Common sense в моральной философии эпохи Просвещения

The Age of Enlightenment had a special meaning for the history of moral philosophy, because in this period the morality becomes a special subject of philosophic interest, philosophic concept of morality is formed. The problem of rational grounding of morality becomes a central one. The important role in this problem solving was the idea of common sense – one of the fundamental ideas of Scottish and French Enlightenment. In the Scottish philosophy concept of «common sense» was developed by representatives of ethical sentimentalism (A. Shaftesbury, F. Hutcheson) and by the founder of the rationalist understanding of morality Th. Reid. In France, the idea of common sense was widely developed in the works of Enlightenment philosophers. Scottish enlighteners understood common sense as a kind of inherent, intuitive principle, put by God into human being. This paper analyzes the significance of the concept «common sense» and its features of interpretations by Scottish philosophers. The quintessence of philosophy of the Age of Enlightenment was practical philosophy of I. Kant, in formation of which the idea of common sense played the key role. German classic clearly defined field of application of common sense. He considered an appeal to common sense in matters of science and philosophy unacceptable, but claimed that it was common sense people must rely in everyday practice. Such an understanding of this idea has allowed Kant to justify main concept of his moral philosophy ­ concept of the autonomous subject.Эпоха Просвещения имела особое значение для истории моральной философии, поскольку именно в это время мораль становится специальным предметом философского интереса, формируется философское понятие морали. Центральной становится проблема рационального обоснования морали. Важнейшее значение для решения этой проблемы имела идея здравого смысла ­ одна из фундаментальных идей шотландского и французского Просвещения. В шотландской философии концепт «здравый смысл» разрабатывался представителями этического сентиментализма (Э. Шефтсбери, Ф. Хатчесон), а также основоположником рационалистического понимания морали ­ Т. Ридом. Во Франции идея здравого смысла получила широкое развитие в работах философов­просветителей. Шотландскими же просветителями здравый смысл (common sense) понимался как некий врожденный, интуитивный принцип, вложенный в человека Богом. В данной работе проанализированы значения концепта «здравый смысл» и особенности его трактовок шотландскими философами. Квинтэссенцией философии эпохи Просвещения является, в свою очередь, практическая философия И. Канта, в становлении которой идея здравого смысла сыграла ключевую роль. Немецкий классик четко определил сферу применения здравого смысла. Он считал апелляцию к здравому смыслу в вопросах науки и философии недопустимой, но утверждал, что именно на здравый смысл должен опираться человек в повседневной практике. Такое понимание этой идеи позволило Канту обосновать главное понятие его моральной философии ­ понятие автономного субъекта.Эпоха Просвещения имела особое значение для истории моральной философии, поскольку именно в это время мораль становится специальным предметом философского интереса, формируется философское понятие морали. Центральной становится проблема рационального обоснования морали. Важнейшее значение для решения этой проблемы имела идея здравого смысла ­ одна из фундаментальных идей шотландского и французского Просвещения. В шотландской философии концепт «здравый смысл» разрабатывался представителями этического сентиментализма (Э. Шефтсбери, Ф. Хатчесон), а также основоположником рационалистического понимания морали ­ Т. Ридом. Во Франции идея здравого смысла получила широкое развитие в работах философов­просветителей. Шотландскими же просветителями здравый смысл (common sense) понимался как некий врожденный, интуитивный принцип, вложенный в человека Богом. В данной работе проанализированы значения концепта «здравый смысл» и особенности его трактовок шотландскими философами. Квинтэссенцией философии эпохи Просвещения является, в свою очередь, практическая философия И. Канта, в становлении которой идея здравого смысла сыграла ключевую роль. Немецкий классик четко определил сферу применения здравого смысла. Он считал апелляцию к здравому смыслу в вопросах науки и философии недопустимой, но утверждал, что именно на здравый смысл должен опираться человек в повседневной практике. Такое понимание этой идеи позволило Канту обосновать главное понятие его моральной философии ­ понятие автономного субъекта

ZPS: visualization of recent adaptive evolution of proteins

<p>Abstract</p> <p>Background</p> <p>Detection of adaptive amino acid changes in proteins under recent short-term selection is of great interest for researchers studying microevolutionary processes in microbial pathogens or any other biological species. However, independent occurrence of such point mutations within genetically diverse haplotypes makes it difficult to detect the selection footprint by using traditional molecular evolutionary analyses. The recently developed Zonal Phylogeny (ZP) has been shown to be a useful analytic tool for identifying the footprints of short-term positive selection. ZP separates protein-encoding genes into evolutionarily long-term (with silent diversity) and short-term (without silent diversity) categories, or zones, followed by statistical analysis to detect signs of positive selection in the short-term zone. However, successful broad application of ZP for analysis of large haplotype datasets requires automation of the relatively labor-intensive computational process.</p> <p>Results</p> <p>Here we present Zonal Phylogeny Software (ZPS), an application that describes the distribution of single nucleotide polymorphisms (SNPs) of synonymous (silent) and non-synonymous (replacement) nature along branches of the DNA tree for any given protein-coding gene locus. Based on this information, ZPS separates the protein variant haplotypes with silent variability (Primary zone) from those that have recently evolved from the Primary zone variants by amino acid changes (External zone). Further comparative analysis of mutational hot-spot frequencies and haplotype diversity between the two zones allows determination of whether the External zone haplotypes emerged under positive selection.</p> <p>Conclusions</p> <p>As a visualization tool, ZPS depicts the protein tree in a DNA tree, indicating the most parsimonious numbers of synonymous and non-synonymous changes along the branches of a maximum-likelihood based DNA tree, along with information on homoplasy, reversion and structural mutation hot-spots. Through zonal differentiation, ZPS allows detection of recent adaptive evolution via selection of advantageous structural mutations, even when the advantage conferred by such mutations is relatively short-term (as in the case of "source-sink" evolutionary dynamics, which may represent a major mode of virulence evolution in microbes).</p

Ribonucleolytic activity of mycoplasmas

Mycoplasmas are incapable of de novo synthesis of nucleotides and must therefore secrete nucleases in order to replenish the pool of nucleic acid precursors. The nucleolytic activity of mycoplasmas is an important factor in their pathogenicity. Bacterial ribonucleases (RNases) may produce a broad spectrum of biological effects, including antiviral and antitumor activity. Mycoplasma RNases are therefore of interest. In the present work, the capacity of Acholeplasma laidlawii and Mycoplasma hominis for RNase synthesis and secretion was studied. During the stationary growth phase, these organisms were found to synthesize Mg2+-dependent RNases, with their highest activity detected outside the cells. Localization of A. laidlawii RNases was determined: almost 90% of the RNase activity was found to be associated with the membrane vesicles. Bioinformational analysis revealed homology between the nucleotide sequences of 14 Bacillus subtilis genes encoding the products with RNase activity and the genes of the mycoplasmas under study. Amino acid sequences of 4 A. laidlawii proteins with ribonuclease activity and the Bsn RNase were also established. © 2014 Pleiades Publishing, Ltd

Опухоли головы и шеи: адъювантная лучевая терапия в режиме гипофракционирования

INTRODUCTION: Effect of adiuvant radiation therapy (RT) on oncologic outcomes is well-known and confirmed by different trials. Optimal time to start RT is 6–8 weeks after surgery. Increasing duration of RT delay beyond that interval leads to decrease in overall survival (OS) and makes loco-regional recurrence (LRC) more probable. However, more than 50% patients do not receive adjuvant treatment in time (Mitra S. et al., 2022). Overall treatment time (77–100 days) is another factor that influences effectiveness of adjuvant RT. In order to keep within that time limits non-conventional regimens of RT can be used.OBJECTIVE: To test safety and feasibility of hypofractionated adjuvant RT in patients with locally advanced squamous cell carcinoma of oral cavity and oropharynx.MATERIALS AND METHODS: Patients with stage III–IV squamous cell carcinoma of oral cavity and oropharynx (n=11) who underwent surgery and have to recieve adjuvant RT in 8 weeks and more after surgery are included. Dose was delivered using Volumetric Modulated Arc Therapy (VMAT) and simultaneous integrated boost.RESULTS: Patients (n=11) completed RT successfully. Surgery-to-RT interval ranges between 9 and 15 weeks. Dose per fraction on high-risk-CTV varies between 2,5 and 2,75 Gy. Acute side-effects (oral mucositis grade II) presented after 27–32 Gy (11–13 fractions) in 9 patient out of 11 and reached maximum (oral mucositis grade III, radiation dermatitis grade II) at the end of the treatment.CONCLUSIONS: Hypofractionated adjuvant RT (VMAT) can be safely used in patients with locally advanced squamous cell carcinoma of oral cavity and oropharynx and local acute toxicity can be controlled.ВВЕДЕНИЕ: Вклад адъювантного лучевого воздействия в конечный результат комбинированного лечения злокачественных новообразований головы (ЗНО) и шеи подтвержден многочисленными исследованиями. Оптимальный срок начала адъювантной лучевой терапии (ЛТ) — 6–8 недель после операции. При упущении рекомендованных сроков послеоперационного облучения отмечено повышение риска рецидива и значимое снижение показателей общей выживаемости. Однако, по данным S.Mitra и соавт. (2022), более половины пациентов с плоскоклеточным раком головы и шеи своевременно не получают адъювантное лучевое лечение. Кроме того, на эффективность комбинированной терапии влияет и общая продолжительность лечения (77–100 дней). Для соблюдения временных рамок лечения ЗНО головы и шеи могут быть использованы альтернативные режимы фракционирования.ЦЕЛЬ: Оценить переносимость и безопасность адъювантной ЛТ в режиме гипофракционирования дозы у больных плоскоклеточным местно-распространенным ВПЧ-негативным раком ротоглотки и полости рта в рамках комбинированного лечения.МАТЕРИАЛЫ И МЕТОДЫ: В работу включены больные плоскоклеточным ВПЧ-негативным раком ротоглотки и полости рта III–IV стадии после оперативного лечения с наличием показаний к проведению адъювантной лучевой терапии в сроки от 8 недель с момента хирургического вмешательства в режиме симультанного интегрированного буста. Методика облучения — объемно-модулированная лучевая терапия (VMAT).РЕЗУЛЬТАТЫ: Пациенты (n=11) завершили адъювантное лучевое лечение в полном объеме. Интервал между оперативным лечением и адъювантной ЛТ варьировал от 9 до 15 недель. Разовая очаговая доза (РОД) на область высокого и крайне высокого риска составила 2,5–2,75 Гр. По достижении СОД 27–32 Гр (11–13 фракция) у 9 пациентов из 11 развился радиоэпителиит II ст.; лучевые реакции достигли своего максимума (радиоэпителиит III ст., лучевой мукозит III ст., лучевой эпидермит II ст.) к завершению курса.ЗАКЛЮЧЕНИЕ: Применение гипофракционных режимов дистанционной лучевой терапии (VMAT) в адъювантном режиме у больных плоскоклеточным местно-распространенным ВПЧ-негативным раком ротоглотки и полости рта представляется безопасным методом лучевого лечения с контролируемой местной лучевой токсичностью

Uropathogenic <i>Escherichia coli</i> metabolite-dependent quiescence and persistence may explain antibiotic tolerance during urinary tract infection

ABSTRACT In the present study, it is shown that although Escherichia coli CFT073, a human uropathogenic (UPEC) strain, grows in liquid glucose M9 minimal medium, it fails to grow on glucose M9 minimal medium agar plates seeded with ≤106 CFU. The cells on glucose plates appear to be in a “quiescent” state that can be prevented by various combinations of lysine, methionine, and tyrosine. Moreover, the quiescent state is characteristic of ~80% of E. coli phylogenetic group B2 multilocus sequence type 73 strains, as well as 22.5% of randomly selected UPEC strains isolated from community-acquired urinary tract infections in Denmark. In addition, E. coli CFT073 quiescence is not limited to glucose but occurs on agar plates containing a number of other sugars and acetate as sole carbon sources. It is also shown that a number of E. coli CFT073 mini-Tn5 metabolic mutants (gnd, gdhA, pykF, sdhA, and zwf) are nonquiescent on glucose M9 minimal agar plates and that quiescence requires a complete oxidative tricarboxylic acid (TCA) cycle. In addition, evidence is presented that, although E. coli CFT073 quiescence and persistence in the presence of ampicillin are alike in that both require a complete oxidative TCA cycle and each can be prevented by amino acids, E. coli CFT073 quiescence occurs in the presence or absence of a functional rpoS gene, whereas maximal persistence requires a nonfunctional rpoS. Our results suggest that interventions targeting specific central metabolic pathways may mitigate UPEC infections by interfering with quiescence and persistence. IMPORTANCE Recurrent urinary tract infections (UTIs) affect 10 to 40% of women. In up to 77% of those cases, the recurrent infections are caused by the same uropathogenic E. coli (UPEC) strain that caused the initial infection. Upon infection of urothelial transitional cells in the bladder, UPEC appear to enter a nongrowing quiescent intracellular state that is thought to serve as a reservoir responsible for recurrent UTIs. Here, we report that many UPEC strains enter a quiescent state when ≤106 CFU are seeded on glucose M9 minimal medium agar plates and show that mutations in several genes involved in central carbon metabolism prevent quiescence, as well as persistence, possibly identifying metabolic pathways involved in UPEC quiescence and persistence in vivo

Uropathogenic Escherichia coli Metabolite-Dependent Quiescence and Persistence May Explain Antibiotic Tolerance during Urinary Tract Infection

In the present study, it is shown that although Escherichia coli CFT073, a human uropathogenic (UPEC) strain, grows in liquid glucose M9 minimal medium, it fails to grow on glucose M9 minimal medium agar plates seeded with ≤106 CFU. The cells on glucose plates appear to be in a “quiescent” state that can be prevented by various combinations of lysine, methionine, and tyrosine. Moreover, the quiescent state is characteristic of ~80% of E. coli phylogenetic group B2 multilocus sequence type 73 strains, as well as 22.5% of randomly selected UPEC strains isolated from community-acquired urinary tract infections in Denmark. In addition, E. coli CFT073 quiescence is not limited to glucose but occurs on agar plates containing a number of other sugars and acetate as sole carbon sources. It is also shown that a number of E. coliCFT073 mini-Tn5 metabolic mutants (gnd, gdhA, pykF, sdhA, and zwf) are nonquiescent on glucose M9 minimal agar plates and that quiescence requires a complete oxidative tricarboxylic acid (TCA) cycle. In addition, evidence is presented that, although E. coli CFT073 quiescence and persistence in the presence of ampicillin are alike in that both require a complete oxidative TCA cycle and each can be prevented by amino acids, E. coli CFT073 quiescence occurs in the presence or absence of a functional rpoS gene, whereas maximal persistence requires a nonfunctional rpoS. Our results suggest that interventions targeting specific central metabolic pathways may mitigate UPEC infections by interfering with quiescence and persistence

Evolution of Salmonella enterica Virulence via Point Mutations in the Fimbrial Adhesin

Whereas the majority of pathogenic Salmonella serovars are capable of infecting many different animal species, typically producing a self-limited gastroenteritis, serovars with narrow host-specificity exhibit increased virulence and their infections frequently result in fatal systemic diseases. In our study, a genetic and functional analysis of the mannose-specific type 1 fimbrial adhesin FimH from a variety of serovars of Salmonella enterica revealed that specific mutant variants of FimH are common in host-adapted (systemically invasive) serovars. We have found that while the low-binding shear-dependent phenotype of the adhesin is preserved in broad host-range (usually systemically non-invasive) Salmonella, the majority of host-adapted serovars express FimH variants with one of two alternative phenotypes: a significantly increased binding to mannose (as in S. Typhi, S. Paratyphi C, S. Dublin and some isolates of S. Choleraesuis), or complete loss of the mannose-binding activity (as in S. Paratyphi B, S. Choleraesuis and S. Gallinarum). The functional diversification of FimH in host-adapted Salmonella results from recently acquired structural mutations. Many of the mutations are of a convergent nature indicative of strong positive selection. The high-binding phenotype of FimH that leads to increased bacterial adhesiveness to and invasiveness of epithelial cells and macrophages usually precedes acquisition of the non-binding phenotype. Collectively these observations suggest that activation or inactivation of mannose-specific adhesive properties in different systemically invasive serovars of Salmonella reflects their dynamic trajectories of adaptation to a life style in specific hosts. In conclusion, our study demonstrates that point mutations are the target of positive selection and, in addition to horizontal gene transfer and genome degradation events, can contribute to the differential pathoadaptive evolution of Salmonella

The Bacterial Fimbrial Tip Acts as a Mechanical Force Sensor

The subunits that constitute the bacterial adhesive complex located at the tip of the fimbria form a hook-chain that acts as a rapid force-sensitive anchor at high flow

Рекомендации по проведению тримодальной терапии рака мочевого пузыря (Невский консенсус 2021)

The aim of this work was to clarify and extend the existing clinical guidelines on organ-sparing treatment of muscleinvasive bladder cancer. The standard protocol of radical conservative treatment for muscle-invasive bladder cancer includes transurethral resection of the bladder, external beam radiotherapy with simultaneous chemotherapy (radiosensitization), which is usually referred to as trimodal therapy. The implementation of trimodal therapy into routine practice in Russia is limited due to the lack of distinct criteria for each of the stages. The involvement of surgeons, radiation oncologists, and chemotherapists, on the one hand, provides the required multidisciplinary approach to cancer treatment; on the other hand, it might impede the entire algorithm. To address this problem, specialists from the Department of Radiology (project moderators), Department of Cancer Urology, and Department of Chemotherapy of N.N. Petrov National Medical Research Center of Oncology under the auspices of Saint Petersburg Oncological Research Society formed a group of experts, including radiation oncologists, urologists, and chemotherapists from federal and local cancer (educational) institutions of Saint Petersburg who had an experience of treating muscle-invasive bladder cancer. The guideline was developed with the consideration of available guidelines published by leading professional associations of radiotherapy and oncology (urological), research articles, and own experience.         Цель работы – уточнение и дополнение клинических рекомендаций по органосохраняющему лечению мышечноинвазивного рака мочевого пузыря. Стандартный протокол радикального консервативного лечения мышечно-инвазивного рака мочевого пузыря включает трансуретральную резекцию мочевого пузыря, дистанционную лучевую терапию с одновременной химиотерапией (радиосенсибилизацию) и называется тримодальной терапией. Широкое внедрение тримодальной терапии в отечественную практику ограничено отсутствием четких критериев для каждого из этапов. Участие в протоколе хирургов, радиационных онкологов и химиотерапевтов, с одной стороны, обеспечивает необходимый мультидисциплинарный характер лечения онкологического больного, с другой – затрудняет реализацию всего алгоритма. Для осуществления поставленной задачи отделениями радиотерапии (модераторы проекта) и онкоурологии, а также отделением химиотерапии и инновационных технологий НМИЦ онкологии им. Н.Н. Петрова под эгидой Петербургского онкологического научного общества сформирована группа экспертов, включающая радиационных онкологов, онкоурологов и химиотерапевтов федеральных и городских онкологических (образовательных) учреждений (г. Санкт-Петербург), имеющих опыт лечения мышечно-инвазивного рака мочевого пузыря. Разработка рекомендаций велась с учетом имеющихся рекомендаций ведущих профессиональных радиотерапевтических и онкологических (урологических) ассоциаций, опубликованных статей и собственного опыта

Uropathogenic Escherichia coli P and Type 1 Fimbriae Act in Synergy in a Living Host to Facilitate Renal Colonization Leading to Nephron Obstruction

The progression of a natural bacterial infection is a dynamic process influenced by the physiological characteristics of the target organ. Recent developments in live animal imaging allow for the study of the dynamic microbe-host interplay in real-time as the infection progresses within an organ of a live host. Here we used multiphoton microscopy-based live animal imaging, combined with advanced surgical procedures, to investigate the role of uropathogenic Escherichia coli (UPEC) attachment organelles P and Type 1 fimbriae in renal bacterial infection. A GFP+ expressing variant of UPEC strain CFT073 and genetically well-defined isogenic mutants were microinfused into rat glomerulus or proximal tubules. Within 2 h bacteria colonized along the flat squamous epithelium of the Bowman's capsule despite being exposed to the primary filtrate. When facing the challenge of the filtrate flow in the proximal tubule, the P and Type 1 fimbriae appeared to act in synergy to promote colonization. P fimbriae enhanced early colonization of the tubular epithelium, while Type 1 fimbriae mediated colonization of the center of the tubule via a mechanism believed to involve inter-bacterial binding and biofilm formation. The heterogeneous bacterial community within the tubule subsequently affected renal filtration leading to total obstruction of the nephron within 8 h. Our results reveal the importance of physiological factors such as filtration in determining bacterial colonization patterns, and demonstrate that the spatial resolution of an infectious niche can be as small as the center, or periphery, of a tubule lumen. Furthermore, our data show how secondary physiological injuries such as obstruction contribute to the full pathophysiology of pyelonephritis