The Dynamics of Zeroth-Order Ultrasensitivity: A Critical Phenomenon in Cell Biology

It is well known since the pioneering work of Goldbeter and Koshland [Proc. Natl. Acad. Sci. USA, vol. 78, pp. 6840-6844 (1981)] that cellular phosphorylation- dephosphorylation cycle (PdPC), catalyzed by kinase and phosphatase under saturated condition with zeroth order enzyme kinetics, exhibits ultrasensitivity, sharp transition. We analyse the dynamics aspects of the zeroth order PdPC kinetics and show a critical slowdown akin to the phase transition in condensed matter physics. We demonstrate that an extremely simple, though somewhat mathematically "singular" model is a faithful representation of the ultrasentivity phenomenon. The simplified mathematical model will be valuable, as a component, in developing complex cellular signaling network theory as well as having a pedagogic value.Comment: 8 pages, 3 figure

Rhythmic Structure of Reading and Cross-Modal Priming Effect of Rhythm on Grammatical Judgements

Ритм является фундаментальным элементом как музыки, так и речи, однако влияние аудиально представленных ритмических паттернов на процессы чтения игнорируется в исследованиях. Здесь мы представляем исследование связанных с событиями потенциалов, проведенное с использованием кросс-модального дизайна. Мы обнаружили увеличение эффекта P600 после регулярной ритмической стимуляции, который был наиболее выражен в правом полушарии. Также мы обнаружили значимое взаимодействие фактора полушария и прайминга. Результаты нашего исследования показывают тесное межмодальное взаимодействие в процессе чтения, а также наличие внутренней ритмической структуры, которая участвует в процессе чтения и может быть синхронизирована с внешней ритмической стимуляцией.Rhythm is a fundamental element of both music and speech, however, the effect of auditorily presented rhythm patterns on reading processes is neglected in the research. Here we present an event-related potentials study conducted using such cross-modal design. We found an increased P600 effect after regular rhythmic stimulation, this effect was the most pronounced in the right hemisphere.We also found a significant interaction between hemispheric factor and priming. These results suggest tight intermodal connections in the reading process as well as the existence of an internal rhythmic structure which is both involved in the reading process and might be synchronized with external rhythmic stimulation

The interplay of intrinsic and extrinsic bounded noises in genetic networks

After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a genetic network. The influence of intrinsic and extrinsic noises on genetic networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: $(i)$ the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, $(ii)$ a model of enzymatic futile cycle and $(iii)$ a genetic toggle switch. In $(ii)$ and $(iii)$ we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possibile functional role of bounded noises

Pharmacological Correction of Stress-Induced Gastric Ulceration by Novel Small-Molecule Agents with Antioxidant Profile

This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance

The rise of feathered dinosaurs:Kulindadromeus zabaikalicus, the oldest dinosaur with ‘feather-like’ structures

Diverse epidermal appendages including grouped filaments closely resembling primitive feathers in non-avian theropods, are associated with skeletal elements in the primitive ornithischian dinosaur Kulindadromeus zabaikalicus from the Kulinda locality in south-eastern Siberia. This discovery suggests that ‘‘feather-like’’ structures did not evolve exclusively in theropod dinosaurs, but were instead potentially widespread in the whole dinosaur clade. The dating of the Kulinda locality is therefore particularly important for reconstructing the evolution of ‘‘feather-like’’ structures in dinosaurs within a chronostratigraphic framework. Here we present the first dating of the Kulinda locality, combining U-Pb analyses (LA-ICP-MS) on detrital zircons and monazites from sedimentary rocks of volcaniclastic origin and palynological observations. Concordia ages constrain the maximum age of the volcaniclastic deposits at 172.8 ± 1.6 Ma, corresponding to the Aalenian (Middle Jurassic). The palynological assemblage includes taxa that are correlated to Bathonian palynozones from western Siberia, and therefore constrains the minimum age of the deposits. The new U-Pb ages, together with the palynological data, provide evidence of a Bathonian age—between 168.3 ± 1.3 Ma and 166.1 ± 1.2 Ma—for Kulindadromeus. This is older than the previous Late Jurassic to Early Cretaceous ages tentatively based on local stratigraphic correlations. A Bathonian age is highly consistent with the phylogenetic position of Kulindadromeus at the base of the neornithischian clade and suggests that cerapodan dinosaurs originated in Asia during the Middle Jurassic, from a common ancestor that closely looked like Kulindadromeus. Our results consequently show that Kulindadromeus is the oldest known dinosaur with ‘‘feather-like’’ structures discovered so far.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Studying Humoral Immune Response at Mild and Asymptomatic COVID-19 Forms

Background. Currently, during the COVID-19 pandemic, one of the most pressing healthcare problems is to ensure the safety of the population of the Russian Federation. There is insufficient information on the duration and intensity of post-infectious immunity in relation to SARS-CoV-2, especially in case of inapparent (without clinical signs), mild or latent forms of infection.Materials and methods. The study involved 99 volunteers with a laboratory confirmed PCR diagnosis of COVID-19 who were residents of the Irkutsk Region and of other regions of the Russian Federation and arrived to work in Bodaybo on a rotational basis. Also the study included 50 conditionally healthy people living in Irkutsk who had negative PCR results for SARS-CoV-2 RNA presence.Specific IgG and IgM antibodies to SARS-CoV-2 were detected in blood serum by enzyme-linked immunosorbent assay (ELISA) using test systems “ELISA anti-SARS-CoV-2 IgG” (FBUN SSC PMB, Obolensk, Russian Federation), “SARS-CoV-2-IgG-IFA-BEST” and “SARS-CoV-2-IgM-IFA-BEST” (Vector-Best, Novosibirsk, Russian Federation).Results. The results of a study of the humoral immunity of patients with asymptomatic and clinical forms of COVID-19 are presented. The data indicate the production of specific IgG in the blood serum of people in 2–3 weeks after SARSCov-2 infection and reaching its maximum level on the 20–21st day. The seroconversion rate  was 94.9 %. It was shown that the geometric mean titer of antibodies in asymptomatic and mild forms of coronavirus infection did not differ statistically and amounted to 1:512 and 1:632, respectively. Higher titers of antibodies (1:1600) were detected in the moderate form.Conclusion. The research results can serve as a basis for studying the dynamics of changes in the indicators  of the humoral immune response in patients with COVID-19 and for clarifying the duration of their post- infectious immunity in order to predict the development of the epidemic situation and to ensure the planning of specific prevention

Cholinergic Deficit Induced by Central Administration of 192IgG-Saporin Is Associated With Activation of Microglia and Cell Loss in the Dorsal Hippocampus of Rats

Alzheimer’s disease (AD) is associated with degeneration of cholinergic neurons in the basal forebrain. Administration of the immunotoxin 192IgG-saporin to rats, an animal model of AD, leads to degeneration of cholinergic neurons in the medial septal area. In the present study, cholinergic cell death was induced by intracerebroventricular administration of 192IgG-saporin. One and a half months after injection, we studied the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression. We found that treatment with 192IgG-saporin resulted in neuronal loss in the CA3 field of the hippocampus. Microglial proliferation was observed in the dentate gyrus of the dorsal hippocampus and white matter. Massive proliferation and activation of microglia in the white matter was associated with strong activation of astrocytes. However, the expression of microglial marker genes significantly increased only in the dorsal hippocampus, not the ventral hippocampus. These effects were not related to non-specific action of 192IgG-saporin because of the absence of the Nerve growth factor receptor in the hippocampus. Additionally, 192IgG-saporin treatment also induced a decrease in the expression of genes that are associated with transport functions of brain vascular cells (Slc22a8, Ptprb, Sdpr), again in the dorsal hippocampus but not in the ventral hippocampus. Taken together, our data suggest that cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus

Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy

DBSolve Optimum: a software package for kinetic modeling which allows dynamic visualization of simulation results

<p>Abstract</p> <p>Background</p> <p>Systems biology research and applications require creation, validation, extensive usage of mathematical models and visualization of simulation results by end-users. Our goal is to develop novel method for visualization of simulation results and implement it in simulation software package equipped with the sophisticated mathematical and computational techniques for model development, verification and parameter fitting.</p> <p>Results</p> <p>We present mathematical simulation workbench DBSolve Optimum which is significantly improved and extended successor of well known simulation software DBSolve5. Concept of "dynamic visualization" of simulation results has been developed and implemented in DBSolve Optimum. In framework of the concept graphical objects representing metabolite concentrations and reactions change their volume and shape in accordance to simulation results. This technique is applied to visualize both kinetic response of the model and dependence of its steady state on parameter. The use of the dynamic visualization is illustrated with kinetic model of the Krebs cycle.</p> <p>Conclusion</p> <p>DBSolve Optimum is a user friendly simulation software package that enables to simplify the construction, verification, analysis and visualization of kinetic models. Dynamic visualization tool implemented in the software allows user to animate simulation results and, thereby, present them in more comprehensible mode. DBSolve Optimum and built-in dynamic visualization module is free for both academic and commercial use. It can be downloaded directly from <url>http://www.insysbio.ru</url>.</p