Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages. In this review, we will focus on platelet activation in hemostatic and inflammatory processes, as well as platelet interactions with neutrophils and monocytes/macrophages. We take a closer look at the contributions of major platelet receptors GPIb, α_IIbβ₃, TLT-1, CLEC-2 and Toll-like receptors (TLRs) as well as secretions from platelet granules on platelet–neutrophil aggregate and neutrophil extracellular trap (NET) formation in atherosclerosis, transfusion-related acute lung injury (TRALI) and COVID-19. Further, we will address platelet–monocyte and macrophage interactions during cancer metastasis, infection, sepsis and platelet clearance.     

Low temperature sintering of barium titanate ceramics assisted by addition of lithium fluoride-containing sintering additives

By addition of LiF-containing sintering additives to commercial BaTiO₃ powder, more than 98% of the theoretical density was reached at a sintering temperature of 900 °C both on powder compacts and laminates. Dielectric measurements were performed on ceramic samples in the temperature and frequency ranges from −20 °C to 125 °C and from 10³ to 10⁶ Hz, respectively. High relative permittivity (_r  3160) and low dielectric loss (tan δ  0.014) were measured for tapes of the favoured material. The breakdown strength for tapes with a thickness of about 80 μm is 30 kV/mm. The microprobe analysis showed, that no interfacial reaction between the dielectric layer and the Ag-electrode had occurred.The newly developed barium titanate ceramics completely densifying at 900 °C turned out to be promising for integration of buried capacitors in LTCC multilayers.     

Structure–Activity Relationships of 2‐Sufonylpyrimidines as Quorum‐Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa

Drug‐resistant Pseudomonas aeruginosa (PA) strains are on the rise, making treatment with current antibiotics ineffective. Hence, circumventing resistance or restoring the activity of antibiotics by novel approaches is of high demand. Targeting the Pseudomonas quinolone signal quorum sensing (PQS‐QS) system is an intriguing strategy to abolish PA pathogenicity without affecting the viability of the pathogen. Herein we report the structure–activity relationships of 2‐sulfonylpyrimidines, which were previously identified as dual‐target inhibitors of the PQS receptor PqsR and the PQS synthase PqsD. The SAR elucidation was guided by a combined approach using ligand efficiency and ligand lipophilicity efficiency to select the most promising compounds. In addition, the most effective inhibitors were rationally modified by the guidance of QSAR using Hansch analyses. Finally, these inhibitors showed the capacity to decrease biofilm mass and extracellular DNA, which are important determinants for antibiotic resistance.     

Non-heme Fe(IV)-oxo intermediates

High-valent non-heme iron-oxo intermediates have been proposed for decades as the key intermediates in numerous biological oxidation reactions. In the past three years, the first direct characterization of such intermediates has been provided by studies of several alphaKG-dependent oxygenases that catalyze either hydroxylation or halogenation of their substrates. In each case, the Fe(IV)-oxo intermediate is implicated in cleavage of the aliphatic C-H bond to initiate hydroxylation or halogenation. The observation of non-heme Fe(IV)-oxo intermediates and Fe(II)-containing product(s) complexes with almost identical spectroscopic parameters in the reactions of two distantly related alphaKG-dependent hydroxylases suggests that members of this subfamily follow a conserved mechanism for substrate hydroxylation. In contrast, for the alphaKG-dependent non-heme iron halogenase, CytC3, two distinct Fe(IV) complexes form and decay together, suggesting that they are in rapid equilibrium. The existence of two distinct conformers of the Fe site may be the key factor accounting for the divergence of the halogenase reaction from the more usual hydroxylation pathway after C-H bond cleavage. Distinct transformations catalyzed by other mononuclear non-heme enzymes are likely also to involve initial C-H bond cleavage by Fe(IV)-oxo complexes, followed by diverging reactivities of the resulting Fe(III)-hydroxo/substrate radical intermediates.     

Effect of spin polarization of Ni(1 1 0) surface on Auger neutralization for grazing scattering of He ions

The survival of ions during grazing scattering of keV He⁺ ions from a clean Ni(1 1 0) surface is studied as function of target temperature. We observe ion fractions in the scattered beams of typically 10⁻³ which show a slight increase with temperature of the target surface. From computer simulations of projectile trajectories we attribute this enhancement for ion fractions to effects of thermal vibrations of lattice atoms on the survival of ions in their initial charge state. Based on concepts of Auger neutralization, we discuss the role of the spin polarization of target electrons on charge transfer. We do not find corresponding signatures in our data and conclude that in the present case of Ni(1 1 0) the spin polarization has to be small.     

Factors affecting length of herdlife in purebred and crossbred dairy cattle

The proportional hazards model with censoring was used to assess the effects of breeding value, disease, calving, size, and udder and lactation traits on length of herdlife of 3881 heifers in five herds. Data were recorded over 10 yr from three lines: a Holstein line, an Ayrshire-based line, and a crossbred line. Influences on survival were assessed from data collected at birth, 34, 50, and 82 wk, first freshening, and at 112 and 308 d postpartum. Median estimated herdlife (age at 50% culling) was 3.9 yr for animals alive at first freshening and increased to 4.3 yr for those that completed a first lactation (308 d postpartum). Herds differed greatly in the pattern of culling after freshening. Crossbred females had 21 wk longer median estimated herdlife than the mean of the purelines at 308 d postpartum. Individual milk yield was positively associated with longevity and had the greatest impact on length of herdlife. Abortion and fertility measured as days to last insemination were negatively associated with length of herdlife. Large heifers tended to have increased longevity. High feed intake postpartum was associated with reduced length of herdlife. Objective measures of conformation, which included measurements of the udder, were not important in determining herdlife.     

Growth and feed efficiency of pureline and crossline dairy heifers

Data on 3957 heifers from the Holstein H line, Ayrshire-based A line, and C line (crossbreds between H and A lines) were used. Growth, feed consumption, and feed efficiency from 26 to 34 wk were examined. The full model included the fixed effects of herd, year of birth, season of birth, and additive, maternal, and heterotic genetic effects with 26-wk weight as a covariate. Heterotic and maternal effects were not significant. Adjusted for the 26-wk weight covariate, H line heifers gained 3 kg more than A line heifers with C line heifers intermediate. Adjusted for 26 and 34-wk weight covariates, H line heifers ate 2 kg less TDN than A line heifers and, hence, were more efficient. Correlations among traits were estimated using the residual variance-covariance matrix from the full model. Body weight at 34 wk was correlated with 26-wk weight (r = .88) but essentially independent of rate of gain (r = .02). It was correlated with feed consumed (r = .51) and negatively associated with gain/feed consumed (r = -.25). Gain was correlated (r = .84) with gain/feed consumed but mildly so (r = .28) with feed consumed. Feed consumption was negatively correlated (r = -.25) with gain/feed consumed when the 26-wk weight covariate was included but became much larger (r = -.95) when both 26 and 34 wk weight covariates were included. Although genetic differences in feed consumption and feed efficiency of growing heifers exist, these are small and closely associated with weights and weight gains.     

Pre-Transplant Serum Leptin Levels and Relapse of Acute Myeloid Leukemia after Allogeneic Transplantation

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59–0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT.     

优化车门ECU功耗的新概念

<正>在现代汽车中,电子控制单元(ECU)的数量不断增长。现代电子零部件增加了许多功能可为驾驶员提供更多的信息和更舒适的环境,     

Anti-Inflammatory Characteristics of Local Anesthetics: Inhibition of TNF-α Secretion of Lipopolysaccharide-Stimulated Leucocytes in Human Blood Samples

Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44–61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, “responders”). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.