpillar, which, when touched by humans, can poison them through their bristles. Therefore, better acknowledging the mechanisms involved in envenomation caused by Lonomia obliqua caterpillar bristle extract (LOCBE) may contribute to further treatments. Recently, we demonstrated that LOCBE induces a pro-inflammatory profile in endothelial cells; thus, we decided to investigate the effects of LOCBE on human polymorphonuclear neutrophils (PMN), which are the first leukocytes that migrate to the inflammatory focus. Our results showed that treatment with LOCBE induced PMN chemotaxis together with alterations in actin cytoskeleton and focal adhesion kinase (FAK) activation, favoring migration. Concurrently, LOCBE induced PMN adhesion to matrix proteins, such as collagen IV, fibronectin, and fibrinogen. Moreover, we observed that LOCBE attenuated PMN apoptosis and increased reactive oxygen species (ROS) production together with nuclear factor kB (NF-κB) activation—a redox-sensitive transcription factor—as well as interleukin (IL)-1β and IL-8 release. We call attention to the ROS-dependent effect of LOCBE on increased cell migration once an antioxidant treatment reverted it. In summary, we report that LOCBE activates PMN, inducing pro-inflammatory responses modulated by ROS. [ABSTRACT FROM AUTHOR]

Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein-coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor Fc?RIIB and the C-type lectin-like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of Fc?RIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain-containing inositol phosphatase (SHIP) downstream of Fc?RIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between Fc?RIIB and dectin-1. Thus, galactosylated IgG1 and Fc?RIIB exert anti-inflammatory properties beyond their impact on activating Fc?Rs. [ABSTRACT FROM AUTHOR]

Abstract: The addition of N-glycans to clinically used proteins enhances their therapeutic features. Here we report the design of a novel peptide tag with an unnatural N-glycosylation site, which may increase the N-glycan content of generally any protein. The designed GlycoTags were attached to A1AT, EPO and AGP and constructs were expressed in HEK293 or CHO cells. Hereby we could prove that the attached unnatural N-glycosylation site is decorated with complex-type N-glycans and that the spacer as well as the C-terminal “tail” sequence are critical for the usage of the novel N-glycosylation site. This demonstrates that the novel GlycoTag is a convenient tool to provide proteins with extra N-glycan moieties by simply adding a peptide tag sequence as small as 22 amino acids. [Copyright &y& Elsevier]

UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase (GNE) is a bifunctional enzyme which catalyzes the two key sequential steps in the biosynthetic pathway of sialic acid, the most abundant terminal monosaccharide on glycoconjugates of eukaryotic cells. GNE knock out (GNE KO) mice are embryonically lethal at day E8.5. Although the role of GNE in the sialic pathway has been well established as well as the importance of sialylation in many diverse biological pathways, less is known about the involvement of GNE in muscle development. To address this issue we have studied the role of GNE during in vitro embryogenesis by comparing the developmental profile in culture of embryonic stem cells (ES) from wild type and from GNE KO E3.5 mice embryos, during 45 days. Neuronal cells appeared rarely in GNE KO ES cultures and did not reach an advanced differentiated stage. Although primary cardiac cells appeared at the same time in both normal and GNE KO ES cultures, GNE KO cardiac cells degraded very soon and their beating capacity decayed rapidly. Furthermore very rare skeletal muscle committed cells were detected in the GNE KO ES cultures at any stage of differentiation, as assessed by analysis of the expression of either Pax7, MyoD and MyHC markers. Beyond the supporting evidence that GNE plays an important role in neuronal cell and brain development, these results show that GNE is strongly involved in cardiac tissue and skeletal muscle early survival and organization. These findings could open new avenues in the understanding of muscle function mechanisms in health and in disease. [ABSTRACT FROM AUTHOR]

All IgG-type antibodies are N-glycosylated in their Fc part at Asn-297. Typically, a fucose residue is attached to the first N-acetylglucosamine of these complex-type N-glycans. Antibodies lacking core fucosylation show a significantly enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and an increased efficacy of anti-tumor activity. In cases where the clinical efficacy of an antibody is to some extent mediated by its ADCC effector function, afucosylated N-glycans could help to reduce dose requirement and save manufacturing costs. Using Chinese hamster ovary (CHO) cells as a model, we demonstrate here that heterologous expression of the prokaryotic enzyme GDP-6-deoxy-d-lyxo-4-hexulose reductase within the cytosol can efficiently deflect the fucose de novo pathway. Antibody-producing CHO cells that were modified in this way secrete antibodies lacking core fucose as demonstrated by MALDI-TOF mass spectrometry and HPAEC-PAD monosaccharide analysis. Engineering of the fucose de novo pathway has led to the construction of IgGs with a strongly enhanced ADCC effector function. The method described here should have broad practical applicability for the development of next-generation therapeutic antibodies. [ABSTRACT FROM PUBLISHER]

• M. anisopliae s.l. isolate was low tolerant to menadione (MND). • Half of MND LC 50 was used as a sublethal dose in the experiments. • Changes in the colony and conidial enzymatic activities were noticed. • Better efficacy against R. microplus with fungal LC 50 and LT 50 reductions. • Mycelial secretome reveals a specific increase in some Pr1 isoforms. Menadione (MND) is known to induce oxidative stress in fungal cells. Here, we explore how exposure to this molecule alters conidial enzyme activities, fungal efficacy against Rhipicephalus microplus, and mycelial secretion (secretome) of an isolate of Metarhizium anisopliae sensu lato. First, the fungus was exposed to different MND concentrations in potato-dextrose-agar (PDA) to determine the LC 50 by evaluating conidia germination (38μM). To ensure high cell integrity, a sublethal dose of MND (half of LC 50) was added to solid (PDA MND) and liquid media (MS MND). Changes in colony growth, a slight reduction in conidia production, decreases in conidial surface Pr1 and Pr2 activities as well as improvements in proteolytic and antioxidant (catalase, superoxide dismutase, and peroxidase) conidial intracellular activities were observed for PDA MND conidia. Additionally, PDA MND conidia had the best results for killing tick larvae, with the highest mortality rates until 15 days after treatment, which reduces both LC 50 and LT 50 , particularly at 108 conidia mL−1. The diversity of secreted proteins after growth in liquid medium + R. microplus cuticle (supplemented or not with half of MND LC 50), was evaluated by mass spectrometry-based proteomics. A total of 654 proteins were identified, 31 of which were differentially regulated (up or down) and mainly related to antioxidant activity (catalase), pathogenicity (Pr1B, Pr1D, and Pr1K), cell repair, and morphogenesis. In the exclusively MS MND profile, 48 proteins, mostly associated with cellular signaling, nutrition, and antioxidant functions, were distinguished. Finally, enzymatic assays were performed to validate some of these proteins. Overall, supplementation with MND in the solid medium made conidia more efficient at controlling R. microplus larvae, especially by increasing, inside the conidia, the activity of some infection-related enzymes. In the liquid medium (a consolidated study model that mimics some infection conditions), proteins were up- and/or exclusively-regulated in the presence of MND, which opens a spectrum of new targets for further study to improve biological control of ticks using Metarhizium species. [ABSTRACT FROM AUTHOR]

The use of nanomaterials incorporated into plastic products is increasing steadily. By using nano-scaled filling materials, thermoplastics, such as polyethylene (PE), take advantage of the unique properties of nanomaterials (NM). The life cycle of these so-called nanocomposites (NC) usually ends with energetic recovery. However, the toxicity of these aerosols, which may consist of released NM as well as combustion-generated volatile compounds, is not fully understood. Within this study, model nanocomposites consisting of a PE matrix and nano-scaled filling material (TiO2, CuO, carbon nano tubes (CNT)) were produced and subsequently incinerated using a lab-scale model burner. The combustion-generated aerosols were characterized with regard to particle release as well as compound composition. Subsequently, A549 cells and a reconstituted 3D lung cell culture model (MucilAir™, Epithelix) were exposed for 4 h to the respective aerosols. This approach enabled the parallel application of a complete aerosol, an aerosol under conditions of enhanced particle deposition using high voltage, and a filtered aerosol resulting in the sole gaseous phase. After 20 h post-incubation, cytotoxicity, inflammatory response (IL-8), transcriptional toxicity profiling, and genotoxicity were determined. Only the exposure toward combustion aerosols originated from PE-based materials induced cytotoxicity, genotoxicity, and transcriptional alterations in both cell models. In contrast, an inflammatory response in A549 cells was more evident after exposure toward aerosols of nano-scaled filler combustion, whereas the thermal decomposition of PE-based materials revealed an impaired IL-8 secretion. MucilAir™ tissue showed a pronounced inflammatory response after exposure to either combustion aerosols, except for nanocomposite combustion. In conclusion, this study supports the present knowledge on the release of nanomaterials after incineration of nano-enabled thermoplastics. Since in the case of PE-based combustion aerosols no major differences were evident between exposure to the complete aerosol and to the gaseous phase, adverse cellular effects could be deduced to the volatile organic compounds that are generated during incomplete combustion of NC. [ABSTRACT FROM AUTHOR]

• Water scarcity is determined for 17 irrigation subdivisions in Pakistan. • Water deprivation index varies from 0.08 to 1.0 m3 deprived /m3 consumed. • Southern areas are up to ten times more water-scare than the northern ones. • The Water Scarcity Footprint of cotton amounts to 1476–2483 m3 deprived per ton. The Water Scarcity Footprint (WSF) serves as a method to estimate the local impacts associated with water consumption in a certain region by considering the volume of water consumed and local water scarcity. Despite the broad application of the WSF on a country and river basin level, the need for further regionalization was recently emphasized by several authors. In this study, water scarcity factors are calculated on high spatio-temporal resolution for 17 irrigation subdivisions located in Punjab, Pakistan on a monthly level based on the WAVE + method using data provided by the hydrological model SWAT and hydraulic model Feflow. The calculated "water deprivation indices" (WDIs) are applied to quantify the WSF of cotton and wheat produced in the study area and compared to the WSFs obtained by using existing WDIs with lower spatial and temporal resolution. The calculated WDIs show a high variability in water scarcity throughout the year from 0.1 to 1.0 m3 deprived /m3 consumed. The production weighted average WSF of cotton calculated with the regionalized WDIs amounts to 2333 m3 deprived per ton, whilst the cotton produced in the south of the study area has a twice as high WSF as the cotton from the northern irrigation subdivisions. The result calculated based on the high resolution WDIs is more than 60% higher than the WSF calculated with the WDIs on the basin level. The regionalized WSF of wheat amounts to 1821 m3 deprived per ton, which aligns with the WSF calculated with the basin specific WDIs. The study underlines the need for water scarcity factors on high spatial (e.g. irrigation subdivision) and temporal (monthly) resolution to provide robust WSF results. [ABSTRACT FROM AUTHOR]