Thiazolium salt mimics the non-coenzyme effects of vitamin B1 in rat synaptosomes.

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2-14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogues of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.

THE EFFECT OF A MULTIMODAL APPROACH ON THE RESULTS OF TREATMENT IN SURGERY: INTEGRATION OF CHEMOTHERAPY, SURGERY, AND RADIOTHERAPY.

This study investigates the safety and efficacy of a multimodal approach, integrating radiotherapy, chemotherapy, and surgery for the management of cancer patients. This review systematically reviewed English-language literature from digital repositories, namely Web of Science, Scopus, Google Scholar, PubMed, and the Cochrane Library. The search strategy employed a targeted selection of keywords: "chemotherapy," "radiotherapy," "multimodal," and "surgery," encompassing publications published before January 2024. This comprehensive approach was designed to encapsulate the breadth of existing research on the integration of these therapeutic modalities in cancer treatment, ensuring a robust analysis of their collective efficacy and safety. While existing literature has examined the efficacy and safety of the multimodal approach in various cancer types, each study typically focuses on a single type, such as breast, brain, or bladder cancer. This review is distinguished by its evaluation of the approach's efficacy across different cancer types, including but not limited to breast, bladder, esophageal, salivary gland, and cervical cancers. The integration of chemotherapy, surgery, and radiotherapy emerges as the optimal strategy for cancer management, irrespective of cancer type or location. This approach is linked to the highest rates of disease-free survival, overall survival, and the lowest complication rates. However, further high-quality randomized trials are necessary to accurately assess the efficacy of this integrated approach in managing various cancer types.

[Pathogenetic aspects of the development of cholelithiasis in patients with metabolic syndrome].

Nowadays there is a steady tendency to increase the number of patients with gallstone disease and metabolic syndrome. Increasingly, gallstone disease is called a non-canonical cluster of metabolic syndrome, because the main components of metabolic syndrome are also modifiable risk factors for gallstone disease. This article discusses the pathogenetic parallels in the development of gallstone disease and metabolic syndrome - insulin resistance and hormones of adipose tissue, lipid metabolism disorders, immune factors and the cytokine system. There are described possible effects of cholecystectomy on metabolism in patients with metabolic syndrome.

Redox state of adipose tissue for patients with gastric cancer and its connection with the body mass index and distance from the tumor.

Excess body weight has been causally linked to an increased risk of different cancer types, including gastric cancer but the mechanisms underlying this relationship are not well understood. Superoxide generation rate, activity of complex I in electron transport chain of mitochondria, activity of matrix metalloproteinase (MMP-2 and 9) of adipose tissues (AT) of patients with gastric cancer in AT located adjacent to tumor (ATAT) and at a distance of 3 cm (ATD) are measured to follow the connection of the redox state with some of the microenvironment indicators (HIF-1α, CD68, Plin5), body mass index (BMI) and cancer metastasis. Superoxide generation rate in ATAT positively correlates with BMI (r = 0.59, p < 0.05) being 4 times higher than in control (p < 0.05). MMP-2, 9 activities in ATAT positively correlate with BMI (r = 0.67, p < 0.05) being 3.3-4.0 higher than in control (p < 0.05). In ATD a statistically significant increase of MMP-2 activity is found. In ATAT for the group of patients with distant metastasis (M1) the superoxide generation rate, MMP-2, 9 activities are about 2 times higher (p < 0.05) than in the subgroup without distant metastases (M0). M1 is also characterized by the increased values of HIF-1α+ (factor 1.25), CD68+ (factor 1.4) and Plin5+ (factor 2.1) compared to M0 category in tumor tissues (p < 0.05). The results can be used for better understanding the mechanism(s) of symbiosis of tumor and adipose tissues as well as serve as a basis for new therapeutic approaches.

DNA oxidation in patients with metastastic colorectal cancer: clinical significance of 8-hydroxy-deoxyguanosine as an independent prognostic factor.

Prognosis of metastatic colorectal cancer (mCRC) patients nowadays is an important subject in the field of oncology. R0-resection of colon with primary tumor and liver metastasis remains the only treatment which significantly improves survival rate. However, recent experimental data show that surgical trauma can indirectly stimulate tumor growth due to mitochondrial dysfunction and unregulated superoxide radical (O2-) generation. AIM: To study the clinical significance of 8-oxo-2'-deoxyguanosine (8-oxodGu) marker, to assess the oncological effects of warm ischemia of liver parenchyma on disease prognosis in patients with mCRC. MATERIAL AND METHODS: 69 urine 24-hour volume tests of patients with mCRC and 17 healthy individuals were studied. Urine 8-oxodGu level was measured using spectrophotometric method with pre-solid phase DNA extraction. The energy system and hepatocyte detoxification system state, levels of O2- in tumor tissue were determined using the method of electron paramagnetic resonance (EPR) and SpinTraps technology at room temperature. Experiments were carried out on a computerized EPR spectrometer RE-1307. EPR spectra were recorded at temperature of liquid nitrogen (196C) in paramagnetically pure quartz dewar on a computerized spectrometer PE-1307 with resonator H011. Error of the method of spectrum integration and spread of spectrum reproduction of one sample was not more than 3%. RESULTS: The average level of marker in healthy individuals was 0.244 day, whereas before the resection and on day 3 after the R0-resection of liver in mCRC patients was 3.42 day and 2.12 day (p < 0.05), respectively. On day 3 after the liver resection due to its metastatic lesions with a total duration of warm ischemia period < 30 min and > 30 min have had marker at level 2.108 day and 2.9883 day (p < 0.0001), respectively. The volume of metastatic tissue significantly and directly correlated with the level of urine 8-oxodGu (R2=0.54, 95% CI 0.0370.0991, p < 0.0001), also duration of surgical intervention (300 min) and duration of worm liver ischemia ( 30 min) during the surgery significantly increased urine level of 8-oxodGu (R2=0.54, 95% CI 0.001 0.004, p < 0.001). CONCLUSIONS: Warm liver ischemia (> 30 min), long-term surgical intervention ( 300 min) and metastatic tissue volume ( 12 cm3) in liver parenchyma in mCRC patients significantly increase urine 8-oxodGu levels. R0-resection of liver metastases in mCRC patients decreases urine 8-oxodGu levels already on day 3 after the surgery. 8-oxodGu is a new factor of oncological prognosis in patients with mCRC.

Colorectal Cancer and Mitochondrial Dysfunctions of the Adjunct Adipose Tissues: A Case Study.

Excess body weight has been causally linked to an increased risk of different cancer types, including colorectal cancer (CRC) but the mechanisms underlying this association are practically unknown. We investigate redox state-superoxide (SO) generation rate, activity of complex I in electron transport chain (ETC) of mitochondria and of dinitrosyl iron complexes by electron paramagnetic resonance; activity of matrix metalloproteinase (gelatinase) MMP-2 and MMP-9 by gel zymography of adipose tissues (AT) from 46 patients (64.0 ± 1.6 y.o.) with CRC (II-III stages, pT2-3N0-2M0) in the AT adjacent to tumor (ATAT) and at a distance of 3 cm from the tumor (ATD) to follow the connection of the AT redox state with some of the tumor microenvironment indicators. We have incubated the AT species with the tumor necrosis factor α (TNF-α) to follow its influence on the measured values. As a control, normal AT (NAT) obtained during the liposuction is used. Tumor-induced changes in mitochondrial ETC of ATAT, particularly for Complex I, lead to the enhanced SO generation and consequent oxidative modifications of DNA in ATAT (up to 6.1 times higher than that in NAT and 3.7 times higher than that in ATD, p < 0.05). Gelatinase activity in ATAT is significantly higher than in ATD. A considerable effect of TNF-α on ATAT and ATD (but not on NAT, i.e., only on the tissues where the reprogramming of metabolism has already occurred under the influence of tumor) manifested in increase of cellular hypoxia, gelatinase activity, and SO generation rate is observed. The results can be used for better understanding the mechanism(s) of metabolic symbiosis of tumor and AT as well as serving as a basis for new therapeutic approaches.

Rectal Cancer: Redox State of Venous Blood and Tissues of Blood Vessels from Electron Paramagnetic Resonance and Its Correlation with the Five-Year Survival.

A role of pro- and antioxidants for reducing rectal cancer (RC) incidence in operative, preoperative, and postoperative treatments is still disputable and controversial. The redox state of venous blood and tissues of blood vessels of 60 patients with RC (T2-4N0-2M0G2) and 20 donors is studied by means of the conventional and spin-trapping electron paramagnetic resonance (EPR). The intensity of the signals from ceruloplasmin (CP), transferrin (TF), and labile iron pool (LIP) at temperature T = 77 K as well as superoxide generation rate and nitric oxide (NO) levels at T = 300 K is measured. The reduced CP and TF activity and decreased NO levels increased LIP levels and superoxide-generating rates are detected in blood species. Correlation analysis for the five-year survival rate as a function of the extracted values is done. The results show that the intensities of the corresponding EPR signals from the "native" and "trapped" paramagnetic centers can be potentially used for the understanding of the molecular mechanisms underlying the RC progression and treatment.

CO-ADMINISTRATION OF LIVE PROBIOTICS WITH CHONDROPROTECTOR IN MANAGEMENT OF EXPERIMENTAL KNEE OSTEOARTHRITIS.

The aim of the study was to study the therapeutic effect of the chondroprotector and live probiotic culture on the repair of cartilage tissue of the knee joint of rats during monoiodoacetate-induced osteoarthritis. The study used 90 white male Wistar rats weighing 180-240 g, which were randomly diluted into nine groups of 10 animals each, with double control and taking into account the intact group. The animals of the therapeutic groups received the chondroprotector and the probiotic separately and alongside. Joint removing and sample preparation were carried out on the 30th day of the experiment. Histological findings of cartilage tissue of the knee joint in positive control groups did not differ from intact. Experimental osteoarthritis caused significant changes in the histoarchitectonics of the cartilaginous tissue, dystrophy of the intercellular substance, fibrosis on the cartilage surface. A separate application of the chondroprotector and probiotic had a positive effect on the prevention of cartilage destruction. Their joint administration had the most significant effect, confirming the hypothesis of the summation of the effect of drugs. Thus, the use of the chondroprotector enhances the positive effect of the probiotic microbiota in anti-inflammatory processes.

Superoxide- and NO-dependent mechanisms of antitumor and antimetastatic effect of L-arginine hydrochloride and coenzyme Q10.

AIM: To study the redox-dependent mechanism of antiradical, antitumor and antimetastatic action of L-arginine hydrochloride (L-Arg) and coenzyme Q10 (CoQ10) in vivo. MATERIALS AND METHODS: The study was performed on С(57)Вl mice with transplanted Lewis lung carcinoma treated by intraperitoneal injections of L-Arg at low or high doses (60 and 360 mg/kg body weight), CoQ10 (0.2 and 1.2 mg/kg body weight) or their combinations. Electron paramagnetic resonance was applied for analysis of mitochondrial electron transport chain, СoQ10 levels, free iron (FI), the level of NO, and the rate of superoxide radical generation. The activity of matrix metalloproteinase (MMP)-2 and -9 in tumor tissue was determined by zymography method in polyacrylamide gel. RESULTS: Administration of L-Arg at high doses caused an inhibition of tumor growth by 48 ± 8.0%, increase of superoxide radical generation rate and NO levels to a value of 1.23 ± 0.14 and 2.26 ± 0.31 nm/g tissue · min, and decreased activity of MMP-2 and -9 (3.55 ± 0.8 and 4.8 ± 1.0 r.u., respectively). Treatment with L-Arg at low doses stimulated tumor growth and increased the levels of MMP-2 and -9 activities (8.44 ± 2.7 and 9.8 ± 3.1 r.u., respectively). Administration of СoQ10 at high doses significantly decreased superoxide radical generation rate to the values of 0.44 ± 0.09 nm/g tissue · min, levels of free iron and NO, and caused tumor growth inhibition by 54 ± 11.3%. The combined use of L-Arg and СoQ10 at high doses caused tumor growth inhibition by 51 ± 7.4% compared to Lewis lung carcinoma-bearing untreated animals (p<0.05). CONCLUSIONS: Administration of L-Arg and СoQ10 caused the dose-dependent effect on the rate of generation of superoxide radicals, level of ubisemyquinone, complexes NOFeS-proteins, levels of FI and NO. L-Arg at low doses positively modulated MMP-9 activity that promoted tumor progression. Upon combined use of L-Arg and СoQ10, superoxide radicals and NO form the redox state that causes decrease of MMP-2, -9 activities with consequent inhibition of tumor invasion and metastasis.

Inflammatory Response Influences Treatment of Localized Aggressive Periodontitis.

We previously reported a systemic hyperinflammatory response to bacterial lipopolysaccharide (LPS) in children with localized aggressive periodontitis (LAP). Additionally, different levels of this response were observed within the LAP group. It is unknown whether this hyperinflammatory response influences the clinical response to periodontal treatment in these children. Therefore, the goal of this study was to evaluate the influence of LPS responsiveness present prior to treatment on the clinical response to treatment within the LAP cohort. Prior to treatment, peripheral blood was collected from 60 African American participants aged 5 to 21 y, free of systemic diseases, and diagnosed with LAP. Blood was stimulated with ultrapure LPS from Escherichia coli, and Luminex assays were performed to quantify 14 cytokine/chemokine levels. Principal component and cluster analyses were used to find patterns of cytokine/chemokine expression among participants and subdivide them into clusters. Three distinct clusters emerged among LAP participants: a high responder group (high level of response for INFg, IL6, and IL12p40), a mixed responder group (low for some and high for other cytokines/chemokines), and a low responder group (low overall cytokine/chemokine response). Periodontal clinical parameters were compared among these groups prior to and 3, 6, and 12 mo following treatment with mechanical debridement and systemic antibiotics. High responders presented the lowest reductions in clinical parameters after treatment, whereas the low responders presented the highest reductions. In our LAP participants, distinct patterns of LPS response were significantly predictive of changes in clinical parameters after treatment. Future studies are needed to evaluate the underlying mechanisms predicting the heterogeneity of LAP activity, severity, and response to treatment (ClinicalTrials.gov NCT01330719).

Disordered redox metabolism of brain cells in rats exposed to low doses of ionizing radiation or UHF electromagnetic radiation.

AIM: To investigate the changes of redox-state of mammalian brain cells as the critical factor of initiation and formation of radiation damage of biological structures in setting of continuous exposure to low doses of ionizing radiation or fractionated ultra high frequency electromagnetic radiation (UHF EMR) at non-thermal levels. MATERIALS AND METHODS: The influence of low-intensity ionizing radiation was studied on outbred female rats kept for 1.5 years in the Chernobyl accident zone. The effects of total EMR in the UHF band of non-thermal spectrum were investigated on Wistar rats. The rate of formation of superoxide radicals and the rate of NO synthesis in mitochondria were determined by the EPR. RESULTS: After exposure to ionizing or UHF radiation, the levels of ubisemiquinone in brain tissue of rats decreased by 3 and 1.8 times, respectively. The content of NO-FeS-protein complexes in both groups increased significantly (р < 0.05). In the conditions of ionizing or EMR the rates of superoxide radical generation in electron-transport chain of brain cell mitochondria increased by 1.5- and 2-fold, respectively (р < 0.05). In brain tissue of rats kept in the Chernobyl zone, significant increase of NO content was registered; similar effect was observed in rats treated with UHFR (р < 0.05). CONCLUSIONS: The detected changes in the electron transport chain of mitochondria of brain cells upon low-intensity irradiation or UHF EMR cause the metabolic reprogramming of cell mitochondria that increases the rate of superoxide radical generation and nitric oxide, which may initiate the development of neurodegenerative diseases and cancer. This article is part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

INHIBITORY POTENTIAL OF POLYHYDROXYLATED FULLERENES AGAINST PROTEIN TYROSINE PHOSPHATASE 1B.

Inhibition of PTP1B by polyhydroxylated fullerenes was studied in silico and in vitro. The enzyme kinetics in the presence of polyhydroxy small gap fullerenes showed that reciprocal value of maximum velocity non-linearly increases with increasing the inhibitor concentration. Analysis of the dose-dependent curve of PTP1B inhibition suggests an apparent positive cooperativity with involvement of at least two binding sites for the hydroxylated fullerene cages. Molecular docking calculations indicated that highly hydroxylated fullerene C60 may occupy the active site and additional allosteric binding site with similar affinity. In silico analysis of a number of fullerenols with 6, 12, 18, 24, 30, and 36 hydroxyl groups showed that the inhibitory activity may depend on the degree of hydroxylation of the nanoparticles surface. These data provide some understanding of the mechanisms of inhibitory action of fullerenols on activity of protein tyrosine phosphatases.

Influence of Periodontal Therapy on Systemic Lipopolysaccharides in Children with Localized Aggressive Periodontitis.

PURPOSE: A previous study has shown that children with localized aggressive periodontitis (LAP) demonstrate a lipopolysaccharide (LPS) hyper-responsiveness in addition to elevated levels of systemic LPS when compared to periodontally healthy children. The purpose of this study was to evaluate whether periodontal therapy modulates systemic lipopolysaccharide levels and whether these levels may influence clinical outcomes. METHODS: Peripheral blood samples and clinical parameters (probing depth [PD], clinical attachment levels [CAL], percent sites greater than four mm, bleeding on probing [BoP], and visible plaque [P]) were collected from 29 LAP patients prior to and at three, six, and 12 months following scaling and root planning and systemic antibiotics. Serum LPS levels were quantified using a chromogenic assay. RESULTS: Twenty-five patients were compliant with the prescribed antibiotic treatment and demonstrated a significant reduction in LPS as well as overall PD, CAL, and plaque at all time points post-therapy. Additionally LPS reductions correlated with reductions in PD, CAL, and plaque. CONCLUSIONS: Localized aggressive periodontitis therapy with antibiotics plays an important role in reducing systemic lipopolysaccharide levels. Since LPS is a key mediator of the LAP hyperinflammatory response, its systemic reduction is especially important for the successful management of these children.

Rotatable magnetic anisotropy in Si/SiO2/(Co2Fe)(x)Ge(1-x) Heusler alloy films.

Polycrystalline (Co2Fe)(x)Ge(1-x) Heusler alloy films are fabricated by sputtering on amorphous substrates and shown to possess three types of magnetic anisotropy. The nearly stoichiometric composition of x = 50 m.f.% shows a rectangular hysteresis loop and isotropic coercive and ferromagnetic resonance fields when the film is field-magnetized along any in-plane direction, thus predominantly possessing rotatable in-plane magnetic anisotropy. Higher-x compositions show evidence of two- and fourfold in-plane anisotropy superposed on the rotatable one. A qualitative model of the observed anisotropic magnetic properties is proposed. The model explains the rotatable anisotropy by taking into account dry friction for the in-plane rotation of the magnetization direction in a fine-grained polycrystalline film with the magnetic grain size smaller than the correlation length of the inter-grain exchange interaction. The observed two- and fourfold magnetic anisotropy contributions are attributed to partial texturing of the fine-grained films, even though the films are grown on amorphous SiO2 substrates. These results should be valuable for understanding and controlling the magnetic behaviour of highly spin-polarized Heusler alloy films used in various magnetic nanodevices.

LPS-induced inflammatory response after therapy of aggressive periodontitis.

We have reported a lipopolysaccharide (LPS)-induced hyper-inflammatory response in localized aggressive periodontitis (LAP). It is unknown whether treatment is able to modulate this LPS responsiveness. Fifty-nine individuals with LAP were treated by mechanical debridement and systemic antibiotics. Clinical parameters and cyto/chemokine responsiveness of whole blood stimulated with Porphyromonas gingivalis or Escherichia coli LPS were monitored at baseline and 3, 6, and 12 months post-treatment. Overall, clinical parameters were improved following treatment. Additionally, P. gingivalis LPS induction of eotaxin, IFNγ, IL10, IL12p40, IL1ß, IL6, IP10, MCP1, MIP1α, GM-CSF, and TNFα was significantly decreased (p < .05). Similarly, induction of eotaxin, INFγ, IL10, IL12p40, GM-CSF, and TNFα by E. coli LPS was also reduced post-treatment. These reductions correlated with decreases in clinical parameters. Importantly, these reductions in LPS responsiveness were most robust at 3 months, and some lost significance at 6 to 12 months post-treatment. In conclusion, LPS-induced hyper-inflammatory response in LAP can be partially modulated by periodontal therapy. Conversely, rebound in the hyper-responsiveness of some mediators, in the presence of improved clinical parameters, suggests that this phenotype could be partially influenced by a genetic trait and play a role in future disease recurrence (ClinicalTrials.gov, NCT01330719).

Analysis of conformational flexibility of loop 110-120 of protein tyrosine phosphatase 1B.

Conformations of the catalytic center of protein tyrosine phosphatase 1B (PTP1B) and surrounding loops are known to be important in catalysis and inhibition of the enzyme. There were 98 conformations from 88 PDB files representing PTP1B with different ligands which were analyzed to investigate the details of loop 110-120 movement and mobility of separate residues. The differences were identified by a special software tool which performs multiple comparisons of selected parts of PDB files. The conformations were divided into 6 clusters. It was found that the loop formed by residues 110-120 can be characterized by four main conformations. Predominantly, the loop 110-120 adopts the main conformation and keeps it during WPD loop movement. Three other conformations appear to be stabilized in case of closed WPD loop and seem to be favorable for PTP1B with subunit structure.

Magnetic properties of epitaxial discontinuous Fe/MgO multilayers.

We report magnetic, dynamic and transport properties of discontinuous metal-insulator multilayers Fe/MgO grown on amorphous Corning glass and single-crystalline MgO (001) substrates. The films of structure Substrate/MgO (3 nm)/[Fe (0.6 nm)/MgO (3.0 nm)] x 10 were prepared in ultra-high vacuum conditions using Pulsed Laser Deposition. It was shown that conditions of epitaxial growth are favorable for MgO substrates. As a result a substantial increase of tunneling magnetoresistance caused by spin-filtering effect was observed and reasonably theoretically explained. The value of TMR - 9.2% at room temperature in 18 kOe magnetic field is three times higher comparing to that for the samples grown on Corning glass substrates.

Discharge Identity of Medullary Inspiratory Neurons is Altered during Repetitive Fictive Cough.

This study investigated the stability of the discharge identity of inspiratory decrementing (I-Dec) and augmenting (I-Aug) neurons in the caudal (cVRC) and rostral (rVRC) ventral respiratory column during repetitive fictive cough in the cat. Inspiratory neurons in the cVRC (n = 23) and rVRC (n = 17) were recorded with microelectrodes. Fictive cough was elicited by mechanical stimulation of the intrathoracic trachea. Approximately 43% (10 of 23) of I-Dec neurons shifted to an augmenting discharge pattern during the first cough cycle (C1). By the second cough cycle (C2), half of these returned to a decrementing pattern. Approximately 94% (16 of 17) of I-Aug neurons retained an augmenting pattern during C1 of a multi-cough response episode. Phrenic burst amplitude and inspiratory duration increased during C1, but decreased with each subsequent cough in a series of repetitive coughs. As a step in evaluating the model-driven hypothesis that VRC I-Dec neurons contribute to the augmentation of inspiratory drive during cough via inhibition of VRC tonic expiratory neurons that inhibit premotor inspiratory neurons, cross-correlation analysis was used to assess relationships of tonic expiratory cells with simultaneously recorded inspiratory neurons. Our results suggest that reconfiguration of inspiratory-related sub-networks of the respiratory pattern generator occurs on a cycle-by-cycle basis during repetitive coughing.

Determination of the percolation threshold in Fe/MgO magnetic granular multilayers.

The evolution of the morphology, magnetic and transport properties of Fe(t nm)/MgO(3.0 nm) multilayers with respect to the nominal metallic layer thickness was investigated. A comparison with existing experimental data on discontinuous metal-insulator multilayers, ultrathin epitaxial Fe films on MgO substrates and granular cermet films is made. It is confirmed that the deposition conditions and the material composition play a crucial role in the percolation process. Nominal thicknesses of Fe layers at which an infinite metallic cluster is formed and the conditions for continuous Fe coverage were determined. Different methods of percolation threshold detection were analysed. We show that investigation of the temperature dependence of resistance in nanostructures could lead to an overestimation of the percolation threshold value, while magnetic measurements alone could lead to its underestimation.

[Inhibition of alkaline phosphatase by thioureido derivatives of methylenebisphosphonic acid].

A series of thioureido derivatives of methylenebisphosphonic acid were synthesized by the reaction of aminomethylenebisphosphonic acid with the corresponding isothiocyanates, and their effect on the activity of alkaline phosphatases from bovine small intestine mucosa (BSIM) and human placenta was studied. It was found that (3-phenylthioureido)methylenebisphosphonate is approximately one order of magnitude more effective in inhibiting the activity of alkaline phosphatase from BSIM than the alkyl derivatives of thioureidomethylenebisphosphonic acid with methyl, ethyl, tert-butyl, or cyclohexyl substituents. The introduction of substituents into the benzene ring of (3-phenylthioureido)methylenebisphosphonate decreased the effect of the inhibitor on the activity of the enzyme. The affinity of (3-phenylureido)methylenebisphosphonate to the alkaline phosphatase of BSIM was also weaker as compared with the corresponding thioureidomethylenebisphosphonate. The insertion of thioureidobisphosphonates into the active site of alkaline phosphatase of human placenta by the method of molecular docking indicated that the methylenebisphosphonate residue and the substituted amino groups of the inhibitor are involved in the mechanisms of complex formation with the enzyme. It is supposed that the improvement of the inhibitory activity of (3-phenylthioureido)methylenebisphosphonate toward alkaline phosphatase of BSIM is due to the additional fixation of the phenyl substituent in the active site of the enzyme.