(Aminoalkyl)diphenylphosphine sulfides: synthesis and application as building blocks in the design of multidentate ligands for cytotoxic Pd(II) complexes.

Amino-functionalized phosphoryl compounds are among the most useful molecular scaffolds in medicinal chemistry, while the potential of their thiophosphorylated analogs, especially those having an alkylamino moiety, is still uncovered. This is mainly due to the lack of convenient synthetic routes to these organophosphorus derivatives. To address this issue, we have suggested the facile approaches to α-(aminomethyl)- and substituted/unsubstituted α-(aminobenzyl)diphenylphosphine sulfides based on either the sequential transformations of (hydroxymethyl)diphenylphosphine sulfide, with the Staudinger reaction of an azide derivative as the key stage, or the addition of Ph2P(S)H to hydrobenzamides followed by the acid hydrolysis. The compounds obtained were reacted with picolinyl chloride to yield functionalized amides which readily underwent direct cyclopalladation, resulting in new representatives of non-classical N-metalated Pd(II) pincer complexes. The latter exhibit promising cytotoxic activity against several human cancer cell lines and apoptosis inducing ability along with the remarkable cytotoxic effects on doxorubicin-resistant cell sublines.

Novel Strategy in Searching for Natural Compounds with Anti-Aging and Rejuvenating Potential.

We suggest a novel approach for searching natural compounds with anti-aging and rejuvenation potential using cell cultures, with a high potential for the further in vivo applications. The present paper discusses ways of defining age for cell populations with large numbers of cells and suggests a method of assessing how young or old a cell population is based on a cell age profile approach. This approach uses experimental distributions of the cells over the cell cycle stages, acquired using flow cytometry. This paper discusses how such a profile should evolve under homeostatic maintenance of cell numbers in the proliferation niches. We describe promising results from experiments on a commercial substance claiming rejuvenating and anti-aging activity acting upon the cultures of human mononuclear cells and dermal fibroblasts. The chosen substance promotes a shift towards larger proportion of cells in synthesis and proliferation stages, and increases cell culture longevity. Further, we describe promising in vivo testing results of a selected food supplement. Based on the described concept of cell age profile and available test results, a strategy to search for natural compounds with regenerative, anti-aging and rejuvenation potential is suggested and proposed for wider and thorough testing. Proposed methodology of age assessment is rather generic and can be used for quantitative assessment of the anti-aging and rejuvenation potential of different interventions. Further research aimed at the tests of the suggested strategy using more substances and different interventions, and the thorough studies of molecular mechanisms related to the action of the substance used for testing the suggested search methodology, are needed.

Unsymmetrical Pd(II) Pincer Complexes with Benzothiazole and Thiocarbamate Flanking Units: Expedient Solvent-Free Synthesis and Anticancer Potential.

Driven by the growing threat of cancer, many research efforts are directed at developing new chemotherapeutic agents, where the central role is played by transition metal complexes. The proper ligand design serves as a key factor to unlock the anticancer potential of a particular metal center. Following a recent trend, we have prepared unsymmetrical pincer ligands that combine benzothiazole and thiocarbamate donor groups. These compounds are shown to readily undergo direct cyclopalladation, affording the target S,C,N-type Pd(II) pincer complexes both in solution and in the absence of a solvent. The solid-phase strategy provided the complexes in an efficient and ecologically friendly manner. The resulting palladacycles are fully characterized using nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy and, in one case, by single-crystal X-ray diffraction (XRD). The solvent-free reactions are additionally analyzed by powder XRD. The pincer complexes exhibit remarkable cytotoxicity against several solid and blood cancer cell lines, including human colorectal carcinoma (HCT116), breast cancer (MCF7), prostate adenocarcinoma (PC3), chronic myelogenous leukemia (K562), multiple plasmacytoma (AMO1), and acute lymphoblastic leukemia (H9), with the dimethylamino-substituted derivative being particularly effective. The latter also induced an appreciable level of apoptosis in both parental and doxorubicin-resistant cells K562 and K562/iS9, vindicating the high anticancer potential of this type of palladacycles.

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases.

Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what ARDs one can develop depending on their genetic background. Within this mainstream paradigm, we wanted to find out whether the known ARD-linked DEGs available in PubMed can reveal a molecular marker that will serve the purpose in anyone's any tissue at any time. We sequenced the periaqueductal gray (PAG) transcriptome of tame versus aggressive rats, identified rat-behavior-related DEGs, and compared them with their known homologous animal ARD-linked DEGs. This analysis yielded statistically significant correlations between behavior-related and ARD-susceptibility-related fold changes (log2 values) in the expression of these DEG homologs. We found principal components, PC1 and PC2, corresponding to the half-sum and the half-difference of these log2 values, respectively. With the DEGs linked to ARD susceptibility and ARD resistance in humans used as controls, we verified these principal components. This yielded only one statistically significant common molecular marker for ARDs: an excess of Fcγ receptor IIb suppressing immune cell hyperactivation.

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells.

Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.

Palladium(II) Pincer Complexes of Functionalized Amides with S-Modified Cysteine and Homocysteine Residues: Cytotoxic Activity and Different Aspects of Their Biological Effect on Living Cells.

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.

Global stability of an age-structured population model on several temporally variable patches.

We consider an age-structured density-dependent population model on several temporally variable patches. There are two key assumptions on which we base model setup and analysis. First, intraspecific competition is limited to competition between individuals of the same age (pure intra-cohort competition) and it affects density-dependent mortality. Second, dispersal between patches ensures that each patch can be reached from every other patch, directly or through several intermediary patches, within individual reproductive age. Using strong monotonicity we prove existence and uniqueness of solution and analyze its large-time behavior in cases of constant, periodically variable and irregularly variable environment. In analogy to the next generation operator, we introduce the net reproductive operator and the basic reproduction number [Formula: see text] for time-independent and periodical models and establish the permanence dichotomy: if [Formula: see text], extinction on all patches is imminent, and if [Formula: see text], permanence on all patches is guaranteed. We show that a solution for the general time-dependent problem can be bounded by above and below by solutions to the associated periodic problems. Using two-side estimates, we establish uniform boundedness and uniform persistence of a solution for the general time-dependent problem and describe its asymptotic behaviour.

The Effect of Cucurbit[7]uril on the Antitumor and Immunomodulating Properties of Oxaliplatin and Carboplatin.

Cucurbit[7]uril (CB[7]) is a molecular container that may form host-guest complexes with platinum(II) anticancer drugs and modulate their efficacy and safety. In this paper, we report our studies of the effect of CB[7]-oxaliplatin complex and the mixture of CB[7] and carboplatin (1:1) on viability and proliferation of a primary cell culture (peripheral blood mononuclear cells), two tumor cell lines (B16 and K562) and their activity in the animal model of melanoma. At the same time, we studied the impact of platinum (II) drugs with CB[7] on T cells and B cells in vitro. Although the stable CB[7]-carboplatin complex was not formed, the presence of cucurbit[7]uril affected the biological properties of carboplatin. In vivo, CB[7] increased the antitumor effect of carboplatin, but, at the same time, increased its acute toxicity. Compared to free oxaliplatin, its complex with CB[7] shows a greater cytotoxic effect on tumor cell lines B16 and K562, while in vivo, the effects of the free drug and encapsulated drug were comparable. However, in vivo studies also demonstrated that the encapsulation of oxaliplatin in CB[7] lowered the toxicity of the drug.

Evaluation of the Immunosafety of Cucurbit[n]uril on Peripheral Blood Mononuclear Cells In Vitro.

Cucurbiturils (CB[n]s) are nanoscale macrocyclic compounds capable of encapsulating a molecule or part of a molecule by forming host-guest complexes. Integration of drugs with CB[n] is used for the following purposes: controlling clearance; protection of the drug from biodegradation; targeted delivery to specific organs, tissues, or cells; reduction of toxicity; and improving solubility. One of the major problems encountered in the application of new drug delivery systems is lack of knowledge of their biological properties. CB[n], unlike many other often toxic nanoparticles, has extremely low toxicity, even at high doses. However, many aspects of the biological actions of these nanoscale cavitands remain unclear, including the immunotropic properties. In this study, we investigated the immunotoxicity and immunomodulation properties of CB[n]. It was found that CB[7] and CB[6] did not decrease the viability of mononuclear cells at all tested concentrations from 0.1-1 mM. Overall, the results indicated an immunomodulatory effect of different concentrations of CB[n]. In the case of a longer cultivation time, CB[n] had an immunostimulating effect, which was indicated by an enhancement of the proliferative activity of cells and increased expression of HLA-DR on lymphocytes.

Historical Persistence of Alcohol-Induced Mortality in the Russian Federations: Legacy of Early Industrialization.

AIMS: The study aims to investigate insofar regional differences in alcohol-induced mortality in Russia, which emerged during the early industrialization of the country, persisted over a prolonged period of time (from late nineteenth to early twenty-first century), surviving fundamental political and social changes Russia experienced. METHODS: Multivariate regression models with historical and contemporary data on alcohol-induced mortality in Russian regions were estimated to document the persistence of spatial patterns of mortality, as well as to identify the possible mediating variables. Numerous robustness checks were used to corroborate the results. RESULTS: Alcohol-induced male mortality in Russian regions in 1880s-1890s is significantly and strongly correlated with male mortality due to accidental alcohol poisoning in Russian regions in 2010-2012. For female mortality, no robust correlation was established. The results for male mortality do not change if one controls for a variety of other determinants of alcohol-induced mortality and are not driven by outlier regions. Consumption of strong alcohol (in particular vodka) appears to be the mediator variable explaining this persistence. CONCLUSIONS: Hazardous drinking behavioral patterns, once they emerge and crystalize during the periods of fragmentation of the traditional society and the early onsets of modernization and urbanization, can be extremely persistent. Even highly intrusive policy interventions at a later stage (like those of the Soviet government) may turn out to be insufficient to change the path-dependent outcomes.

Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defects in human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show that the transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of the protocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediate segment of the developing nephron where it is required for the elongation of Henle's loop. Finally, mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate a key role for SOX11 in normal kidney development and may suggest that variants in this gene predispose to CAKUT in humans.

Political regimes, income and health: Evidence from sub-national comparative method.

This paper investigates the effect of political regimes on healthcare outcomes with a novel approach. Instead of focusing on cross-country comparisons, like most studies do, we utilize the within-country variation of political regimes across individual regions. We use the case of the Russian Federation, where large sub-national differences exist in both health outcomes and political regimes in different provinces. General differences in sub-national politics in Russia have been subject of investigation of a large literature our paper adds to. The paper shows that the effect of political regimes on health is heterogeneous and depends on the type of health problems more salient for the region. More pluralist and competitive regimes are able to produce better results than the less competitive ones in rich regions, while in poor regions political pluralism and competition have an adverse impact on health.

Highly Cytotoxic Palladium(II) Pincer Complexes Based on Picolinylamides Functionalized with Amino Acids Bearing Ancillary S-Donor Groups.

The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl2(NCPh)2 in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based derivatives, the realization of κ3-N,N,S-coordination was supported by X-ray diffraction. The cytotoxic effects of these complexes were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The comparative studies allowed us to determine that the presence of the sulfide ancillary donor group is crucial for cytotoxic activity of this type of Pd(II) complexes. The main structure-activity relationships and the most promising palladocycles were outlined. The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can bind with DNA and inhibit topoisomerase I activity.

Stability of Ecosystems Under Invasions.

This paper considers a model of foodwebs taking into account species extinction and invasion. We show that system stability depends not only on usual parameters (mortality rates, self-limitation coefficients, and resource abundances), but also on an additional parameter ("biodiversity potential"). The main result is as follows. For foodwebs with random parameters, we obtain an estimate of probability that the foodweb exposed to invasion survives. This estimate involves different system parameters, size and its topological properties.

Differences of IL-1ß Receptors Expression by Immunocompetent Cells Subsets in Rheumatoid Arthritis.

IL-1ß is involved in the induction and maintenance of chronic inflammation in rheumatoid arthritis (RA). Its activity is regulated and induced by soluble and membrane-bound receptors, respectively. The effectiveness of the cytokine depends not only on the percentage of receptor-positive cells in an immunocompetent subset but also on the density of receptor expression. The objective of this study was to investigate the expression of IL-1ß membrane-bound receptors (IL-1R1 and IL-1R2) in terms of the percentage of receptor-positive cells and the number of receptors per cell in different subsets of immune cells in RA patients before and after a course of basic (excluding anticytokine) therapy and in healthy individuals. The resulting data indicate differences in the expression of IL-1ß receptors among T cells, B cells, and monocytes in healthy volunteers and in rheumatoid arthritis patients. The importance of determining both the relative percentage of cells expressing receptors to immunomodulatory cytokines and the number of membrane-bound receptors per cell is highlighted by evidence of unidirectional or multidirectional changing of these parameters according to cell subset and health status.

Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study.

Paroxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventy-four patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0·60% in granulocytes and 0·15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH- patients, both after first- and second-line IST: 68% vs. 45%, P = 0·0164 and 53% vs. 13%, P = 0·0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH- patients (P = 0·0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2·56, P = 0·0180) and baseline absolute reticulocyte count (ARC) ≥30 × 10(9) /l (odds ratio 5·19, P = 0·0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 × 10(9) /l showed significant distinctions for cumulative incidence of response, overall and failure-free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.

Hybrid Nanocomposites Based on Poly(3,6-dianiline-2,5-dichloro-1,4-benzoquinone): Synthesis, Structure and Properties.

Hybrid nanocomposites based on poly(3,6-dianiline-2,5-dichloro-1,4-benzoquinone) (PDACB) in salt form and graphene oxide (GO) have been obtained for the first time, and the significant influence of the preparation method on the composition and structure of nanocomposites and their functional properties has been demonstrated. Nanocomposites were prepared in three ways: via ultrasonic mixing of PDACB and GO; via in situ oxidative polymerization of 3,6-dianiline-2,5-dichloro-1,4-benzoquinone (DACB) in the presence of GO; and by heating a suspension of previously prepared PDACB and GO in DMF with the removal of the solvent. The results of the study of the composition, chemical structure, morphology, thermal stability and electrical properties of nanocomposites obtained via various methods are presented. Nanocomposites obtained by mixing the components in an ultrasonic field demonstrated strong intermolecular interactions between PDACB and GO both due to the formation of hydrogen bonds and π-stacking, as well as through electrostatic interactions. Under oxidative polymerization of DACB in the presence of GO, the latter participated in the oxidative process, being partially reduced. At the same time, a PDACB polymer film was formed on the surface of the GO. Prolonged heating for 4 h at 85 °C of a suspension of PDACB and GO in DMF led to the dedoping of PDACB with the transition of the polymer to the base non-conductive form and the reduction of GO. Regardless of the preparation method, all nanocomposites showed an increase in thermal stability compared to PDACB. All nanocomposites were characterized by a hopping mechanism of conductivity. Direct current (dc) conductivity σdc values varied within two orders of magnitude depending on the preparation conditions.

Evaluation of the Immunosafety of Cucurbit[n]uril In Vivo.

Cucurbiturils are a family of macrocyclic oligomers capable of forming host-guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as potential carriers for drug delivery. However, the immune system's interactions with different drug carriers, including cucurbiturils, are still under investigation. In this study, we focused on cucurbiturils' immunosafety and immunomodulation properties in vivo. We measured blood counts and lymphocyte subpopulations in blood, spleen, and bone marrow, and assessed the in vivo toxicity to spleen and bone marrow cells after intraperitoneal administration to BALB/c mice. When assessing the effect of cucurbit[6]uril on blood parameters after three intraperitoneal injections within a week in laboratory animals, a decrease in white blood cells was found in mice after injections of cucurbit[6]util, but the observed decrease in the number of white blood cells was within the normal range. At the same time, cucurbit[7]uril and cucurbit[8]uril did not affect the leukocyte counts of mice after three injections. Changes in the number of platelets, erythrocytes, and monocytes, as well as in several other indicators, such as hematocrit or erythrocyte volumetric dispersion, were not detected. We show that cucurbiturils do not have immunotoxicity in vivo, with the exception of a cytotoxic effect on spleen cells after сucurbit[7]uril administration at a high dosage. We also evaluated the effect of cucurbiturils on cellular and humoral immune responses. We founded that cucurbiturils in high concentrations affect the immune system in vivo, and the action of various cucurbiturils differs in different homologues, which is apparently associated with different interactions in the internal environment of the body.

Sex differences in lung cancer incidence and mortality in Russia in the light of computed tomography usage expansion: breakpoint and age-period-cohort analyses.

BACKGROUND: Russia has one of the highest lung cancer burdens globally, particularly in men. Mortality started to decline in the 1990s after the reduction in smoking prevalence. However, Russia's recent experience is largely unknown. This study aims to describe recent trends in the incidence and mortality of lung cancer in Russia along with the use of computed tomography (CT). METHODS: We obtained incidence data from national cancer reports covering 1993-2021 and mortality and population data from the Russian Fertility and Mortality Database covering 1965-2021. The number of CT scanners was obtained from the OECD. Changes in age-standardized rates (Segi-Doll, per 100,000) were assessed using segmented regression and temporal effects using age-period-cohort analysis. RESULTS: Lung cancer rates in men have been substantially higher than in women and have declined sharply since their peak in the 1990s. The latest breakpoints in incidence in women were in 2012 (95 % CI: 2000; 2014) from stagnation with an annual change of 0.7 % (-0.2; 1.5) to 3.4 % (1.6; 5.2) increase. In men, the decrease in incidence stopped in 2013 (2011; 2014) from -1.8 % (-2.1; -1.4) to 0.3 % (-0.7; 1.3). The growing number of CT scans accompanied the recent changes in incidence rates. Incidence declined sharply in 2020 in men and women. There were no substantial changes in declining mortality trends. Period effects were visible after 2012 when incidence rates increased and deviated from mortality. After accounting for the period effect, generations born after the 1950s had lower risks. CONCLUSION: Increasing lung cancer incidence rates in Russia in the late 2010s, especially in women, and the stable mortality trends could be a possible sign of diagnostic or treatment period effect. The increased use of CT should be monitored for possible benefits and harms.

Heavy Metal Ions(II) Sorption by a Cellulose-Based Sorbent Containing Sulfogroups.

This article concerns the effect of the chemical modification of short flax fiber on its sorption properties for heavy metal ions. The main purpose of the modification was to achieve the oxidation of flax cellulose with sodium metaperiodate to form dialdehyde cellulose. Additionally, the research shows the subsequent interaction of dialdehyde cellulose with 1-amino-8-hydroxynaphthalene-3,6-disulfonic acid and its transformation into a derivative capable of forming chelate complexes with heavy metal ions. Additionally, this article presents the results of equilibrium and kinetics studies of the sorption of Cu(II), Cd(II), and Fe(II) ions from aqueous solutions by primary and modified cellulose sorbents. SEM spectra indicate changes in the surface structure of the modified sorbents compared to the original one. IR spectra show the appearance of amino- and sulfogroups in short flax fibers in the process of their modification. The research revealed the efficiency of the method and the possibility of its use for the purification of aqueous solutions from heavy metal ions in industrial processes.