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The chemosensory pathway HtChe2 from the marine bacterium Halomonas titanicae KHS3 controls the activity of a diguanylate cyclase. Constitutive activation of this pathway results in colony morphology alterations and an increased ability to form biofilm. Such characteristics resemble the behavior of the Wsp pathway of Pseudomonas. In this work, we investigate the specificity of Htc10, the only chemoreceptor coded within the HtChe2 gene cluster. The purine derivatives guanine and hypoxanthine were identified as ligands of the recombinantly produced Htc10 ligand‐binding domain, with dissociation constants in the micromolar range, and its structure was solved by X‐ray protein crystallography. The sensor domain of Htc10 adopts a double Cache folding, with ligands bound to the membrane‐distal pocket. A high‐resolution structure of the occupied guanine‐binding pocket allowed the identification of residues involved in ligand recognition. Such residues were validated by site‐directed mutagenesis and isothermal titration calorimetry analyses of the protein variants. Moreover, heterologous expression of Htc10 in a Pseudomonas putida mutant lacking the native Wsp chemoreceptor promoted biofilm formation, a phenotype that was further enhanced by Htc10‐specific ligands. To our knowledge, this is the first description of binding specificity of a chemoreceptor that controls the activity of an associated diguanylate cyclase, opening the way for dynamic studies of the signaling behavior of this kind of sensory complex. [ABSTRACT FROM AUTHOR]

Aminaphtone is a chemical drug that has been used for more than thirty years to treat a variety of vascular disorders, with good clinical results and a satisfying safety profile. In the last two decades, multiple clinical studies have reported the efficacy of the drug in different clinical scenarios of altered microvascular reactivity, describing the downregulation of adhesion molecules (i.e., VCAM, ICAM, Selectins), vasoconstrictor peptides (i.e., Endothelin-1), and pro-inflammatory cytokine expression (i.e., IL-6, IL-10, VEGF, TGF-beta) by Aminaphtone. In this review, we summarize the current knowledge concerning Aminaphtone, with particular attention to rheumatological conditions in which microvascular disfunction plays a pivotal role, such as Raynaud's phenomenon and systemic sclerosis. These latter conditions may represent a promising field of application for Aminaphtone, due to the growing pre-clinical, clinical, and instrumental reports of efficacy. However, randomized, double-blind, placebo-controlled clinical trials are lacking and are desirable. [ABSTRACT FROM AUTHOR]

We report the structural, biochemical, and functional characterization of the product of gene PA0962 from Pseudomonas aeruginosa PAO1. The protein, termed Pa Dps, adopts the Dps subunit fold and oligomerizes into a nearly spherical 12-mer quaternary structure at pH 6.0 or in the presence of divalent cations at neutral pH and above. The 12-Mer Pa Dps contains two di-iron centers at the interface of each subunit dimer, coordinated by conserved His, Glu, and Asp residues. In vitro, the di-iron centers catalyze the oxidation of Fe2+ utilizing H2O2 (not O2) as an oxidant, suggesting Pa Dps functions to aid P. aeruginosa to survive H2O2-mediated oxidative stress. In agreement, a P. aeruginosa Δdps mutant is significantly more susceptible to H2O2 than the parent strain. The Pa Dps structure harbors a novel network of Tyr residues at the interface of each subunit dimer between the two di-iron centers, which captures radicals generated during Fe2+ oxidation at the ferroxidase centers and forms di-tyrosine linkages, thus effectively trapping the radicals within the Dps shell. Surprisingly, incubating Pa Dps and DNA revealed unprecedented DNA cleaving activity that is independent of H2O2 or O2 but requires divalent cations and 12-mer Pa Dps. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an immune mediated connective tissue disease characterized by microvascular dysfunction, aberrant immune response, and progressive fibrosis. Although the immuno-pathophysiological mechanisms underlying SSc are not fully clarified, they are often associated with a dysfunctional macrophage activation toward an alternative (M2) phenotype induced by cytokines [ i.e. , IL-4, IL-10, IL-13, and transforming growth factor (TGF-β)] involved in the fibrotic and anti-inflammatory process. A spectrum of macrophage activation state has been identified ranging from M1 to M2 phenotype, gene expression of phenotype markers, and functional aspects. This systematic review aims to analyze the importance of M2 macrophage polatization during the immune mediated process and the identification of specific pathways, cytokines, and chemokines involved in SSc pathogenesis. Moreover, this review provides an overview on the in vitro and in vivo studies aiming to test therapeutic strategies targeting M2 macrophages. A systematic literature review was performed according to the preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA). The search encompassed the online medical databases PubMed and Embase up to the 30th of June 2024. Original research manuscripts (in vitro study, in vivo study), animal model and human cohort , were considered for the review. Exclusion criteria encompassed reviews, case reports, correspondences, and conference abstracts/posters. The eligible manuscripts main findings were critically analyzed, discussed, and summarized in the correspondent tables. Out of the 77 screened abstracts, 49 papers were deemed eligible. Following a critical analysis, they were categorized according to the primary (29 original articles) and secondary (20 original articles) research objectives of this systematic review. The data from the present systematic review suggest the pivotal role of M2 macrophages differentiation and activation together with the dysregulation of the immune system in the SSc pathogenesis. Strong correlations have been found between M2 macrophage presence and clinical manifestations in both murine and human tissue samples. Interestingly, the presence of M2 cell surface markers on peripheral blood monocytes has been highlighted, suggesting a potential biomarker role for this finding. Therapeutic effects reducing M2 macrophage activities have been observed and/or tested for existing and for new drugs, demonstrating potential efficacy in modulating the pro-fibrotic immune response for treatment of SSc. The increased M2 macrophage activation in course of SSc seems to offer new insights on the self-amplifying inflammatory and fibrotic response by the immune system on such disease. Therefore, the revaluation of immunomodulatory and ongoing antifibrotic therapies, as well as novel therapeutical approaches in SSc that contribute to limit the M2 macrophage activation are matter of intense investigations. • Macrophages act as key players together with other immune cells during the development of SSc pathogenesis. • Pro-fibrotic M2 macrophages surface markers are present in affected organs in both SSc murine model and SSc patients. • Peripheral SSc blood monocytes exhibit surface markers akin to those found in affected organ-resident M2 macrophages. • Immunotherapy and antifibrotic therapies engaging M2 showed promising results and are matter of further studies. [ABSTRACT FROM AUTHOR]

For sustainable biomethane production, energy crops should not compete for land against feed and food. In response to this requirement, a set of practices for an innovative way to produce food and biomethane was developed in Italy with the Biogasdoneright™ model, which introduces the double‐cropping system along with digestate fertilization and minimum tillage. Triticale is a promising feedstock as energy crop in such systems. Ninteen varieties of triticale harvested at milk and dough development stages were evaluated. Principal component analysis showed that cellulose content positively affects methane production whereas starch content has only a very weak relation with specific methane yield and methane formation rate. Despite these relations, triticale chemical composition did not influence the profitability of bioenergy production as much as the total biomass solids yields, the total solids concentration at harvest, and the timing of growth. Triticale can be considered a suitable energy crop for biomethane targeting at least 4600 Nm3 CH4 per hectare. © 2022 Society of Chemical Industry and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

• Limited literature on vaccination acceptance interventions for adults in LMICs. • Intervention trends across healthcare workers, elders, and marginalized populations. • Recommend multi-component interventions and tailoring interventions to local context. Evidence-based strategies can maximize vaccination intent and uptake among adults. This systematic review summarizes the existing literature on strategies to improve vaccination intent and uptake among adults in low- and middle-income countries (LMICs) to inform future implementation in various populations and contexts. Eligible studies were identified through a systematic search in Medline, Embase, Cochrane Libraries, as well as grey literature databases published between January 2010 and March 2021. The search was limited to studies in LMICs that evaluated adult vaccination interventions. Data were extracted from the included studies and evaluated against the World Health Organization's Behavioral and Social Drivers of Vaccination Framework. The National Institutes of Health study quality assessment tools were used to evaluate study quality. The initial literature review identified 2,854 records, 22 of which met the inclusion criteria. The majority (n = 19 or 86%) of studies were from middle-income countries, with the remaining studies (n = 3 or 13%) set in low-income countries. The majority (15/22, 68%) of interventions were multi-component. 82% (18/22) of studies addressed thoughts and feelings, 59% (13/22) addressed social processes, and 73% (16/22) addressed practical issues. Five studies reported primary outcomes of vaccination intent, and the remaining 17 reported vaccine uptake. 36% (8/22) of the studies cited statistically significant positive intervention effects on vaccination intent or uptake. Few of the included studies (6/22, 27%) were RTCs, and most studies (15/22, 68%) were of poor study quality. The studies reporting the highest increase in vaccination intent and uptake were multi-component interventions that addressed all three determinants of vaccination. The results of this review highlight levers that can be used to encourage vaccine intent and uptake in the ongoing rollout of COVID-19 vaccines, as well as the deployment of other vaccines to adult populations in LMICs. Of the included studies, multicomponent interventions were most effective, mainly when targeting multiple determinants of vaccination. However, poor study quality indicates the need for additional research to validate these findings. [ABSTRACT FROM AUTHOR]

Ferritins are iron storage proteins assembled from 24 subunits into a spherical and hollow structure. The genomes of many bacteria harbor genes encoding two types of ferritin-like proteins, the bacterial ferritins (Ftn) and the bacterioferritins (Bfr), which bind heme. The genome of P. aeruginosa PAO1 (like the genomes of many bacteria) contains genes coding for two different types of ferritin-like molecules, ftnA (PA4235) and bfrB (PA3531). The reasons for requiring the presence of two distinct types of iron storage protein in bacterial cells have remained largely unexplained. Attempts to understand this issue in P. aeruginosa through the recombinant expression of the ftnA and bfrB genes in E. coli host cells, coupled to the biochemical and structural characterization of the recombinant 24-mer FtnA and 24-mer BfrB molecules, have shown that each of the recombinant molecules can form an Fe3+-mineral core. These observations led to the suggestion that 24-mer FtnA and 24-mer BfrB molecules coexist in P. aeruginosa cells where they share iron storage responsibilities. Herein, we demonstrate that P. aeruginosa utilizes a single heterooligomeric 24-mer Bfr assembled from FtnA and BfrB subunits. The relative content of the FtnA and BfrB subunits in Bfr depends on the O2 availability during cell culture, such that Bfr isolated from aerobically cultured P. aeruginosa is assembled from a majority of BfrB subunits. In contrast, when the cells are cultured in O2-limiting conditions, the proportion of FtnA subunits in the isolated Bfr increases significantly and can become the most abundant subunit. Despite the variability in the subunit composition of Bfr, the 24-mer assembly is consistently arranged from FtnA subunit dimers devoid of heme and BfrB subunit dimers each containing a heme molecule. [ABSTRACT FROM AUTHOR]

A plethora of measures are being combined in the attempt to reduce SARS-CoV-2 spread. Due to its sustainability, contact tracing is one of the most frequently applied interventions worldwide, albeit with mixed results. We evaluate the performance of digital contact tracing for different infection detection rates and response time delays. We also introduce and analyze a novel strategy we call contact prevention, which emits high exposure warnings to smartphone users according to Bluetooth-based contact counting. We model the effect of both strategies on transmission dynamics in SERIA, an agent-based simulation platform that implements population-dependent statistical distributions. Results show that contact prevention remains effective in scenarios with high diagnostic/response time delays and low infection detection rates, which greatly impair the effect of traditional contact tracing strategies. Contact prevention could play a significant role in pandemic mitigation, especially in developing countries where diagnostic and tracing capabilities are inadequate. Contact prevention could thus sustainably reduce the propagation of respiratory viruses while relying on available technology, respecting data privacy, and most importantly, promoting community-based awareness and social responsibility. Depending on infection detection and app adoption rates, applying a combination of digital contact tracing and contact prevention could reduce pandemic-related mortality by 20–56%. [ABSTRACT FROM AUTHOR]

In this study, biogas and biomethane production during mesophilic anaerobic digestion of wheat substrates coming from national crops and naturally contaminated with deoxynivalenol (DON) and/or T-2/HT-2 toxins was investigated. Biochemical methane potential (BMP) tests of both wholewheat flour and of the main milling fractions were carried out to assess the effect on the concentration of mycotoxins on the anaerobic biological process and their residual presence in the final digestate. The good methane average production achieved (337.0 ± 24.5 NL CH4/kg VS) was substantially comparable with the yields gained from similar biomasses at mesophilic conditions. Moreover, an effective reduction (60.7–100%) of DON concentration was obtained in all the tested substrates (range of contamination in the samples, 368–12,916 μg/kg) whereas the sum of T-2 and HT-2 toxin levels in digestates was always

Objectives Fibroblast-to-myofibroblast transition and extracellular matrix overproduction represent progressive events in chronic inflammatory and fibrotic diseases, in which TGFβ1 is one of the key mediators. Phosphodiesterase 4 (PDE4) acts as a proinflammatory enzyme through the degradation of cyclic adenosine monophosphate and it is overexpressed in skin fibroblasts. The study investigated how apremilast (a PDE4 inhibitor) interferes with the intracellular signalling pathways responsible for the TGFβ1-induced fibroblast-to-myofibroblast transition and profibrotic extracellular matrix protein synthesis. Methods Cultured human skin fibroblasts were stimulated with TGFβ1 (10 ng/ml) alone or combined with apremilast (1 and 10 μM) for 4, 16 and 24 h. Other aliquots of the same cells were previously stimulated with TGFβ1 and then treated with apremilast (1 and 10 μM) for 4, 16 and 24 h, always under stimulation with TGFβ1. Gene and protein expression of αSMA, type I collagen (COL1) and fibronectin were evaluated, together with the activation of small mothers against decapentaplegic 2 and 3 (Smad2/3) and extracellular signal-regulated kinase (Erk1/2) proteins. Results Apremilast reduced the TGFβ1-induced increase in αSMA, COL1 and fibronectin gene expression at 4 and 16 h, and protein synthesis at 24 h of treatment in cultured fibroblasts, even for cells already differentiated into myofibroblasts by way of a previous stimulation with TGFβ1. Apremilast inhibited the TGFβ1-induced Smad2/3 and Erk1/2 phosphorylation at 15 and 30 min. Conclusion Apremilast seems to inhibit in vitro the fibroblast-to-myofibroblast transition and the profibrotic activity induced by TGFβ1 in cultured human skin fibroblasts by downregulating Smad2/3 and Erk1/2 intracellular signalling pathways. [ABSTRACT FROM AUTHOR]

Biogas plants are a widespread renewable energy technology. However, the use of digestate for agronomic purposes has often been a matter of concern. It is controversial whether biogas plants might harbor some pathogenic clostridial species, which represent a biological risk. Moreover, the inhabitance of Clostridium hard-cheese spoiling species in anaerobic digesters can be problematic for hard-cheese manufacturing industries, due to the issue of cheese blowing defects. This study investigated the effect of mesophilic anaerobic digestion processes on the Clostridium consortia distribution over time. Specifically, three lab-scale CSTRs treating agricultural biomass were characterized by considering both the whole microbial community and the cultivable clostridial spores. It is assessed an overall reduction of the Clostridium genus during the anaerobic digestion process. Moreover, it was evidenced a slight, but steady decrease of the cultivable clostridial spores, mainly represented by two pathogenic species, C. perfringens and C. bifermentans, and one hard-cheese spoiling species, C. butyricum. Thus, it is revealed an overall reduction of the clostridial population abundance after the mesophilic anaerobic digestion treatment of agricultural biomass. [ABSTRACT FROM AUTHOR]

A density functional theory study of the intrinsic stability of pure and bimetallic wires is presented. Several bimetallic combinations forming one-atom thick wires are studied. An explanation for the experimental instability of Cu wires in contrast to the stability of Au and Ag wires is given, which relies on the higher surface energy of the former. All the possible intercalations between Ni, Pd, Pt, Cu, Ag, and Au are studied. The bimetallic wires AuCu and AuAg were found to be the most stable ones. The reactivity of the latter two systems is also examined using hydrogen adsorption as a microscopic probe. It was found that at the inter-metal interface, up to second neighbors, Cu and Ag become more reactive and Au becomes more inert than the corresponding pure wires. These results are explained within the d-band model. [ABSTRACT FROM AUTHOR]

• Theoretical study combined DFT + XANES simulations. • Electronic and morphological structures of Cu20 clusters. • New properties of transition metal clusters. We present ab initio simulations of X-ray Absorption Near-Edge Structure (XANES) spectra, performed on model clusters built by fast simulated annealing and optimized by Density Functional Theory (DFT) minimization. As is known, larger stability of Cu clusters with 20 atoms was found in comparison with those with 19 and 21 atoms. Based on this knowledge, we show the sensitivity of the XANES technique on the number of atoms n , (c.a 20), and on the morphology of the Cu n nanoclusters. For this study we used both L3 and K edges and found the former more sensitive. In addition, in the case of the K XANES edge, we carry out the simulations using four different methods, to observe their performance in arrays of a few atoms. Even more, we obtain a good agreement between our results and previous predictions on the HOMO-LUMO gaps for these systems. [ABSTRACT FROM AUTHOR]

The objective is to detect any possible correlation between the modified Rodnan skin score (mRSS) and dermal thickness (DT) measured by skin high-frequency ultrasound (US) and the percentage of circulating fibrocytes in patients with limited cutaneous systemic sclerosis (lcSSc). Eight lcSSc patients and five healthy subjects (control group, CNT) were enrolled. The skin involvement was evaluated by mRSS and US (18 and 22 MHz probes) in all 13 subjects in the 17 standard skin areas evaluated by mRss. Circulating fibrocytes were isolated from the peripheral blood mononuclear cells (PBMCs) of all lcSSc patients and the CNT group to analyze their percentage at baseline time (T0) when the experiments started with PBMCs' isolation and collection and after 8 days of culture (T8). Non-parametric tests were used for the statistical analysis. A positive correlation between the percentage of circulating fibrocytes at T0, mRSS (p = 0.04 r = 0.96), and DT-US, evaluated by the 22 MHz and the 18 MHz probes (p = 0.03, r = 0.66 and p = 0.05, r = 0.52, respectively), was observed in lcSSc patients. Conversely, at T8, there was no correlation (p > 0.05) between these parameters in lcSSc group. In the CNT group, no correlations between mRSS or DT-US and the percentage of circulating fibrocytes were observed both at T0 and T8. The study shows the presence of a significant relationship between the percentage of circulating fibrocytes and DT, as evidenced by both mRSS and US, in limited cutaneus SSc. This observation may well suggest the reasonable hypothesis of a crucial contribution of circulating fibrocytes to skin fibrosis progression, which might be considered as further biomarkers. [ABSTRACT FROM AUTHOR]

The paper describes two versions of an inquiry-based activity in geometry, designed as a game between two players. The game is inspired by Hintikka's semantic game, which is a familiar tool in the field of logic to define truth. The activity is designed in a dynamic geometry environment (DGE). The inquiry is initially guided by the game itself and later by a questionnaire that helps students discover the geometry theorem behind the game. The activity is emblematic of describing a geometry-based inquiry that can be implemented with various Euclidean geometry theorems. The analysis of the first "student vs. student" version associates the example space produced by the students with their dialogue, to identify the different functions of variation. Based on the results of this version, we designed a "student vs. computer" version and created filters for the automatic analysis of the players' moves. Our findings show that students who participated in the activity developed forms of strategic reasoning that helped them discover the winning configuration, formulate if-then statements, and validate or refute conjectures. Automation of the analysis creates new research opportunities for analyzing and assessing students' inquiry processes and makes possible extensive experimentation on inquiry-based knowledge acquisition. [ABSTRACT FROM AUTHOR]

The impact of relative humidity (RH) and temperature variation on the mechanical behaviour of paintings on canvas was investigated, based on the various environmental recommendations that are applied by museums and institutions worldwide. Paint samples were constructed based on the works of twentieth-century artists such as Soulages and Riopelle. The various samples are based on criteria such as paint media, additives, pigment type, canvas type, thickness, type of application, and drying time. Once they are fully dry, paint films behave as elastic, viscoelastic, or viscoplastic materials depending on the chemical nature of their components. These properties, as well as tensile strength, were determined by a series of tensile tests. Other samples were included, originating from discarded oil paintings on canvas from the seventeenth and nineteenth centuries. To carry out mechanical tests under controlled conditions of temperature and RH, a climatic chamber was built around the column of a universal testing machine. Samples were submitted to stress relaxation tests to observe their response to changes in environmental conditions. RH was increased from 20 to 90% and temperature from 15 to 60°C. Reactivity diagrams were drawn based on the results. The endurance limit under mechanical fatigue was determined from the diagrams and helped define the risks associated with each painting type when exposed to the accepted environmental recommendations. [ABSTRACT FROM AUTHOR]

The efficacy of tocilizumab (TCZ), a monoclonal antibody to the interleukin (IL)-6 receptor, in suppressing disease activity in glucocorticoid-naïve patients with new-onset polymyalgia rheumatica (PMR) was studied. Its effect on a panel of cytokines and growth factors was evaluated. Three patients, fulfilling the PMR ACR/EULAR criteria, received TCZ at the dosage of 8 mg/kg every 4 weeks for three times followed by prednisone 0.2 mg/kg in case of inefficacy. Concentrations of IL-10, IL-6, tumour necrosis factor (TNF)-α, IL-1β, IL-10, IL-17, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and leukaemia inhibitory factor (LIF) were measured at baseline, after 72 h of the first TCZ infusion and then at weeks 1, 4, 5, 8, 9, 12, 13, 14, 16, and 22. A slight clinical improvement was seen only after the first TCZ infusion, but was largely inferior to that of conventional doses of GC administered subsequently. An ischaemic visual accident suggestive of GCA occurred in one patient during TCZ treatment. IL-6 was increased at baseline compared to controls, further increased after the first TCZ infusion, and was suppressed by GC. IL-17 production decreased during TCZ treatment and reverted to pre-treatment levels after GC. VEGF e PDGF showed a less constant pattern, but an increase of VEGF concentration antedated visual symptoms. The other cytokines were not detectable in patients and controls. In our small sample, TCZ was not able to suppress inflammation at the same degree as GC. As a result, monotherapy with TCZ in PMR cannot be recommended, although its efficacy as adjunctive treatment in GC-resistant patients should be further evaluated. [ABSTRACT FROM AUTHOR]

The impact of relative humidity (RH) and temperature variation on the mechanical behaviour of paintings on canvas was investigated, based on the various environmental recommendations that are applied by museums and institutions worldwide. Paint samples were constructed based on the works of twentieth-century artists such as Soulages and Riopelle. The various samples are based on criteria such as paint media, additives, pigment type, canvas type, thickness, type of application, and drying time. Once they are fully dry, paint films behave as elastic, viscoelastic, or viscoplastic materials depending on the chemical nature of their components. These properties, as well as tensile strength, were determined by a series of tensile tests. Other samples were included, originating from discarded oil paintings on canvas from the seventeenth and nineteenth centuries. To carry out mechanical tests under controlled conditions of temperature and RH, a climatic chamber was built around the column of a universal testing machine. Samples were submitted to stress relaxation tests to observe their response to changes in environmental conditions. RH was increased from 20 to 90% and temperature from 15 to 60°C. Reactivity diagrams were drawn based on the results. The endurance limit under mechanical fatigue was determined from the diagrams and helped define the risks associated with each painting type when exposed to the accepted environmental recommendations. [ABSTRACT FROM AUTHOR]

Heme oxygenase from Leptospira interrogans is an important virulence factor. During catalysis, redox equivalents are provided to this enzyme by the plastidic-type ferredoxin-NADP+ reductase also found in L. interrogans. This process may have evolved to aid this bacterial pathogen to obtain heme-iron from their host and enable successful colonization. Herein we report the crystal structure of the heme oxygenase-heme complex at 1.73 Å resolution. The structure reveals several distinctive features related to its function. A hydrogen bonded network of structural water molecules that extends from the catalytic site to the protein surface was cleared observed. A depression on the surface appears to be the H+ network entrance from the aqueous environment to the catalytic site for O2 activation, a key step in the heme oxygenase reaction. We have performed a mutational analysis of the F157, located at the above-mentioned depression. The mutant enzymes were unable to carry out the complete degradation of heme to biliverdin since the reaction was arrested at the verdoheme stage. We also observed that the stability of the oxyferrous complex, the efficiency of heme hydroxylation and the subsequent conversion to verdoheme was adversely affected. These findings underscore a long-range communication between the outer fringes of the hydrogen-bonded network of structural waters and the heme active site during catalysis. Finally, by analyzing the crystal structures of ferredoxin-NADP+ reductase and heme oxygenase, we propose a model for the productive association of these proteins. [ABSTRACT FROM AUTHOR]

Background: Alternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells. Methods: Cultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography. Results: ET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1-mediated effects were contrasted by ETA/BRA treatment in both cultured cell types. Conclusion: ET-1 seems to induce the M2 phenotype in cultured human macrophages, a process apparently contrasted by the action of the ETA/BRA, suggesting possible clinical implications in those fibrotic diseases characterized by increased ET-1 concentrations, such as systemic sclerosis but also type 2 diabetes. [ABSTRACT FROM AUTHOR]

Summary The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body. [ABSTRACT FROM AUTHOR]

In this work, the fabrication, the electrical and optical characterization of red organic light emitting transistors using thin film made of alumina grown by atomic layer deposition (ALD) coupled with PMMA (poly(methyl-methacrylate)) as gate dielectric material are reported. Use of ALD-grown Al 2 O 3 is shown to greatly reduce the operation range and the threshold voltage in this class of devices as compared to polymer-based dielectric counterpart, while at the same time comparable optical performances are maintained. Further, reducing the oxide layer thickness demonstrates the possibility of fine tuning the device working conditions, while maintaining optoelectronic performances, robustness and very low leakage current. [ABSTRACT FROM AUTHOR]

Detecting pathogens and mounting immune responses upon infection is crucial for animal health. However, these responses come at a high metabolic price (McKean and Lazzaro, 2011, Kominsky et al., 2010), and avoiding pathogens before infection may be advantageous. The bacterial endotoxins lipopolysaccharides (LPS) are important immune system infection cues (Abbas et al., 2014), but it remains unknown whether animals possess sensory mechanisms to detect them prior to infection. Here we show that Drosophila melanogaster display strong aversive responses to LPS and that gustatory neurons expressing Gr66a bitter receptors mediate avoidance of LPS in feeding and egg laying assays. We found the expression of the chemosensory cation channel dTRPA1 in these cells to be necessary and sufficient for LPS avoidance. Furthermore, LPS stimulates Drosophila neurons in a TRPA1-dependent manner and activates exogenous dTRPA1 channels in human cells. Our findings demonstrate that flies detect bacterial endotoxins via a gustatory pathway through TRPA1 activation as conserved molecular mechanism. [ABSTRACT FROM AUTHOR]

Combining objects with diverse properties has often the advantage of giving rise to novel functionalities. In this scenario, metal-filled and decorated carbon nanotubes ( m -CNTs) represent a class of hybrid carbon-based nanostructured materials with enormous interest for application in several fields, ranging from nanoelectronics and spintronics to nanomedicine and magnetic data recording. The present review will provide the reader with an overview of state-of-the-art hybrid architectures based on m -CNT systems, methods currently employed for their fabrication, the set of their unique properties and how they can be applied toward novel devices with multifunctional properties for a broad range of applications. [ABSTRACT FROM AUTHOR]

Background: Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized. Results: We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI. Conclusions: Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions. [ABSTRACT FROM AUTHOR]

Background Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized. Results We present an assessmet of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI. Conclusions Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions. [ABSTRACT FROM AUTHOR]

Bimetallic catalysts have manifold technological applications; their reactivity can greatly exceed that of the original single metals. In this work, we investigate an ideal model-system consisting of a complete monolayer of Pd underneath the surface of Au(111). First, we investigate the stability of this system, and then its interaction with hydrogen. We analyze in detail the energetics and the electronic interactions for the Volmer step of the hydrogen evolution reaction (HER), and the further absorption below the surface layer of gold. We combine Density Functional Theory based on computational techniques with the theory of electrocatalysis. [ABSTRACT FROM AUTHOR]

Edges play a determining role in the electronic and transport properties of graphene, however, their actual morphology and configuration remain unknown. Using ab initio thermodynamics, we have systematically studied the stability and structure of armchair and zigzag edges of graphene in pure O2 and combined O2 and H2 environments. In total, 81 different nanostructures were investigated, however, only a few of them domain the phase diagram. Our calculations show that zigzag edges are less stable than armchair edges. Nonetheless, the former exhibit a much richer diversity in terms of structures. The oxygen-terminated edges occupy the largest regions in the phase stability diagram in comparison with hydrogen-oxygen-terminated edges, which correspond to carboxyl and alcohol functional groups. [ABSTRACT FROM AUTHOR]

Background Heme oxygenase catalyzes the conversion of heme to iron, carbon monoxide and biliverdin employing oxygen and reducing equivalents. This enzyme is essential for heme-iron utilization and contributes to virulence in Leptospira interrogans . Methods A phylogenetic analysis was performed using heme oxygenases sequences from different organisms including saprophytic and pathogenic Leptospira species. L . interrogans heme oxygenase (LepHO) was cloned, overexpressed and purified. The structural and enzymatic properties of LepHO were analyzed by UV–vis spectrophotometry and 1 H NMR. Heme-degrading activity, ferrous iron release and biliverdin production were studied with different redox partners. Results A plastidic type, high efficiently ferredoxin-NADP + reductase (LepFNR) provides the electrons for heme turnover by heme oxygenase in L . interrogans . This catalytic reaction does not require a ferredoxin. Moreover, LepFNR drives the heme degradation to completeness producing free iron and α-biliverdin as the final products. The phylogenetic divergence between heme oxygenases from saprophytic and pathogenic species supports the functional role of this enzyme in L . interrogans pathogenesis. Conclusions Heme-iron scavenging by LepHO in L . interrogans requires only LepFNR as redox partner. Thus, we report a new substrate of ferredoxin-NADP + reductases different to ferredoxin and flavodoxin, the only recognized protein substrates of this flavoenzyme to date. The results presented here uncover a fundamental step of heme degradation in L . interrogans . General significance Our findings contribute to understand the heme-iron utilization pathway in Leptospira . Since iron is required for pathogen survival and infectivity, heme degradation pathway may be relevant for therapeutic applications. [ABSTRACT FROM AUTHOR]

The contents of the existential minimum are related to the fundamental right to an ecologically balanced environment, according to Article 225 of the Brazilian Federal Constitution. An analysis of the concept of environment and its fundamentality is provided and the fundamental (social) rights that are part of the classical contents of the existential minimum nucleus are given. The authors would like to contribute towards the inclusion of fundamental law to a balanced environment within the concept of the existential minimum due to its indispensability for the dignity of the person, which is the basis and guiding principle of the Brazilian republic. All the rights of the person depend intrinsically on a healthy environment proper to human life. [ABSTRACT FROM AUTHOR]

:The Drosophila homolog of the Alzheimer's disease protein APP, known as APPL, regulates axon growth during brain development. [ABSTRACT FROM AUTHOR]

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI. [ABSTRACT FROM AUTHOR]

Abstract: Cyanide-modified Pt(111) surfaces have been recently used to study atomic-ensemble effects in electrocatalysis. These studies have been based on the assumption that cyanide acts as a third body, blocking some surface sites but leaving the electronic properties of the surrounding ones unaltered, although this is in apparent contradiction with the observation of a positive shift of 0.2V in the onset of hydrogen adsorption on cyanide-modified Pt(111) electrodes, as compared with clean Pt(111). We have performed theoretical calculations in order to provide support to this assumption and explain the positive shift in the onset of hydrogen adsorption, which is shown to be due to the formation of CNHad. [Copyright &y& Elsevier]

The present Review opens with an overview of metal oxides and the description of their material properties. The first part mainly deals with various preparation techniques and growth mechanisms, which have been largely developed in the last few decades to fabricate different types of metal oxide nanostructures. The second part, on the other hand, will provide the Reader with an up-to-date summary of different applications in which metal oxides nanostructures have been successfully implemented and/or suggested. In particular, great attention will be dedicated to the implementation of metal oxide nanostructures for gas sensing as well as light emission applications, for which both working principles and integration, as well as the latest reported cutting edge results are herein reported. Finally, we emphasize on the current potentials of metal oxide nanostructured materials and future challenges that this field in continuous expansion is currently facing. [ABSTRACT FROM AUTHOR]

Background: Identification of protein structural cores requires isolation of sets of proteins all sharing a same subset of structural motifs. In the context of an ever growing number of available 3D protein structures, standard and automatic clustering algorithms require adaptations so as to allow for efficient identification of such sets of proteins. Results: When considering a pair of 3D structures, they are stated as similar or not according to the local similarities of their matching substructures in a structural alignment. This binary relation can be represented in a graph of similarities where a node represents a 3D protein structure and an edge states that two 3D protein structures are similar. Therefore, classifying proteins into structural families can be viewed as a graph clustering task. Unfortunately,because such a graph encodes only pairwise similarity information, clustering algorithms may include in the same cluster a subset of 3D structures that do not share a common substructure. In order to overcome this drawback we first define a ternary similarity on a triple of 3D structures as a constraint to be satisfied by the graph of similarities.Such a ternary constraint takes into account similarities between pairwise alignments, so as to ensure that the three involved protein structures do have some common substructure. We propose hereunder a modification algorithm that eliminates edges from the original graph of similarities and gives a reduced graph in which no ternary constraints are violated. Our approach is then first to build a graph of similarities, then to reduce the graph according to the modification algorithm, and finally to apply to the reduced graph a standard graph clustering algorithm. Such method was used for classifying ASTRAL-40 non-redundant protein domains, identifying significant pairwise similarities with Yakusa, a program devised for rapid 3D structure alignments.Conclusions: We show that filtering similarities prior to standard graph based clustering process by applying ternary similarity constraints i) improves the separation of proteins of different classes and consequently ii) improves the classification quality of standard graph based clustering algorithms according to the reference classification SCOP. [ABSTRACT FROM AUTHOR]

Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non-classical HLA class I antigen and/or NKCAL expression. In contrast to these assumptions, experimental evidence suggests that in some cases dysplastic and malignant cells can acquire classical HLA class I antigen expression and/or lose the ability to express HLA class II antigens. In light of the latter findings as well as of the revival of the cancer immune surveillance theory, a reevaluation of the interpretation of changes in HLA antigen and NKCAL expression in malignant lesions is warranted. In this article, we first briefly describe the conventional types of changes in HLA antigen and NKCAL expression that have been identified in malignant cells to date. Second, we discuss the evidence indicating that, in at least some cell types, classical HLA class I antigen expression can be acquired and/or the ability to express HLA class II antigens is lost. Third, we review the available evidence for the role of immune selective pressure in the generation of malignant lesions with changes in HLA antigen expression. This information contributes to our understanding of the role of the immune system in the control of tumor development and to the optimization of the design of immunotherapeutic strategies for the treatment of cancer. [ABSTRACT FROM AUTHOR]

lthough the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal-maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of monoglycerides by glycerolysis of methyl oleate, an unsaturated fatty acid methyl ester, was studied on acid–base solid catalysts as an alternative to the current commercial technology that uses liquid base catalysts. Initially, the reaction conditions such as catalyst particle size and stirring rate required for operating the four-phase semi-continuous reactor under a kinetically controlled-regime were determined. Then the optimization of the reaction parameters for achieving high monoglyceride yields was performed using MgO. MgO compared favorably with the corresponding homogeneously catalyzed process. In fact, when using high reaction temperatures (493–523K), glycerol/methyl oleate molar ratios between 2 and 6, and catalyst/reactant ratios of about 30g/mol, glycerolysis of methyl oleate yields up to 77% monoglycerides in 2h, a much higher value than those usually obtained via the liquid base-catalyzed homogeneous process (40–60%). The acid–base site requirements for the glycerolysis reaction were investigated using single oxides with different electronegativities. A good correlation was found between the catalytic activity and the base site density. In addition, results show that glycerolysis of methyl oleate requires strong base sites such as those of MgO. [Copyright &y& Elsevier]

Abstract: This review on graphene, a one-atom thick, two-dimensional sheet of carbon atoms, starts with a general description of the graphene electronic structure as well as a basic experimental toolkit for identifying and handling this material. Owing to the versatility of graphene properties and projected applications, several production techniques are summarized, ranging from the mechanical exfoliation of high-quality graphene to the direct growth on carbides or metal substrates and from the chemical routes using graphene oxide to the newly developed approach at the molecular level. The most promising and appealing properties of graphene are summarized from an exponentially growing literature, with a particular attention to matching production methods to characteristics and to applications. In particular, we report on the high carrier mobility value in suspended and annealed samples for electronic devices, on the thickness-dependent optical transparency and, in the mechanical section, on the high robustness and full integration of graphene in sensing device applications. Finally, we emphasize on the high potential of graphene not only as a post-silicon materials for CMOS device application but more ambitiously as a platform for post-CMOS molecular architecture in electronic information processing. [Copyright &y& Elsevier]

To investigate the effects of 17beta-estradiol (E2) on extracellular matrix (ECM) protein synthesis (collagen type I, fibronectin, and laminin) using cultures of normal and scleroderma (SSc) skin fibroblasts. Primary fibroblasts cultures, obtained from skin biopsies of six female voluntary subjects and three female SSc patients, were treated for 24 h with E2 (10−10M) alone or in combination with tamoxifene (TAM, 10−7M) as an estrogen receptor (ER) antagonist. ECM protein synthesis was analyzed by immunocytochemistry and Western blotting. E2 induced a significant increase of fibronectin, collagen type I, and laminin synthesis both in normal ( P < 0.01, P < 0.05, P < 0.01, respectively) and SSc fibroblasts ( P < 0.001, P < 0.05, P < 0.001, respectively) when compared to untreated fibroblasts. TAM induced a significant decrease of ECM protein synthesis when compared to E2-treated TAM-untreated fibroblasts. This study seems to support important modulatory effects of E2 in the fibrotic progression of the SSc process via ER interactions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) prevalence is greater in females than in males, supporting estrogens as modulators of immune response. Leflunomide (LEF) is employed in the RA treatment. We studied the combinatory effects of LEF active metabolite A77 1726 (LEF-M) and 17beta-estradiol (E2) on inflammatory cytokine production by cultured macrophages obtained from activated human monocytes (THP-1 cells). Macrophages were cultured with LEF-M alone and in combination with E2. IL-6, TNF-α, and TGF-β were evaluated by immunocytochemistry (ICC), Western blot (WB), and reverse transcriptase-polymerase chain reaction (RT-PCR). ICC, as well as WB and RT-PCR, showed that LEF-M, in respect to untreated cells, significantly downregulated the cytokine production (IL-6 P < 0.01, TNF-α P < 0.001, TGF-β P < 0.01). On the contrary, E2 increased the cytokine production, a result that was significantly reversed when LEF-M was subsequently added (IL-6, TNF-α, TGF-β P < 0.001 vs. E2). E2 seems to contrast the LEF-M activity. These results might support a more efficient therapeutical effect of LEF in male with respect to female RA patients. [ABSTRACT FROM AUTHOR]

AbstractThe geometrical configurations of atoms in protein structures can be viewed as approximate relations among them. Then, finding similar common substructures within a set of protein structures belongs to a new class of problems that generalizes that of finding repeated motifs. The novelty lies in the addition of constraints on the motifs in terms of relations that must hold between pairs of positions of the motifs. We will hence denote them as relational motifs. For this class of problems, we present an algorithm that is a suitable extension of the KMR paradigm and, in particular, of the KMRC as it uses a degenerate alphabet. Our algorithm contains several improvements that become especially useful when—as it is required for relational motifs—the inference is made by partially overlapping shorter motifs, rather than concatenating them. The efficiency, correctness and completeness of the algorithm is ensured by several non-trivial properties that are proven in this paper. The algorithm has been applied in the important field of protein common 3D substructure searching. The methods implemented have been tested on several examples of protein families such as serine proteases, globins and cytochromes P450 additionally. The detected motifs have been compared to those found by multiple structural alignments methods. [ABSTRACT FROM AUTHOR]

Transplantation of acute myeloid leukemia (AML) patients with grafts from related haploidentical donors has been shown to result in a potent graft-versus-leukemia effect. This effect is mediated by NK cells because of the lack of activation of inhibitory killer cell immunoglobulin-like receptors (KIRs) which recognize HLA-Bw4 and HLA-C alleles. However, conflicting results have been reported about the impact of KIR ligand mismatching on the outcome of unrelated HLA-mismatched hematopoietic stem cells transplants (HSCT) to leukemic patients. The interpretation of these conflicting results is hampered by the scant information about the level of expression of HLA class I alleles on leukemic cells, although this variable may affect the activation of inhibitory KIRs. Therefore in the present study, utilizing a large panel of human monoclonal antibodies we have measured the level of expression of HLA-A, -B and -C alleles on 20 B-chronic lymphoid leukemic (B-CLL) cell preparations, on 16 B-acute lymphoid leukemic (B-ALL) cell preparations and on 19 AML cell preparations. Comparison of the level of HLA class I antigen expression on leukemic cells and autologous normal T cells identified selective downregulation of HLA-A and HLA-B alleles on 15 and 14 of the 20 B-CLL, on 2 and 5 of the 16 B-ALL and on 7 and 11 of the 19 AML patients tested, respectively. Most interestingly HLA-C alleles were markedly downregulated on all three types of leukemic cells; the downregulation was most pronounced on AML cells. The potential functional relevance of these abnormalities is suggested by the dose-dependent enhancement of NK cell activation caused by coating the HLA-HLA-Bw4 epitope with monoclonal antibodies on leukemic cells which express NK cell activating ligands. Our results suggest that besides the HLA and KIR genotype, expression levels of KIR ligands on leukemic cells should be included among the criteria used to select the donor-recipient combinations for HSCT. [ABSTRACT FROM AUTHOR]