Platelet Surface-Associated Activation and Secretion-Mediated Inhibition of Coagulation Factor XII

Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from α-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto-inhibition mechanism (k_i/k_a = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface-associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface-associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis.     

The Formation of Structural Abnormalities in Karelian Birch Wood is Associated with Auxin Inactivation and Disrupted Basipetal Auxin Transport

Journal of Plant Growth Regulation - Figured wood of Karelian birch (Betula pendula Roth var. carelica (Merckl.) Hämet-Ahti) is highly appraised for its ornamental properties. The reasons for...     

Comparative lipidomic analysis of inflammatory mediators in the aqueous humor and tear fluid of humans and rabbits

Metabolomics - Alopecia areata is a well-known autoimmune disease affecting humans. Polyamines are closely associated with proliferation and inflammation, and steroid hormones are involved in...     

Diversity of Physiological and Biochemical Characters of Microdochium Fungi

The biological characterization of Microdochium majus, M. nivale, and M. seminicola strains with wide geographical origins showed the diversity of their pathogenic properties and metabolite compounds, allowing them to exist in their habitats. Significant differences in the ability of Microdochium fungi to cause lesions on wheat and oat leaves were found. The intensity of symptoms depended on the species and substrate origin of the strains. On average M. seminicola strains were able to cause less leaf necrosis than M. majus and M. nivale. The volatile organic compound (VOC) profile of Microdochium fungi included 29 putative fungal metabolites. The spectrum of the identified VOCs in M. seminicola strains was much richer than that in M. majus and M. nivale strains. In addition, the strains of M. seminicola emitted at least six sesquiterpenes. Mycotoxin analysis by HPLC/MS/MS revealed that the analyzed Microdochium strains did not produce any toxic metabolites typically produced by filamentous fungi.     

Resistance of winter wheat varieties to tan spot in the North Caucasus region of Russia

Tan spot caused by Pyrenophora tritici-repentis (Died.) Drechsler, in recent years, occupies an increasingly large area on the territory of Russia. Due to the wide distribution and economic significance of this disease, the search for resistant plants to the pathogen is relevant. This paper presents the results of a field assessment for 2017–2019 of 34 regionally distributed winter wheat varieties of Russian selection for resistance to P. tritici-repentis in the North Caucasus region of Russia. Field resistance - the development of the disease up to 30% against the background of artificial infection for three years was shown by 20.5% of the studied varieties. Wheat varieties were assessed for resistance to isolates of tan spot identified as races 1, 3, and 4 in the greenhouse at the seedling stage. The number of resistant accessions for each race was different and ranged from 12 to 20. The 12 varieties showed resistance to race 1, 14 varieties to race 3, 20 varieties to race 4. This research showed that the resistance to tan spot of studied varieties was race-specific. A functional allele of the susceptibility gene Tsn1 to P. tritici-repentis isolates, producing the toxin Ptr ToxA, was diagnosed by PCR method. Of the analyzed 34 varieties, 13 had a dominant allele of the Tsn1 (Tsn1⁺), and 21 had a recessive allele in the tsn1tsn1 homozygous state. All Tsn1⁺ varieties, and most varieties with recessive alleles tsn1tsn1, were susceptible to tan spot in the field. Varieties Dolya, Gurt, Lebed and Sila, which showed field resistance, had the tsn1tsn1 genotype. The expected reaction of varieties with different allelic composition of the Tsn1 gene to inoculation with the isolate of race 1, according to the generally accepted model of “gene-to-gene” interaction, did not coincide with that observed in reality, which confirms the results obtained by other authors. Research results demonstrate the effect of weather conditions on the susceptibility of wheat varieties to tan spot. In years with higher humidity and higher average air temperatures, the susceptibility response to the disease was observed in more varieties than in drier years. The studies show that the main part (79.5%) of winter wheat varieties of Russian selection widely zoned in the North Caucasus region of Russia are susceptible to P. tritici-repentis. Varieties that have been resistant to the pathogen in the adult phase in the field for three years and to the pathogen races in which the recessive allele of the tsn1 gene has been identified may be of interest as sources of resistance for developing new disease-resistant varieties.     

Inhibition of ERK1/2 signaling prevents epileptiform behavior in rats prone to audiogenic seizures

It has recently been proposed that extracellular signal‐regulated kinases 1 and 2 (ERK1/2) are one of the factors mediating seizure development. We hypothesized that inhibition of ERK1/2 activity could prevent audiogenic seizures by altering GABA and glutamate release mechanisms. Krushinsky–Molodkina rats, genetically prone to audiogenic seizure, were recruited in the experiments. Animals were i.p. injected with an inhibitor of ERK1/2 SL 327 at different doses 60 min before audio stimulation. We demonstrated for the first time that inhibition of ERK1/2 activity by SL 327 injections prevented seizure behavior and this effect was dose‐dependent and correlated with ERK1/2 activity. The obtained data also demonstrated unchanged levels of GABA production, and an increase in the level of vesicular glutamate transporter 2. The study of exocytosis protein expression showed that SL 327 treatment leads to downregulation of vesicle‐associated membrane protein 2 and synapsin I, and accumulation of synaptosomal‐associated protein 25 (SNAP‐25). The obtained data indicate that the inhibition of ERK1/2 blocks seizure behavior presumably by altering the exocytosis machinery, and identifies ERK1/2 as a potential target for the development of new strategies for seizure treatment.

     

Insulin receptor-related receptor as an extracellular alkali sensor

The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family,?can be activated by alkaline media both in?vitro and in?vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.     

A new route to N(1)-5R-tetrazole complexes via azidation to nitriles coordinated to Pt(II) and Pt(IV)

New tetrazolate complexes trans-[PtCl₂(RCN₄)₂]²⁻, trans-[PtCl₄(RCN₄)₂]²⁻ with Ph₃PCH₂Ph⁺ and (CH₃)₂NH₂⁺ counterions have been obtained by azidation of nitriles coordinated to Pt(II) and Pt(IV) {trans-[PtCl₂(RCN)₂] and trans-[PtCl₄(RCN)₂] (R = Et, Ph)} and characterized. The composition and the molecular structure of the complexes obtained were established by the СHN elemental analyses, ¹Н and ¹³С NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray diffraction. The coordination of nitriles to Pt(II) and Pt(IV) is shown significantly activate the azidation: the reaction proceeds with a higher rate and at relatively low temperature compared with the classical 1,3-dipolar addition of azides to nitriles.