Temperature anomalies of oscillating diffusion in ac-driven periodic systems.

We analyze the impact of temperature on the diffusion coefficient of an inertial Brownian particle moving in a symmetric periodic potential and driven by a symmetric time-periodic force. Recent studies have revealed the low-friction regime in which the diffusion coefficient shows giant damped quasiperiodic oscillations as a function of the amplitude of the time-periodic force [I. G. Marchenko et al., Chaos 32, 113106 (2022)1054-150010.1063/5.0117902]. We find out that when temperature grows the diffusion coefficient increases at its minima; however, it decreases at the maxima within a finite temperature window. This curious behavior is explained in terms of the deterministic dynamics perturbed by thermal fluctuations and mean residence time of the particle in the locked and running trajectories. We demonstrate that temperature dependence of the diffusion coefficient can be accurately reconstructed from the stationary probability to occupy the running trajectories.

Giant oscillations of diffusion in ac-driven periodic systems.

We revisit the problem of diffusion in a driven system consisting of an inertial Brownian particle moving in a symmetric periodic potential and subjected to a symmetric time-periodic force. We reveal parameter domains in which diffusion is normal in the long time limit and exhibits intriguing giant damped quasiperiodic oscillations as a function of the external driving amplitude. As the mechanism behind this effect, we identify the corresponding oscillations of difference in the number of locked and running trajectories that carry the leading contribution to the diffusion coefficient. Our findings can be verified experimentally in a multitude of physical systems, including colloidal particles, Josephson junction, or cold atoms dwelling in optical lattices, to name only a few.

Bedaquiline for multidrug-resistant TB in paediatric patients.

BACKGROUND: TMC207-C211 (NCT02354014) is a Phase 2, open-label, multicentre, single-arm study to evaluate pharmacokinetics, safety/tolerability, antimycobacterial activity and dose selection of bedaquiline (BDQ) in children (birth to <18 years) with multidrug-resistant-TB (MDR-TB).METHODS: Patients received 24 weeks' BDQ with an anti-MDR-TB background regimen (BR), followed by 96 weeks of safety follow-up. Results of the primary analysis are presented based on data up to 24 weeks for Cohort 1 (≥12-<18 years; approved adult tablet at the adult dosage) and Cohort 2 (≥5-<12 years; age-appropriate 20 mg tablet at half the adult dosage).RESULTS: Both cohorts had 15 patients, of whom respectively 53% and 40% of Cohort 1 and Cohort 2 children had confirmed/probable pulmonary MDR-TB. Most patients completed 24 weeks´ BDQ/BR treatment (Cohort 1: 93%; Cohort 2: 67%). Geometric mean BDQ area under the curve 168h values of 119,000 ng.h/mL (Cohort 1) and 118,000 ng.h/mL (Cohort 2) at Week 12 were within 60-140% (86,200-201,000 ng.h/mL) of adult target values. Few adverse event (AE) related discontinuations or serious AEs, and no QTcF >460 ms during BDQ/BR treatment or deaths occurred. Of MGIT-evaluable patients, 6/8 (75%) Cohort 1 and 3/3 (100%) Cohort 2 culture converted.CONCLUSION: In children and adolescents aged ≥5-<18 years with MDR-TB, including pre-extensively drug-resistant-TB (pre-XDR-TB) or XDR-TB, 24 weeks of BDQ provided a comparable pharmacokinetic and safety profile to adults.

Mechanism of caspase-2 activation upon DNA damage.

The mechanism of caspase-2 activation in response to DNA damage was studied using human ovarian cancer cells Caov-4 treated with chemotherapeutic agent cisplatin. It was shown that mutations of the three cleavage sites of caspase-2 do not affect the assembly of the macromolecular complex of caspase-2 and its activation, but, conversely, stabilize this complex, most likely, via the inhibition of the dissociation of the active caspase-2.

Discovery of Novel Isatin-Based p53 Inducers.

A series of isatin Schiff base derivatives were identified during in silico screening of the small molecule library for novel activators of p53. The compounds selected based on molecular docking results were further validated by a high-content screening assay using U2OS human osteosarcoma cells with an integrated EGFP-expressing p53-dependent reporter. The hit compounds activated and stabilized p53, as shown by Western blotting, at higher rates than the well-known positive control Nutlin-3. Thus, the p53-activating compounds identified by this approach represent useful molecular probes for various cancer studies.

Annual risk of tuberculous infection measured using serial skin testing, Orel Oblast, Russia, 1991-2005.

OBJECTIVE: To compare trends in direct annual risk of tuberculous infection (ARTI) during 1991-2005 in relation to tuberculosis (TB) incidence and to indirect estimates of ARTI derived from the prevalence of tuberculin skin test (TST) positivity in schoolchildren in Orel Oblast, Russia. DESIGN: In 2005, we abstracted annual TST results and vaccination histories from a representative sample of schoolchildren in Orel Oblast, Russia, where bacille Calmette-Guerin (BCG) vaccination and annual TST of children are nearly universal. We calculated direct ARTI based on the percentage of children tested with TST conversions each year, excluding conversions following BCG vaccination. RESULTS: We analysed records from 13 206 children, with a median of 10 recorded TST results per child. The ARTI increased from 0.2% in 1991 to 1.6% in 2000, paralleling trends in TB incidence. Similar results were observed when the ARTI was estimated based on prevalence of infection among children aged 3-5 years using a 12 mm cut-off to define TST positivity. Results differed substantially when 10 or 15 mm cut-offs were used or when prevalence was determined among children aged 6-8 years. CONCLUSION: ARTI measured through TST conversion increased as TB incidence increased in Orel Oblast. ARTI measured through serial TSTs can thus provide an indicator of changing trends in TB incidence.

[Characteristics of lung foci revealed by computed tomography in high-risk children and adolescents for tuberculosis].

OBJECTIVE: To give an X-ray pattern of single lung foci revealed by computed tomography (CT) in children and adolescents examined for tuberculosis. MATERIAL AND METHODS: The results of CT in 52 children and adolescents infected by Mycobacterium tuberculosis were analyzed. All the followed up children and adolescents underwent X-ray study using a two-slice spiral Somatom Emotion Duo (Siemens). The study used first the conventional chest spiral CT scanning procedure for children according to the Thorax Routine program and then reconstruction. Target spiral scanning of the area of interest was, if needed, carried out by employing high resolution CT with 2-mm thick images taken at 1.5-mm spacing. A maximal intensity project program was used to separate vessels and foci. RESULTS: The single foci were encountered frequently in the lung of the examinees and characterized by a perilymphatic site; in 88.0% they were connected with the interlobular interstitium, interlobar fissure, and paracostal pleura; in 92.2% the foci were detectable in the subpleural and cortical parts of the lung, had a moderate intensity, well-defined outlines, and were 2-6 mm in size. At the same time, there were no pathological changes in the lymph nodes of the lung roots and mediastinum. The long-term (2-month-to-5-year) followup in this group of children indicated that there were no X-ray changes in the lung foci revealed by CT. CONCLUSION: The single foci in the lung of Mycobacterium tuberculosis-infected children without X-ray changes in the lymph nodes of the lung roots and mediastinum may be manifestations of the normal lung structure--these may be intrapulmonary lymph nodes. Further follow-up in this group of these children must be in agreement with the management tactics of those infected with Mycobacterium tuberculosis.

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress.

During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.

[Radiological control of silvicultural production in Perm Krai].

Results of the studies carried out in 2009-2012 on the 137Cs content in edible fungi, berries and fruits of wild-growing bushes and the low shrubs growing in forest ecosystems of a number of regions of the Perm Krai are presented. It is shown that the activity of radio caesium in the studied samples does not exceed the maximal allowed levels approved in the Russian Federation.

[The concentration of procalcitonin in blood andi enteric exudation in patients at early post-operation period].

The study sampling included 46 patients operated on the occasion of acute surgical pathology of abdominal organs. The concentration of procalcitonin was analyzed at 2-3 days after operation in simultaneously obtained samples of blood serum and exudation of small intestine. The level of procalcitonin was analyzed using enzyme-linked immunosorbent assay with test-systems with sensitivity 0.01 ng/ml. The concentration of procalcitonin in content of small intestine was lower than in blood serum (p<0.001) and in most samples of enteric exudation (n=33) did not exceed 0.01 ng/ml. The analysis of correlation interdependences established that concentration of procalcitonin in intestinal exudation has no dependencies with its level in blood serum. The admixture of blood as a result of traumatization of mucous membrane under application of naso-jejunal probe is one of main causes of occurrence of procalcitonin in content of intestine.

miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress.

The tumour suppressor p53 is a crucial regulator of cell cycle arrest and apoptosis by acting as a transcription factor to regulate a variety of genes. At least in part, this control is exerted by p53 via regulating expression of numerous microRNAs. We identified two abundantly expressed microRNAs, miR-16 and miR-26a, whose expression is regulated by p53 during the checkpoint arrest induced by the genotoxic drug, doxorubicin. Importantly, among the targets of these miRs are two critical checkpoint kinases, Chk1 and Wee1. The p53-dependent augmentation of miR-16 and miR-26a expression levels led to the cell cycle arrest of tumour cells in G1/S and increased apoptosis. Strikingly, the bioinformatics analysis of survival times for patients with breast and prostate cancers has revealed that co-expression of mir-16 and miR-26a correlated with a better survival outcome. Collectively, our data provide a novel mechanism whereby p53 represses Chk1 and Wee1 expression, at least partially, via upregulation of miR-16 and miR-26a and thus sensitizes tumour cells to genotoxic therapies.

[Cytogenetic profile in patients with primary myelodysplastic syndrome].

AIM: To analyze the prevalence of chromosome aberrations presented in the revised International Prognostic Scoring System (R-IPSS) in patients with de novo myelodysplastic syndrome (MDS). Subjects and methods. Chromosome aberrations were analyzed in 197 patients aged 14 to 86 years (median age 64 years) with de novo MDS. RESULTS: Karyotype abnormalities were revealed in 129 (65.5%) patients with de novo MDS. According to the IPSS criteria, the karyotypes found 52 (26.4%) patients were assigned to an intermediate prognostic group whereas in accordance with the R-IPSS guidelines, an intermediate karyotype group included chromosome abnormalities in 32 (16.2%) patients. Out of 5 R-IPSS prognostic types, the favorable karyotype group was the largest (48.2%). The very favorable and unfavorable karyotype groups comprised few patients with MDS: 3 and 3.6%, respectively. Despite the fact that it was not mentioned in the R-IPSS, a monosomal karyotype was verified in 24 (12.2%) patients There was a correlation of the (normal and complex) karyotype with bone marrow blast counts (r=0.469; p=0.000), but not with age. CONCLUSION: A variety of cytogenetic damages cannot identify the prognostic potential of all chromosome aberrations occurring in patients with MDS even if prognostic factors increased up to 5.

[Viral and drug-induced liver damage in children with tuberculosis: prevalence, clinical features].

UNLABELLED: THE AIM OF THE RESEARCH: Improving the effectiveness of diagnostics and treatment of viral and drug-induced lesions of the liver (DILL) at a tuberculosis in children by identifying the frequency of their distribution, peculiarities of diagnostics and clinics. MATERIALS AND METHODS: We examined 242 children in the age from 2 months to 17 years, the patients with different forms of tuberculosis. RESULTS: The prevalence of hepatitis in children with tuberculosis: B - 1,2%, C-0.4%, G - 4,6%, TT - 8,7%. DILL was diagnosed in 67.5% of children - TB patients, in 48% of the children with DILL an asymptomatic course of the disease was noted, however, in 54.4% of the children with DILL cytolitic syndrome was expressed (ALT> standards). CONCLUSION: The prevalence of viral hepatitis B and C among children with TB is low. The infection with viruses of hepatitis G and TT is more often, but has no significant impact as on the course of tuberculosis, and on the severity of the liver damage. Drug-induced liver damage is a dominant view of pathology of the liver in children - TB patients and is mostly asymptomatic, but with a pronounced cytolitic syndrome.

[Caspase-2: what do we know today?].

Apoptosis (programmed cell death) is essential machinery for multicellular organisms. Apoptosis plays an important role in cell differentiation, damaged cell elimination and immune system homeostasis. This review is focused on various mechanisms of signal transduction through caspase-2 which believed to be one of the most enigmatical protease involved in apoptosis. Caspase-2 is activated upon stimulation by such agents as genotoxic stress, death receptors ligation, ER stress, metabolic changes, etc. In addition, caspase-2 may act as a tumor suppressor and has been implicated in cell response to oxidative stress and neurodegenerative progression during ischemic brain damage. Thus, variety of signal pathways triggered by caspase-2 place this protease apart from other members of the family and suggests a prominent role in apoptosis. Here, we analyse different functions of this unique caspase and discuss possible applications of accumulated knowledge in advanced oncology and medicine.

[The role of immunodeficiencies in development of complications during vaccination of children with BCG vaccine].

AIM: Study of the interrelation between the presence of immune deficiency and development of complications during vaccination of newborns with BCG vaccine. MATERIALS AND METHODS: In 24 children with complications of vaccine process in the form of cold abscess and lymphadenitis indicators of lymphocyte subpopulation levels were studied by flow cytofluorimetry on Beckman Coulter cytofluoriemter by using monoclonal antibodies with markers CD45+CD3+ - T-cell, CD45+CD3+CD4+ - T-helpers, CD45+CD3+CD8+ - T-supressors-cytotoxic killers, CD45+CD3 CD16+CD56+ - natural killers, CD45+CD3-CD19+ - B-lymphocytes. The level of IgG, IgA, IgM in sera was determined by immune diffusion method in agar by Mancini. RESULTS: In 4 children selective deficiency of IgA, in 5 - hyper-IgM syndrome was detected, which is an innate immunodeficiency and is characterized by the lack of sera IgA, reduction of IgG level and increase of IgM. In 9 children a reduction of CD16+ natural killer lymphocytes was detected, in some cases combined with a reduction of CD8+ T-supressors-cytotoxic killers. CONCLUSION: The reason of development of complications during BCG administration is the presence of immunodeficiency in children. In these children severe course of the vaccine process, presence of axillary lymphadenitis was observed, therapy of these children continued from 4 to 6 months.

[Novel splicing isoform of actin-binding protein alpha-actinin 4 in epidermoid carcinoma cells A431].

Alpha-actinin 4 (ACTN4) belongs to actin binding proteins of the spectrin superfamily. Structural organisation of actin fibres and focal contacts is considered to be its primary function in a cell. Besides that, nucleocytoplasmic shuffling of ACTN4 and its involvement in nuclear processes were demonstrated. Lately, additional isoforms of ACTN4 resulted from an alternative splicing has been described in various cell types and malignant tumours. In this study, we present investigation of a novel ACTN4 isoform of 80 kDa. The isoform was found in human epidermoid carcinoma cells A431, and it was not detected in human skin fibroblasts, normal human keratinocytes and transformed human embryonic cells HEK293T. Analysis of ACTN4 mRNA in A431 cells showed the presence of a splice variant that lacked the exons 2-8. The deleted exons code two calponin homology domains responsible for ACTN4 binding to F-actin. Intracellular distribution of the described ACTN4 isoform (ACTN4ISO) overexpressed in HEK293T cells differed from that of the full size protein. In the cytoplasm, ACTN4ISO was allocated diffusively with no colocalisation with actin cytoskeleton structures. Intranuclear distribution of ACTN4ISO also differed from that of the full size ACTN4. Nevertheless, immunochemical analysis demonstrated possibility of ACTN4ISO to form heterodimers with the full size protein. Additional investigations of novel isoform interactions with ACTN4 protein partners might clarify its functional features in A431 cells.

[Age-specific characteristics of acute myeloid leukemia karyotype].

AIM: To study distribution of some karyotype variants among patients of different age with acute myeloid leukemia (AML). MATERIAL AND METHODS: Distribution of balanced, normal, unbalanced, complex and monosomic karyotype among 244 patients with de novo AML in age groups 16-20, 21-30, 31-40, 41-50, 51-60, 61 and older was analysed. RESULTS: There is difference in frequency of balanced and complex karyotype in patients under and over 60 years. Number of AML patients with balanced aberrations including favourable variants t(8;21), t(15;17) and inv(16) falls after 60 years of age (6.7% versus 15.0% in patients aged 16-20 years; p < 0.001), while a complex karyotype occurs more frequently in AML patients at the age of 61 and older (56.8% versus 2.7% in the group 16-20 years; p < 0.001). With age, more frequently detected is the most unfavourable monosomic karyotype with aberrations similar to those in myelodysplastic syndrome (57.1% in patients aged 16-60 years and in 80.0% in the group of 61 years of age and over). CONCLUSION: Age-specific karyotype features detected may be explained by different biological mechanisms involved in leukosogenesis in young and elderly AML patients.

[The nosological structure of mortality of low-weight fetuses in Novosibirsk].

The nosological structure of mortality was studied among low-weight fetuses, by analyzing 667 autopsy protocols over 2006-2008. There were 255 cases of spontaneous miscarriage and 412 cases of medically indicated abortion. Spontaneous and artificial abortions most frequently occur in repeated pregnant women at 26-27 weeks gestational age. In the nosological structure of fetal mortality, intrauterine fetal asphyxia was most commonly in spontaneous miscarriage; intrauterine pneumonias and generalized infection ranked second; in artificial abortion, the number of congenital malformations doubled and that of intrauterine fetal asphyxia reduced. In spontaneous and artificial abortions, the incidence of decompensated chronic placental insufficiency increased by twice.

[The nosological structure of congenital fetal malformations in Novosibirsk].

The authors comparatively studied the nosological structure of congenital malformations (CM) in 395 fetuses at 22-27 weeks post-conception age and the efficiency of prenatal diagnosis in Novosibirsk. They analyzed 227 and 168 autopsy protocols of fetuses with CM over the periods from 2000 to 2002 and from 2006 to 2008, respectively. In the nosological structure of mortality among low-weight fetuses, CM ranked third in 2000-2002 and second in 2006-2008. During all the observation periods, the structure of CM showed 4 major systemic CMs: multiple anomalies of development, the central nervous and urogenital systems, heart, and vessels; multiple CMs occupying a prominent place. There was a preponderance of hydrocephalus and spinal hernias among central nervous system CMs, that of hydronephrosis with megaureter among urogenital CMs, and that of ventricular septal defect among CMs of the heart and vessels. The efficiency of prenatal diagnosis in the above observation periods was 46-75%.

[A case of neonatal galactosemia].

The paper describes a rare case of hereditary thesaurismosis, galactosemia, in a full-term neonate girl aged 12 days with morphologically verified fetal giant-cell cholestatic hepatitis with the development of ascitis and jaundice.