Genotypic and phenotypic characteristics of <i>Mycobacterium tuberculosis</i> drug resistance in TB children

Background. Russian Federation is included in the list of 30 countries with the highest burden of tuberculosis, including MDR tuberculosis. The most important part of this problem is the primary MDR/XDR TB in children.The aim: a comparative analysis of the phenotypic and genotypic profile of drug resistance to anti-tuberculosis drugs (ATP) according to whole genome sequencing of M. tuberculosis strains from children.Materials and methods. Whole genome sequencing (WGS) results of 61 M. tuberculosis isolates from children with tuberculosis in 2006–2020 in the Russian Federation were analyzed for anti-TB drug resistance mutations, according to the WHO catalog and were compared with the results of phenotypic drug sensitivity.Results. The M. tuberculosis belonged to two genetic groups: Beijing genotype – 82 % (50/61) dominant Central Asian Russian (31/50) and B0/W148 (16/50) subtypes, and non-Beijing (Ural, S, LAM) – 18 % (11/61). Three isolates belonged to Asian Ancestral subtype (3/50). Of the 61 isolates, only 14.7 % (9/61) were sensitive to antiTB drugs, 49.2 % (30/61) were MDR and 14.7 % (9/61) were pre-XDR. Comparison of the resistance profile (MDR/pre-XDR) with genotype revealed an upward shift for Beijing isolates, in particular Beijing B0/W148 (15/16) subline compared to other Beijing (19/34) (Chi-square with Yates correction = 5.535; p &lt; 0.05) and nonBeijing (5/12) (Chi-square with Yates correction = 6.741; p &lt; 0.05) subtypes. Discrepancies between genotypic and phenotypic drug resistance profiles were found in 11.5 % (7/61) of cases.Conclusions. Based on the analysis of WGS data, the genotypic characteristics of M. tuberculosis and the most complete set of drug resistance mutations were obtained, indicating a significant prevalence in MDR and pre-XDR TB of cases caused by epidemic subtypes of Beijing (B0/W148 and Central Asian Russian). The molecular mechanisms of adaptation of M. tuberculosis to the treatment of anti-TB drugs are not unique for the child population but reflect the general processes of the spread of MDR/XDR in Russia

Understanding complex dynamics of behavioral, neurochemical and transcriptomic changes induced by prolonged chronic unpredictable stress in zebrafish

Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy. © 2020, The Author(s).The research was supported by the Russian Science Foundation (RSF) Grant 19‐15‐00053. KAD is supported by the President of Russia Graduate Fellowship, the Special Rector’s Productivity Fellowship for SPSU PhD Students, and the Russian Foundation for Basic Research (RFBR) grant 18‐34‐00996. ADP was supported by St. Petersburg University (project ID 51555422). The research team was supported by St. Petersburg State University state budgetary funds (project ID 51130521). AVK is the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC) and President of the International Stress and Behavior Society (ISBS, www.stress-and-behavior.com) that coordinated this collaborative multi-laboratory project. The consortium provided a collaborative idea exchange platform for this study. It is not considered as an affiliation, and did not fund the study. AVK is supported by the Southwest University Zebrafish Platform Construction Fund. TGA’s research is supported by the budgetary funding for basic research from the Scientific Research Institute of Physiology and Basic Medicine (AAAA-A16-116021010228-0, Novosibirsk, Russia). This study utilized equipment of the Core Facilities Centre “Centre for Molecular and Cell Technologies” of St. Petersburg State University. The funders had no role in the design, analyses, and interpretation of the submitted study, or decision to publish

Clinical significance of HIV-1 coreceptor usage

The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage

The HIV-1 transmission bottleneck

It is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient’s genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor’s general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient’s genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses

Антикризовий фінансовий менеджмент на енергетичних підприємствах як передумова інноваційної перебудови енергетичної галузі України

В умовах складності та динамічності ринку електричної енергії України, поширення кризових явищ, посилення конкуренції, складності внутрішніх бізнес-процесів виникає проблема забезпечення фінансової безпеки, інвестиційної привабливості та конкурентоспроможності підприємств енергетичної галузі. Сучасні тенденції розповсюдження кризових явищ на ринку електричної енергії обумовлюють важливість та необхідність використання інструментів антикризового управління фінансами на підприємствах, одним із яких є оцінювання їх фінансового стану. Його застосування дозволить розробити систему антикризових заходів щодо управління фінансами підприємств та забезпечити їх фінансову безпеку, інвестиційну привабливість та конкурентоспроможність в сучасних умовах господарювання. Метою даної статті є розробка методичного підходу до визначення рівня фінансового стану та глибини кризи підприємств енергетичної галузі України. В статті запропоновано методичний підхід до визначення рівня фінансового стану та глибини кризи підприємств енергетичної галузі України. Його відмінною рисою від існуючих є: встановлення нормативних значень для 22 показників фінансового стану та рівнів глибини кризи для підприємств енергетичної галузі України. Встановлено, що в сучасних умовах господарювання проблемами діяльності підприємств енергетичної галузі України є: знос основних засобів, низька ліквідність. нестача чистого оборотного капіталу, збитковість. Виявлено, що на протязі 2012-2017 рр. лише 12,20% підприємств енергетичної галузі України знаходилися у сприятливому фінансовому стані; 19,51% – у дестабілізаційному; 19,51% – у передкризовому; 14,63% – у кризовому та 34,15% – у катастрофічному. У стані кризи підприємства стають дуже чутливими до впливу негативних чинників, що формуються у внутрішньому та зовнішньому середовищах. Це, в свою чергу, впливає на вибір неефективних антикризових заходів та поглиблення кризи. Тому виникає необхідність у визначенні стану та пошуку напрямів удосконалення фінансової складової системи антикризового управління на підприємствах. Це дозволить підвищити результативність імплементації антикризових заходів в систему управління господарською діяльністю підприємств енергетичної галузі України.There is a problem for providing financial security, investment attractiveness and competitiveness of energy sector enterprises in complex and dynamic conditions of Ukrainian electricity market, gain of crisis situations, magnification of competition and complexity of internal business processes. Modern tendencies of gain the crisis situations in electric energy market are determined the importance and necessity for using the instruments of financial anti-crisis management in enterprises. One of them is estimation financial condition of enterprises. Its application will allow to develop the system of anti-crisis measures for enterprises financial management and to provide their financial security, investment attractiveness and competitiveness in modern economic conditions. The purpose of this publication is to develop the methodical approach to estimate the financial situation level and the depth crisis of energy sector enterprises in Ukraine. To achieve the purpose the following tasks were posed and solved: find the indicators of enterprise financial situation; determine normative values for financial situation indicators of energy sector enterprises in Ukraine; estimate financial situation complex integral indicator of energy sector enterprises in Ukraine; find out level and crisis type of energy sector enterprises in Ukraine. In this publication the methodical approach to determine the financial situation level and the crisis depth of energy sector enterprises in Ukraine has been proposed. Its distinctive feature from existing ones is: setting normative values for 22 financial situation indicators and crisis levels for energy sector enterprises in Ukraine. It is established that activity problems of energy sector enterprises in Ukraine are: fixed assets depreciation, low liquidity, shortage of net working capital, unprofitability. It was revealed that during 2012-2017 only 12.20% of energy sector enterprises in Ukraine were in favourable financial situation; 19.51% were in destabilization; 19.51% were in pre-crisis; 14.63% were in crisis and 34.15%were in catastrophic. The enterprises become very sensitive to negative factors effects of internal and external environment in crisis situations. It influences the choice of ineffective anti-crisis measures and deepening crisis situation. Therefore, there is advisability to estimate financial condition and to search improvement areas of financial component of enterprises anti-crisis management. This will increase effectiveness of anti-crisis measures management of energy sector enterprises in Ukraine

Calcifying Bacteria Flexibility in Induction of CaCO3 Mineralization

Microbially induced CaCO3 precipitation (MICP) is considered as an alternative green technology for cement self-healing and a basis for the development of new biomaterials. However, some issues about the role of bacteria in the induction of biogenic CaCO3 crystal nucleation, growth and aggregation are still debatable. Our aims were to screen for ureolytic calcifying microorganisms and analyze their MICP abilities during their growth in urea-supplemented and urea-deficient media. Nine candidates showed a high level of urease specific activity, and a sharp increase in the urea-containing medium pH resulted in efficient CaCO3 biomineralization. In the urea-deficient medium, all ureolytic bacteria also induced CaCO3 precipitation although at lower pH values. Five strains (B. licheniformis DSMZ 8782, B. cereus 4b, S. epidermidis 4a, M. luteus BS52, M. luteus 6) were found to completely repair micro-cracks in the cement samples. Detailed studies of the most promising strain B. licheniformis DSMZ 8782 revealed a slower rate of the polymorph transformation in the urea-deficient medium than in urea-containing one. We suppose that a ureolytic microorganism retains its ability to induce CaCO3 biomineralization regardless the origin of carbonate ions in a cell environment by switching between mechanisms of urea-degradation and metabolism of calcium organic salts