Duodenase, a serine protease from bovine duodenum mucosa, was located in endoplasmic reticulum, the Golgi secretory granules of epithelial cells and ducts of Brunner's glands by the A‐gold ...immunocyto‐chemical method. Duodenase exhibits trypsin‐like and chymotrypsin‐like specificities with a preference for substrates having lysine at the P1 and proline at the P2 positions. The kinetic constants for the hydrolysis of 21 potential duodenase substrates are reported. The best substrates were found to be α‐N‐tosylglycylprolyllysine 4‐nitroanilide (kcat/Km of 35 000 M−1 s−1), α‐N‐succinylthreonylprolyllysme 4‐nitroanilide (kcat/Km of 18000 M−1 s−1) and α‐N‐serylprolyllysine 4‐nitroanilide (Kcat/km of 2600 M−1 s−1), all of which contain the P1–P3 sequence of the enteropeptidase zymogen/activation site. On the basis of its catalytic properties and sites of localization, duodenase has been postulated to be an activator of the enteropeptidase precursor. A tetradecapeptide (LVTQEVSPKIVGGS) having the P9‐P5'sequence of the cleavage site of zymogen activation of bovine proenteropeptidase was synthesized, and kinetic parameters of its hydrolysis by duodenase were determined (Km of 87 μ; kcat of 1.4 s−1; kcat/Km of 16000 M−1 s−1). Crystals of duodenase frozen in a stream of liquid nitrogen diffracted synchrotron X‐rays to 0.2‐nm resolution.
The modification of Bowman-Birk soybean protease inhibitor (BBI) with the monoaldehyde derivative of block copolymer of ethylene oxide and propylene oxide (PE), M(r) 2,000 is described. The conjugate ...contains five covalently bound polymer chains per protein molecule, and retains the ability to inhibit trypsin and chymotrypsin-like proteinases. The distribution of native BBI and the BBI-PE conjugate was examined in mice. After i.v. injection of 125IBBI and 125IBBI-PE, both inhibitors distributed very rapidly to the liver, kidney, and lungs, and more slowly to the brain. At the same time-points (up to 24 h), radioactivity in the blood and organs of mice injected with modified inhibitor was higher than that of the native inhibitor. The blood concentration time profile following i.v. administration of two BBI preparations at a dose 3 mg/kg was reasonable well described by a two-compartment open model with first-order elimination kinetics. The total clearance of BBI-PE decreased by a factor of 8, body mean residence time increased by a factor of 5 in comparison with BBI. A physiological pharmacokinetic model was developed to describe the tissue-to-blood distribution of two inhibitors. One-compartment physiological organ model (flow limited) was used to describe of time-course profiles of BBI concentration in organs. A two-compartment physiological organ model (membrane limited) was used to predict tissue-to-blood distribution of conjugated BBI in some organs of mice (liver, lungs). The predicted concentration curves of BBI and BBI-PE in blood and organs in mice (with the exception of kidney) showed good agreement with the observed values.
We study the decay phase of solar flares in several spectral bands using a method based on that successfully applied to white light flares observed on an M4 dwarf. We selected and processed 102 ...events detected in the Sun-as-a-star flux obtained with SDO/AIA images in the 1600~Å and 304~Å channels and 54 events detected in the 1700~Å channel. The main criterion for the selection of time profiles was a slow, continuous flux decay without significant new bursts. The obtained averaged time profiles were fitted with analytical templates, using different time intervals, that consisted of a combination of two independent exponents or a broken power law. The average flare profile observed in the 1700~Å channel decayed more slowly than the average flare profile observed on the M4 dwarf. As the 1700~Å emission is associated with a similar temperature to that usually ascribed to M dwarf flares, this implies that the M dwarf flare emission comes from a more dense layer than solar flare emission in the 1700~Å band. The cooling processes in solar flares were best described by the two exponents model, fitted over the intervals t1=0, 0.5\(t_{1/2}\) and t2=3, 10\(t_{1/2}\) where \(t_{1/2}\) is time taken for the profile to decay to half the maximum value. The broken power law model provided a good fit to the first decay phase, as it was able to account for the impact of chromospheric plasma evaporation, but it did not successfully fit the second decay phase.
Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other ...solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. ...The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.
Abstract
We present multi-epoch optical spectra of the
γ
-ray bright blazar 1156+295 (4C +29.45, Ton 599) obtained with the 4.3 m Lowell Discovery Telescope. During a multiwavelength outburst in late ...2017, when the
γ
-ray flux increased to 2.5 × 10
−6
phot cm
−2
s
−1
and the quasar was first detected at energies ≥100 GeV, the flux of the Mg
ii
λ
2798 emission line changed, as did that of the Fe emission complex at shorter wavelengths. These emission-line fluxes increased along with the highly polarized optical continuum flux, which is presumably synchrotron radiation from the relativistic jet, with a relative time delay of ≲2 weeks. This implies that the line-emitting clouds lie near the jet, which points almost directly toward the line of sight. The emission-line radiation from such clouds, which are located outside the canonical accretion-disk related broad-line region, may be a primary source of seed photons that are up-scattered to
γ
-ray energies by relativistic electrons in the jet.
Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete ...nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor ...microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME, angiogenesis, and intratumoral metabolism. Targeting of tumor-promoting SRs can be a promising therapeutic approach in anti-cancer therapy. In our review we provide evidence for both tumor supporting and tumor inhibiting functions of scavenger receptors expressed on TAMs. We focused on the key differences in the prognostic and functional roles of SRs that are specific for cancer types. We highlighted perspectives for inhibition of tumor-promoting SRs in anti-cancer therapy.
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