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Global strategies, including application of chemical plant protection products, are important in the cultivation of safe corps and preservation of human health. A promising area of preventive medicine, agronomy, agroecology and agroengineering is the optimization of methods of pesticide formulations application. The aim of the work was a hygienic assessment of the most common and latest methods of crops treatment with chemical pesticides. Results. The biological effectiveness of different types of pesticides is achieved by different application rates of the working solution. The most common method of pesticide application is spraying, which ensures the application of pesticides in the drop-liquid state and is characterized by low consumption of active substance per unit area, variablecontrolled distribution on the treatment surface, provides good adhesion and retention on facilities, allows the use of combined formulations. One of the most effective ways to minimize the negative impact of chemical plant protection products and achieve economic success is a rational approach to the choice of pesticide application, as it takes into account the hazard class of pesticides, the presence of water protection zones, the sensitivity of target crops, etc. Conclusion. Rational application of pesticides includes minimizing the overall effect of pesticides on human health and the environment and achieving high-targeted biological efficiency. Adherence to the methodology of choosing the type of pesticide application and selection of the type of spray is a key point in optimizing the rational use of chemical plant protection products, which requires a detailed study from the standpoint of both efficiency and safety. Control over compliance with the recommendations should be included in sanitary-hygienic and sanitary-ecological monitoring. [ABSTRACT FROM AUTHOR]

This work is the second part of our study to develop alternative experimental mathematic models for predecting toxicity of insecticides, where we carried out a statistical analysis and comparative estimation of the toxicometric parameters obtained experimentally and calculated according to the proposed equations. In the first stage calculations were carried out and the most reliable models were proposed. The purpose of the research is the scientific substantiation and statistical analysis of the calculation models for predicting the toxicity of insecticides of different classes. For research we took the insecticides of the following chemical classes: neonicotinoids, pyrethroids, organophosphorus compounds. Statistical analysis of the linear and nonlinear regression equations obtained for insecticides was conducted. The equations described the dependence of subthreshold doses in the chronic experiment of all insecticides, the median lethal doses at oral admission of pyrithoids and neonicotinoids from molecular weight; and toxicometry parameters of all insecticides and their individual groups (pyrithoids, neonicotinoids, organophosphorus compounds) on melting temperature and the octanol-water partition coefficient. On the basis of a comparison of the toxicometry parameters obtained experimentally (actual parameters) and calculated according to the proposed equations checking of possibility of using of the calculating models for predicting the danger of the investigated groups of insecticides was performed. For substantiated pairs of resultant and factorial variables for pyrethroids, neonicotinoids, and organophosphorus pesticides a reliable correlation was established (ractucal> rtable at p = 0.05) or trend (ractucal> rtable at p = 0.1). A good and very good consistency of the features selected for the calculations according to the Cronbach’s alpha (index ranged from 0.8 and above) was indicated. The developed algorithm makes it possible to significantly simplify the conduction of toxicological studies of the studied classes of insecticides. [ABSTRACT FROM AUTHOR]

The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient's immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based signature scores were developed to correlate systemic immunity with patient responses to different cancer treatments, including immunotherapy, prognostically and predictively. Our approach and findings illustrate the potential utility of a simple blood test as a flexible tool for stratifying cancer patients into therapy response groups based on systemic immunoprofiling., Competing Interests: Declaration of interests This research was funded by BostonGene, Corp. N.F. is the Chief Medical Officer of BostonGene, Corp., and all authors affiliated with BostonGene, Corp. were employees thereof at the time the study was performed. M.F.G., A.Bagaev, D.D., A.Z., B.S., E.T., P.T., and A.A.S. are inventors on patents related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cellular deconvolution algorithms virtually reconstruct tissue composition by analyzing the gene expression of complex tissues. We present the decision tree machine learning algorithm, Kassandra, trained on a broad collection of >9,400 tissue and blood sorted cell RNA profiles incorporated into millions of artificial transcriptomes to accurately reconstruct the tumor microenvironment (TME). Bioinformatics correction for technical and biological variability, aberrant cancer cell expression inclusion, and accurate quantification and normalization of transcript expression increased Kassandra stability and robustness. Performance was validated on 4,000 H&E slides and 1,000 tissues by comparison with cytometric, immunohistochemical, or single-cell RNA-seq measurements. Kassandra accurately deconvolved TME elements, showing the role of these populations in tumor pathogenesis and other biological processes. Digital TME reconstruction revealed that the presence of PD-1-positive CD8 + T cells strongly correlated with immunotherapy response and increased the predictive potential of established biomarkers, indicating that Kassandra could potentially be utilized in future clinical applications., Competing Interests: Declaration of interests N.F. is the Chief Medical Officer of BostonGene, Corp. and a professor at the University of Texas MD Anderson Cancer Center. A. Zaitsev, M. Chelushkin, V.Z., B.S., D.D., E. Nuzhdina, A. Bagaev, and R.A. are inventors on patent applications related to Kassandra. All other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Here, we show that Porphyromonas gingivalis ( Pg ), an endogenous oral pathogen, dampens all aspects of interferon (IFN) signaling in a manner that is strikingly similar to IFN suppression employed by multiple viral pathogens. Pg suppressed IFN production by down-regulating several IFN regulatory factors (IRFs 1, 3, 7, and 9), proteolytically degrading STAT1 and suppressing the nuclear translocation of the ISGF3 complex, resulting in profound and systemic repression of multiple interferon-stimulated genes. Pg -induced IFN paralysis was not limited to murine models but was also observed in the oral tissues of human periodontal disease patients, where overabundance of Pg correlated with suppressed IFN generation. Mechanistically, multiple virulence factors and secreted proteases produced by Pg transcriptionally suppressed IFN promoters and also cleaved IFN receptors, making cells refractory to exogenous IFN and inducing a state of broad IFN paralysis. Thus, our data show a bacterial pathogen with equivalence to viruses in the down-regulation of host IFN signaling., Competing Interests: The authors declare no competing interest.

Previous studies demonstrated that the purified endogenous inhibitor (NCX(IF)) of the cardiac Na(+)/Ca(2+) exchanger (NCX1) has the capacity to modulate cardiac muscle contractility. Here, we tested the effects of purified NCX(IF) on arrhythmias induced by ouabain in the atria and ventricle strips of guinea pig. For the sake of comparison NCX(IF) was compared to lidocaine and KB-R7943. In the ventricle strip, NCX(IF) ( approximately 10 U/ml) results in rapid, complete and stable inhibition of ouabain-induced arrhythmias (the inhibition of arrhythmia is not followed by revival of irregular contractions). Under similar experimental conditions the atria strips require somewhat higher doses of NCX(IF) (25-50 U/ml) for complete suppression of arrhythmia. In the atria strip, NCX(IF) (10-25 U/ml) increases the threshold dose (1 microM) of ouabain for arrhythmia onset 2.2+/-0.5-fold (n=5, p<0.05) as well as prolongs the lag-phase for arrhythmia appearance 4.0+/-0.5-fold (n=5, p<0.01). The lag period for arrhythmia onset was also lengthened (2.0+/-0.4-fold) by NCX(IF) in the ventricle strips (n=6, p<0.002). At low frequency of pacing (1 Hz), all three tested substances, lidocaine, KB-R7943, and NCX(IF) can effectively suppress the ouabain-induced arrhythmia. However, at higher frequency (2 Hz), lidocaine is ineffective in suppressing arrhythmia, whereas KB-R7943 becomes pro-arrhythmic. In contrast to reference drugs, NCX(IF) retains its anti-arrhythmic capacity at high frequencies, either in the atria (n=6, p<0.01) or ventricle (n=5, p<0.05) strips. In conclusion, NCX(IF) results in rapid, effective and stable suppression of arrhythmia both in the atria and ventricle preparations under conditions at which the reference drugs become ineffective.

A low molecular weight inhibitor (NCX(IF)) of the cardiac Na/Ca exchanger, isolated from the calf ventricle tissue, is capable of regulating the muscle strip's contractility and relaxation without involving the beta-activation pathway. The structural analysis of NCX(IF) requires highly purified preparations that fulfill the demanding requirements for mass spectra and NMR analyses. No such preparation is yet available. To this end, new HPLC procedures were developed by a combination of the reverse phase, normal phase, and HILIC (hydrophilic liquid chromatography) techniques. The specific activity of NCX(IF) is 10(5) times higher in the purified preparations (as compared to the crude extract) showing a 2-5% yield of total inhibitory activity and 20-100 microg content of final material. The purification yield reveals that 1 kg ventricle muscle contains 0.1-0.2 mg NCX(IF), meaning that the tissue concentrations of NCX(IF) may reach 10(-7)-10(-6) M. The diode-array scanning of purified preparations of NCX(IF) shows a homogeneous 3D peak with a maximal absorption at 202 nm. These spectral properties may represent a five-membered ring (e.g., proline, histidine) and/or simple chemical groups (like amine, carbonyl, ester, etc.), but not an aromatic ring or complex conjugates (alkyne, alkene, aldehyde, etc.). NCX(IF) does not respond to phenol/sulfur reagent, suggesting that it lacks reducing (aldo) sugar. NCX(IF) shows a faint response to fluorescamine, meaning that it may contain an amino group (or its derivative). It is believed that a combination of presently developed procedures with LC/MS and LC/MS/MS may provide a useful tool for structural analysis of NCX(IF).

The endogenous inhibitory factor (NCX(IF)) of the cardiac Na/Ca exchanger (NCX1) is a low molecular weight substance, which has a strong capacity to modulate the ventricle muscle contractility. Previously, we have shown that NCX(IF) can completely inhibit either the forward (Na(i)-dependent Ca-uptake) or reverse (Na(o)-dependent Ca-release) mode of Na/Ca exchange as well as its partial reaction, the Ca/Ca exchange. Although the preliminary studies have shown that NCX(IF) can rapidly (within few milliseconds) interact with a putative inhibitory site of the Na/Ca exchanger protein (or within its vicinity), it was not clear whether the NCX(IF) can directly interact with the ion transport sites of the exchanger protein or the interaction site of NCX(IF) is distinct from the ion-binding/transport site of NCX1. In order to segregate between these possibilities the NCX(IF) was tested for its capacity to compete with Ca at the cytosolic side by using the preparation of sarcolemma vesicles having predominantly the inside-out orientation. For this goal, the initial rates of Na(i)-dependent (45)Ca-uptake were measured in the presence of extravesicular (cytosolic) NCX(IF) under conditions in which the concentration of extravesicular Ca was varied (2-200 microM) and intravesicular Na was kept fixed at saturating concentration (160 mM). Under these conditions the NCX(IF) results in several fold decrease in V(max) values, while having no significant effect on the K(m). Taking into account the molecular weight of 350-550 Da (derived from the gel-filtration and mass-spectra data), the experimentally measured inhibitory potency of NCX(IF) can be estimated as the IC(50) = 0.3-0.6 microM. Therefore, it is concluded that the NCX(IF) is reasonably potent blocker, which interacts with cytosolic domain thereby preventing the ion-translocation (and not ion-binding) events.

Recently, an endogenous inhibitory factor (NCXIF) of the cardiac Na/Ca exchanger (NCX1) has been isolated, purified, and preliminary characterized. Here, we demonstrate that low doses of NCXIF (10(-7)10(-8) M) induce strong inotropic effects in the guinea and rat ventricle strips, while having no detectable effects in the atria even at 10(-5) M. The inotropic effects of NCXIF are species-specific; the rat ventricle muscle is 20 to 50 times more sensitive to varying doses of NCXIF than the guinea pig. On the other hand the extent of maximal inotropic response is more prominent in the guinea pig model (up to 6-fold enhancement) than in the rat (up to 2-fold enhancement). The NCXIF accelerates the single-twitch relaxation (lusitropic effect) in dose-dependent manner, reaching approximately 2-fold shortening of twitch width at saturating doses. The dose-dependence curves of lusitropic and inotropic effects exhibit a reciprocal relationship, meaning that these two effects might share common mechanisms. To test a possible involvement of catecholamines, the effects of NCXIF were examined in the presence or absence of beta-adrenergic blocker, deralin. The saturating doses of deralin (1- 3 microM) do not alter either the NCXIF-induced acceleration of relaxation or twitch enhancement, meaning that the NCXIF effects cannot be mediated by occasional release of endogenous catecholamines. The capacity of NCXIF to modulate the ventricle contractility unconnectedly to the beta-adrenergic activation may provide new rational clues for future pharmacological interventions.

In our previous study, we ware successful in isolation and purification of an endogenous inhibitor of the Na/Ca exchanger (NCX1) from the calf ventricle extracts. The purified factor has characterized to have strong positive inotropic effect on isometric contractions of isolated ventricle strips of guinea pig. A possibility is that besides the NCX1 the endogenous factor may also interact with other ion-transport systems (e.g., Na,K-ATPase) involved in modulation of muscle contractility-relaxation. Therefore, a primary goal of the present study was to detect a possible effect of newly found NCX1 inhibitor on Na,K-ATPase and Ca-ATPase activities. The preparations of isolated sarcolemma vesicles were used for this goal. Although the crude extracts of calf ventricles can inhibit both the Na/Ca exchange and Na,K-ATPase, these two inhibitory activities can be separated on the Sephadex G-10 column, meaning that different molecular entities might be responsible for inhibition of Na/Ca exchange and Na,K-ATPase. Addition of 100 U of purified endogenous factor to the assay medium results in nearly complete inhibition of forward (Na(i)-dependent Ca-uptake) and reverse (Na(o)-dependent Ca-efflux) modes of Na/Ca exchange. On the other hand, no effect was detected on activities of Na,K-ATPase and Ca-ATPase even in the presence of 500 U of purified factor in the assay medium. In light of the present data, it is concluded that the endogenous inhibitor of NCX1 does not resemble the targeting properties of digitalis like compound. Obviously, more systematic studies are required in the future for resolving a possible interaction of the endogenous inhibitor of NCX1 with other ion-transport systems involved in calcium homeostasis and action potential.

The cardiac sarcolemma Na/Ca exchanger is a key system for controlling the intracellular calcium levels during the excitation-contraction coupling. Here, we test the hypothesis that the heart tissue contains a putative endogenous factor having a capacity to modulate the Na/Ca exchanger and muscle contractility. The concentrated cardiac extracts inhibit the Na(i)- or Ca(i)-dependent (45)Ca uptakes in isolated cardiac sarcolemma vesicles as well as the Na(o)-dependent Ca efflux, monitored by extravesicular Ca probe fluo-3. The inhibitory activity has been purified approximately 2000-fold by normal and reversed-phase HPLC procedures. The inhibitory activity is eluted from the Sephadex G-10 in the range of 350-550 Da, suggesting that the inhibitory factor is a low-molecular-weight substance. The mass spectra analysis shows a number of signals within m/z 380-560; however, it is not clear at this moment whether these recordings represent the mass of putative inhibitory factor or irrelevant impurities. The endogenous inhibitory factor of Na/Ca exchange does not resemble the properties (HPLC retention time, mass spectra, amino acid analysis, etc.) of autoinhibitory XIP peptide. The addition of inhibitory factor to muscle strip of guinea pig ventricles induces 2- to 5-fold enhancement of isometric contractions, thereby exhibiting a strong positive inotropic effect. This effect is a dose-dependent phenomenon, which can be reversed by washing the inhibitory factor from the organ bath. Assuming a molecular weight of 350-550 Da, the effective concentrations of putative inhibitor must be <10(-6) M. Therefore, the present findings demonstrate that the mammalian heart contains a low-molecular-weight factor that can inhibit Na/Ca exchange and enhance the cardiac contractility., (Copyright 2000 Academic Press.)

An E. coli strain producing only a thermostable toxin (ST) and belonging to serogroup 0153 (ETEC 0153; ST) was isolated from the stools of 9 infants with diarrhea, 4 of them premature, during the last half of August, 1988. All the 4 prematures passed frequent fluid stools. In 5 of the 9 infants, other pathogens were found in addition to the ETEC strain, including rotavirus, Plesiomonas and Shigella sonnei. Until recently, ETEC strains like that described were considered rare all over the world. During the past 2 years ETEC strains belonging to that serogroup and toxin type were reported as a major cause for infantile diarrhea in Spain in 5 outbreaks. Infantile diarrhea caused by an ETEC strain in Israel is reported here for the first time.

Urolesan was used in the treatment of patients with chronic ischemic heart disease. It was established that urolesan favours improvement of the state of the vascular component of microcirculation, aggregation of erythrocytes, increase of the peripheral circulation, normalization of the blood coagulation system, optimization of external respiration, normalization of the activity of serum aminotransferases. These changes were particularly pronounced in exertion stenocardia.