Overexpression of RPOTmp Being Targeted to Either Mitochondria or Chloroplasts in Leads to Overall Transcriptome Changes and Faster Growth.

The transcription of organellar genes is performed by three nuclear-encoded RNA polymerases: RPOTm, RPOTmp, and RPOTp. The RPOTmp protein possesses ambiguous transit peptides, allowing participation in gene expression control in both mitochondria and chloroplasts, although its function in plastids is still under discussion. Here, we show that the overexpression of RPOTmp in , targeted either to mitochondria or chloroplasts, disturbs the dormant seed state, and it causes the following effects: earlier germination, decreased ABA sensitivity, faster seedling growth, and earlier flowering.

Microstructure of the Advanced Titanium Alloy VT8M-1 Subjected to Rotary Swaging.

In this study, the microstructural behavior of the advanced Ti-5.7Al-3.8Mo-1.

Effectiveness of dapagliflozin as an insulin adjunct in type 1 diabetes: a semi-mechanistic exposure-response model.

Dapagliflozin-induced improvement of glycemic control in patients with inadequately controlled type 1 diabetes (T1D) is complicated by the delicate balance between blood glucose and exogenous insulin. In this work, we developed a semi-mechanistic population exposure-response model using pooled patient-level data to characterize the joint effect of dapagliflozin and insulin on average daily glucose concentrations and glycated hemoglobin (HbA1c) levels in patients with T1D. A non-linear mixed-effects model was developed in Monolix (Lixoft, France) and R software (R Project, www.

Innovative aberration correction in ultrasound diagnostics with direct phase estimation for enhanced image quality.

The paper addresses a crucial challenge in medical radiology and introduces a novel general approach, which utilises applied mathematics and information technology techniques, for aberration correction in ultrasound diagnostics. Ultrasound imaging of inhomogeneous media inherently suffers from variations in ultrasonic speed between tissue. The characteristics of aberrations are unique to each patient due to tissue morphology.

Evaluation of LFA-1 Peptide-Methotrexate Conjugates in Modulating Endothelial Cell Inflammation and Cytokine Regulation.

Interactions between vascular endothelial cells and inflammatory leukocytes are intermediated via cell adhesion molecules and they become one of the key events for vascular cell injury and development of atherosclerosis. This study evaluated the effects of MTX-peptide conjugates as anti-inflammatory agents on human coronary artery endothelial cells (HCAEC) and Molt-3 T cells. Cyclic peptides, cLABL and cLBEL, were derived from the α- and β-subunits of leukocyte function-associated antigen-1 (LFA-1), respectively.

A mechanistic modeling platform of SGLT2 inhibition: Implications for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by abnormally high blood glucose concentrations due to dysfunction of the insulin-producing beta-cells in the pancreas. Dapagliflozin, an inhibitor of renal glucose reabsorption, has the potential to improve often suboptimal glycemic control in patients with T1DM through insulin-independent mechanisms and to partially mitigate the adverse effects associated with long-term insulin administration. In this work, we have adapted a systems pharmacology model of type 2 diabetes mellitus to describe the T1DM condition and characterize the effect of dapagliflozin on short- and long-term glycemic markers under various treatment scenarios.

Effect of the Texture of the Ultrafine-Grained Ti-6Al-4V Titanium Alloy on Impact Toughness.

In this work, the strength properties and impact toughness of the ultrafine-grained (UFG) Ti-6Al-4V titanium alloy produced by severe plastic deformation (SPD) in combination with upsetting were studied, depending on the direction of crack propagation. In the billets processed by equal-channel angular pressing (ECAP), the presence of anisotropy of ultimate tensile strength (UTS) and ductility was observed, conditioned by the formation of a metallographic and crystallographic texture. At the same time, the ECAP-processed UFG alloy exhibited satisfactory values of impact toughness, ~0.

Knowledge dissemination and central indexing of resources in pharmacometrics: an ISOP education working group initiative.

Pharmacometrics is a constantly evolving field that plays a major role in decision making in drug development and clinical monitoring. Scientists in Pharmacometrics, especially in their early phases of career, are often faced with the challenge of identifying adequate resources for self-training and education. Hence, the ISoP Education Committee through its working group dedicated to Central Indexing and knowledge Dissemination has built a database of worldwide educational programs and most common references in Pharmacometrics.

-Cre-Mediated Genetic Deletion of Reveals a Role of Septins in Macrophage Cytokinesis and -Driven Tumorigenesis.

By crossing -floxed mice with -Cre mice carrying the Cre recombinase inserted in the Lysozyme-M () gene locus we aimed the specific deletion of septin7 in myeloid cells, such as monocytes, macrophages and granulocytes. :Cre mice show no alterations in the myeloid compartment. -deleted macrophages (BMDMs) were isolated and analyzed.

Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (A) mutation.

Hypothalamic melanocortin 4 receptors (MC4R) regulate energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans. Fibroblast growth factor 21 (FGF21) is a promising antiobesity agent, but its effects on melanocortin obesity are unknown.

On the chaotic and hyper-chaotic dynamics of nanobeams with low shear stiffness.

We construct a mathematical model of non-linear vibration of a beam nanostructure with low shear stiffness subjected to uniformly distributed harmonic transversal load. The following hypotheses are employed: the nanobeams made from transversal isotropic and elastic material obey the Hooke law and are governed by the kinematic third-order approximation (Sheremetev-Pelekh-Reddy model). The von Kármán geometric non-linear relation between deformations and displacements is taken into account.

Chinese hamster ovary cell line DXB-11: chromosomal instability and karyotype heterogeneity.

Background: Chinese hamster ovary cell lines, also known as CHO cells, represent a large family of related, yet quite different, cell lines which are metabolic mutants derived from the original cell line, CHO-ori. Dihydrofolate reductase-deficient DXB-11 cell line, one of the first CHO derivatives, serves as the host cell line for the production of therapeutic proteins. It is generally assumed that DXB-11 is identical to DUKX or CHO-DUK cell lines, but, to our knowledge, DXB-11 karyotype has not been described yet.

A model-based approach to investigating the relationship between glucose-insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes.

Aims: To develop a quantitative systems pharmacology model to describe the effect of dapagliflozin (a sodium-glucose co-transporter-2 [SGLT2] inhibitor) on glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients, and to identify key determinants of treatment-mediated glycated haemoglobin (HbA1c) reduction.

Materials And Methods: Glycaemic control during dapagliflozin treatment was mechanistically characterized by integrating components representing dapagliflozin pharmacokinetics (PK), glucose-insulin homeostasis, renal glucose reabsorption, and HbA1c formation. The model was developed using PK variables, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase IIa dapagliflozin trial in patients with T2DM (NCT00162305).

EEG Analysis in Structural Focal Epilepsy Using the Methods of Nonlinear Dynamics (Lyapunov Exponents, Lempel-Ziv Complexity, and Multiscale Entropy).

This paper analyzes a case with the patient having focal structural epilepsy by processing electroencephalogram (EEG) fragments containing the "sharp wave" pattern of brain activity. EEG signals were recorded using 21 channels. Based on the fact that EEG signals are time series, an approach has been developed for their analysis using nonlinear dynamics tools: calculating the Lyapunov exponent's spectrum, multiscale entropy, and Lempel-Ziv complexity.

Differentiating the Sodium-Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling.

The aim of this research was to differentiate dapagliflozin, empagliflozin, and canagliflozin based on their capacity to inhibit sodium-glucose cotransporter (SGLT) 1 and 2 in patients with type 2 diabetes using a previously developed quantitative systems pharmacology model of renal glucose filtration, reabsorption, and excretion. The analysis was based on pooled, mean study-level data on 24-hour urinary glucose excretion, average daily plasma glucose, and estimated glomerular filtration rate collected from phase I and II clinical trials of SGLT2 inhibitors. Variations in filtered glucose across clinical studies were shown to drive the apparent differences in the glucosuria dose-response relationships among the gliflozins.

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3.

Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa.

Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors.

Aim: To develop a quantitative drug-disease systems model to investigate the paradox that sodium-glucose co-transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM).

Materials And Methods: A physiologically based four-compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration-time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM.

Mortality Rate Due to Circulatory and Alcohol-Dependent Diseases in Different Climatic Zones of Russia.

Aim: Evaluation of the impact of climatic factors on the formation of mortality due to circulatory diseases and a group of diseases related to alcohol consumption identified as alcohol-dependent.

Methods: The study subject was the adult population residing in different climatic zones of Russia: in the second, third and fourth zones, with different conditions: average annual temperature (5.2°C; 1-2°C; -2.

Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord.

Background/objectives: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf, and Gap43 neuroplasticity genes in lumbar spinal cord.Approach/Methods:Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n = 8).

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3.

Mitogen-activated protein kinase 6/extracellular signal-regulated kinase 3 (MAPK6/ERK3) is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a insertion in exon 2 due to pulmonary dysfunction and by defects in function, activation, and positive selection of T cells. To study the role of ERK3 , we generated mice carrying a conditional allele with exon 3 flanked by sites.

Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus.

Aims: To assess the dapagliflozin exposure-response relationship in Japanese and non-Japanese patients with type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients.

Materials And Methods: Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24-hour urinary glucose excretion [UGE]) in Japanese and non-Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed.

A Mass Burial of Fossil Lions (Carnivora, Felidae, Panthera (Leo) ex gr. fossilis-spelaea) from Eurasia.

The vertebrate fauna from the cave deposits in Imanai Cave in the Southern Urals (53°02' N, 56°26'E) has been studied. It contains 715 bones that belonged to at least 11 individuals of fossil lion (Panthera (Leo) ex gr. fossilis-spelaea).

Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics.

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models.