Search

The Susceptible-Infected-Recovered (SIR) model for the spread of an infectious disease in a population of constant size is considered. In order to control the spread of infection, we propose the model with four bounded controls which describe vaccination of newborns, vaccination of the susceptible, treatment of infected, and indirect strategies aimed at a reduction of the incidence rate (e. g. quarantine). The optimal control problem of minimizing the total number of the infected individuals on a given time interval is stated and solved. The optimal solutions are obtained with the use of the Pontryagin Maximum Principle and investigated analytically. Numerical results are presented to illustrate the optimal solutions. [ABSTRACT FROM PUBLISHER]

Cancer-promoting proinflammatory microenvironment influences colorectal cancer (CRC) development. We examined the biomarkers of inflammation, intestinal differentiation, and DNA activity correlated with the clinical parameters to observe progression and prognosis in the adenocarcinoma subtype of CRC. Their immunohistology, immunoblotting, and RT-PCR analyses were performed in the adenocarcinoma and neighboring healthy tissues of 64 patients with CRC after routine colorectal surgery. Proinflammatory nuclear factor kappa B (NFκB) signaling as well as interleukin 6 (IL-6) and S100 protein levels were upregulated in adenocarcinoma compared with nearby healthy colon tissue. In contrast to nitrotyrosine expression, the oxidative stress marker 8-Hydroxy-2′-deoxyguanosine (8-OHdG) was increased in adenocarcinoma tissue. Biomarkers of intestinal differentiation β-catenin and mucin 2 (MUC2) were inversely regulated, with the former upregulated in adenocarcinoma tissue and positively correlated with tumor marker CA19-9. Downregulation of MUC2 expression correlated with the increased 2-year survival rate of patients with CRC. Proliferation-related mammalian target of rapamycin (mTOR) signaling was activated, and Ki67 frequency was three-fold augmented in positive correlation with metastasis and cancer stage, respectively. Conclusion: We demonstrated a parallel induction of oxidative stress and inflammation biomarkers in adenocarcinoma tissue that was not reflected in the neighboring healthy colon tissue of CRC. The expansiveness of colorectal adenocarcinoma was confirmed by irregular intestinal differentiation and elevated proliferation biomarkers, predominantly Ki67. The origin of the linked inflammatory factors was in adenocarcinoma tissue, with an accompanying systemic immune response. [ABSTRACT FROM AUTHOR]

This article considers the issues of ensuring operational performance and environmental sustainability of marine diesel engines by using biodiesel fuel. This research was conducted on 5S60ME-C8 MAN-B&W Diesel Group and 6DL-16 Daihatsu Diesel marine diesel engines, which are operated using RMG380 petroleum fuel and B10 and B30 biodiesel fuels. The efficiency of biofuel usage was assessed based on environmental (reduced nitrogen oxide concentration in exhaust gases) and economic (increased specific effective fuel consumption) criteria. It was found that the use of B10 and B30 biofuels provides a reduction in nitrogen oxide concentration in exhaust gases by 14.71–25.13% but at the same time increases specific effective fuel consumption by 1.55–6.01%. Optimum fuel injection advance angles were determined that ensure the best thermal energy, economic and environmental performance of diesel engines. The optimum angle of biofuel supply advance is determined experimentally and should correspond to the limits recommended by the diesel engine operating instructions. It has been proven experimentally that the use of biofuel increases the environmental sustainability of marine diesel engines by 13.75–29.42%. It increases the diesel engines environmental safety in case of emergency situations as well as accidental and short-term emissions of exhaust gases with an increased content of nitrogen oxides into the atmosphere phenomena that are possible in starting modes of diesel engine operation as well as in modes of sudden load changes. It is the increase in the environmental friendliness of marine diesel engines in the case of using biofuel that is the most positive criterion and contributes to the intensity of biofuel use in power plants of sea vessels. [ABSTRACT FROM AUTHOR]

Glucocorticoids are used during glioblastoma treatment to prevent the cerebral edema effect surrounding normal brain tissue. The aim of our study was to investigate the long-term effects of multiple administrations of glucocorticoids onto the glycosylated components (proteoglycans and glycosaminoglycans) of normal brain extracellular matrix and the glucocorticoid receptor (GR, Nr3c1) in an experimental model in vivo. Two-month-old male C57Bl/6 mice (n = 90) were injected intraperitoneally with various doses of dexamethasone (DXM) (1; 2.5 mg/kg) for 10 days. The mRNA levels of the GR, proteoglycans core proteins, and heparan sulfate metabolism-involved genes were determined at the 15th, 30th, 60th, and 90th days by a real-time RT–PCR. The glycosaminoglycans content was studied using dot blot and staining with Alcian blue. A DXM treatment increased total GAG content (2-fold), whereas the content of highly sulfated glycosaminoglycans decreased (1.5–2-fold). The mRNA level of the heparan sulfate metabolism-involved gene Hs3St2 increased 5-fold, the mRNA level of Hs6St2 increased6–7-fold, and the mRNA level of proteoglycan aggrecan increased 2-fold. A correlation analysis revealed an association between the mRNA level of the GR and the mRNA level of 8 of the 14 proteoglycans-coding and 4 of the 13 heparan sulfate metabolism-involved genes supporting GR involvement in the DXM regulation of the expression of these genes. In summary, multiple DXM administrations led to an increase in the total GAG content and reorganized the brain extracellular matrix in terms of its glycosylation pattern. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common and aggressive brain tumor in adults. Despite surgery, radiation, and chemotherapy, survival rates remain low, which emphasizes the urgent need for improved therapies. Current preclinical models use untreated tumors, which do not reflect the clinical scenario where patients already receive initial treatments. This review examines the effects of current treatments on the properties of recurrent tumors and evaluates preclinical models that incorporate these standard treatments to better mimic real patient conditions. Improving these models could help to identify more effective treatments, potentially leading to better outcomes for glioblastoma patients. Glioblastoma (GBM) presents a significant public health challenge as the deadliest and most common malignant brain tumor in adults. Despite standard-of-care treatment, which includes surgery, radiation, and chemotherapy, mortality rates are high, underscoring the critical need for advancing GBM therapy. Over the past two decades, numerous clinical trials have been performed, yet only a small fraction demonstrated a benefit, raising concerns about the predictability of current preclinical models. Traditionally, preclinical studies utilize treatment-naïve tumors, failing to model the clinical scenario where patients undergo standard-of-care treatment prior to recurrence. Recurrent GBM generally exhibits distinct molecular alterations influenced by treatment selection pressures. In this review, we discuss the impact of treatment—surgery, radiation, and chemotherapy—on GBM. We also provide a summary of treatments used in preclinical models, advocating for their integration to enhance the translation of novel strategies to improve therapeutic outcomes in GBM. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention. [ABSTRACT FROM AUTHOR]

The local dynamics of a system of oscillators with a large number of elements and with diffusive- and advective-type couplings containing a large delay are studied. Critical cases in the problem of the stability of the zero equilibrium state are singled out, and it is shown that all of them have infinite dimensions. Applying special methods of infinite normalization, we construct quasinormal forms, namely, nonlinear boundary value problems of the parabolic type, whose nonlocal dynamics determine the behavior of the solutions of the initial system in a small neighborhood of the equilibrium state. These quasinormal forms contain either two or three spatial variables, which emphasizes the complexity of the dynamical properties of the original problem. [ABSTRACT FROM AUTHOR]

This study has reviewed the many roles of lumican as a biomarker of tissue pathology in health and disease. Lumican is a structure regulatory proteoglycan of collagen-rich tissues, with cell instructive properties through interactions with a number of cell surface receptors in tissue repair, thereby regulating cell proliferation, differentiation, inflammation and the innate and humoral immune systems to combat infection. The exponential increase in publications in the last decade dealing with lumican testify to its role as a pleiotropic biomarker regulatory protein. Recent findings show lumican has novel roles as a biomarker of the hypercoagulative state that occurs in SARS CoV-2 infections; thus, it may also prove useful in the delineation of the complex tissue changes that characterize COVID-19 disease. Lumican may be useful as a prognostic and diagnostic biomarker of long COVID disease and its sequelae. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer accounts for 11.4% of all cancer cases and 18.0% of all cancer deaths. Understanding the molecular mechanisms underlying lung adenocarcinoma (LUAD), one of the most common lung cancers, is imperative to enhance diagnostic accuracy, drug development, and prognostic evaluation. The present study explored the interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4), as well as the influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on the glycolysis, proliferation, and metastasis ability in LUAD cell lines and their effects on the tumor growth in xenograft animal models. GPC4 promotes HS3ST1-mediated glycolysis, and the hypoxia-derived exosomal lncRNA OIP5-AS1 promotes glycolysis via the miR-200c-3p axis in LUAD cells. The hypoxia-derived exosomal lncRNA OIP5-AS1 enhances LUAD cell proliferation and metastasis in vitro and promotes LUAD tumor growth and metastasis via miR-200c-3p in vivo. These findings highlight that the hypoxia-derived exosomal lncRNA OIP5-AS1 may participate in LUAD progression. Objective: The diagnosis of lung adenocarcinoma (LUAD) is often delayed due to the typically asymptomatic nature of the early-stage disease, causing advanced-stage LUAD diagnosis in most patients. Hypoxia is widely recognized as a driving force in cancer progression. Exosomes originating from hypoxic tumor cells promote tumorigenesis by influencing glycolysis, migration, invasion, and immune infiltration. Given these insights, our study aimed to explore the role of hypoxia-derived exosomal long non-coding RNA (lncRNA) OIP5-AS1 in LUAD cell lines and mouse models. Materials and Methods: Exosomes were meticulously isolated and authenticated based on their morphology and biomarkers. The interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4) was examined using immunoprecipitation. The influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on glycolysis was assessed in LUAD cell lines. The effect of the hypoxia-derived exosomal lncRNA OIP5-AS1 on cell proliferation and metastasis was evaluated using colony formation, cell viability, cell cycle, and apoptosis analyses. Its effects on tumor size were confirmed in xenograft animal models. Results: Our study revealed the mechanism of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. We discovered that GPC4 promotes HS3ST1-mediated glycolysis and that the hypoxia-derived exosomal lncRNA OIP5-AS1 enhances glycolysis by regulating miR-200c-3p in LUAD cells. Notably, this lncRNA stimulates LUAD cell proliferation and metastasis and fosters LUAD tumor size via miR-200c-3p. Our findings underscore the potential role of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. Conclusions: The hypoxia-derived exosomal lncRNA OIP5-AS1 promotes LUAD by regulating HS3ST1-GPC4-mediated glycolysis via miR-200c-3p. [ABSTRACT FROM AUTHOR]

Most epithelial ovarian cancer (EOC) patients are diagnosed with peritoneal dissemination. Cellular interactions are an important aspect of EOC cells when they detach from the primary site of the ovary. However, the mechanism remains underexplored. Our study aimed to reveal the role of chondroitin sulfate proteoglycan 4 (CSPG4) in EOC with a major focus on cell–cell interactions. We examined the expression of CSPG4 in clinical samples and cell lines of EOC. The proliferation, migration, and invasion abilities of the CSPG4 knockdown cells were assessed. We also assessed the role of CSPG4 in spheroid formation and peritoneal metastasis in an in vivo model using sh-CSPG4 EOC cell lines. Of the clinical samples, 23 (44.2%) samples expressed CSPG4. CSPG4 was associated with a worse prognosis in patients with advanced EOC. Among the EOC cell lines, aggressive cell lines, including ES2, expressed CSPG4. When CSPG4 was knocked down using siRNA or shRNA, the cell proliferation, migration, and invasion abilities were significantly decreased compared to the control cells. Proteomic analyses showed changes in the expression of proteins related to the cell movement pathways. Spheroid formation was significantly inhibited when CSPG4 was inhibited. The number of nodules and the tumor burden of the omentum were significantly decreased in the sh-CSPG4 mouse models. In the peritoneal wash fluid from mice injected with sh-CSPG4 EOC cells, significantly fewer spheroids were present. Reduced CSPG4 expression was observed in lymphoid enhancer-binding factor 1-inhibited cells. CSPG4 is associated with aggressive features of EOC and poor prognosis. CSPG4 could be a new treatment target for blocking peritoneal metastasis by inhibiting spheroid formation. [ABSTRACT FROM AUTHOR]

Prostate cancer is among the top five cancer types according to incidence and mortality. One of the main obstacles in prostate cancer management is the inability to foresee its course, which ranges from slow growth throughout years that requires minimum or no intervention to highly aggressive disease that spreads quickly and resists treatment. Therefore, it is not surprising that numerous studies have attempted to find biomarkers of prostate cancer occurrence, risk stratification, therapy response, and patient outcome. However, only a few prostate cancer biomarkers are used in clinics, which shows how difficult it is to find a novel biomarker. Cell adhesion to the extracellular matrix (ECM) through integrins is among the essential processes that govern its fate. Upon activation and ligation, integrins form multi-protein intracellular structures called integrin adhesion complexes (IACs). In this review article, the focus is put on the biomarker potential of the ECM- and IAC-related molecules stemming from both body fluids and prostate cancer tissue. The processes that they are involved in, such as tumor stiffening, bone turnover, and communication via exosomes, and their biomarker potential are also reviewed. [ABSTRACT FROM AUTHOR]

The vacuum residue hydrocracker naphtha (VRHN) is a chemically unstable product that during storage changes its colour and forms sediments after two weeks. It cannot be directly exported from the refinery without improving its chemical stability. In this research, the hydrotreatment of H-Oil naphtha with straight run naphtha in a commercial hydrotreater, its co-processing with fluid catalytic cracking (FCC) gasoline in a commercial Prime-G+ post-treater, and its co-processing with vacuum gas oil (VGO) in a commercial FCC unit were discussed. The hydrotreatment improves the chemical stability of H-Oil naphtha and reduces its sulphur content to 3 ppm. The Prime-G+ co-hydrotreating increases the H-Oil naphtha blending research octane number (RON) by 6 points and motor octane number (MON) by 9 points. The FCC co-cracking with VGO enhances the blending RON by 11.5 points and blending MON by 17.6 points. H-Oil naphtha conversion to gaseous products (C1–C4 hydrocarbons) in the commercial FCC unit was found to be 50%. The use of ZSM 5 containing catalyst additive during processing H-Oil naphtha showed to lead to FCC gasoline blending octane enhancement by 2 points. This enabled an increment of low octane number naphtha in the commodity premium near zero sulphur automotive gasoline by 2.4 vol.% and substantial improvement of refinery margin. The processing of H-Oil naphtha in the FCC unit leads also to energy saving as a result of an equivalent lift steam substitution in the FCC riser. [ABSTRACT FROM AUTHOR]

This paper is devoted to the analysis of mathematical models of chemotherapy for malignant tumors growing according to the Gompertz law or the generalized logistic law. The influence of the therapeutic agent on the tumor dynamics is determined by a therapy function depending on the time-varying concentration of the drug in the patient's body. The case of a non-monotonic therapy function with two maxima is studied. It reflects the use of two different therapeutic agents. The state variables of the dynamics are the tumor volume and the amount of the therapeutic agent able to suppress malignant cells (concentration of the drug in the body). The treatment protocol (the rate of administration of the therapeutic agent) is the control in the dynamics. The optimal control problem for this models is considered. It is the problem of the construction of treatment protocols that provide the minimal tumor volume at the end of the treatment. The solution of this problem was obtained by the authors in previous works via the optimal control theory. The form of the considered therapy functions provides a specific structure for the optimal controls. The managerial insights of this structure are discussed. In this paper, the structure of the viability set is described for the model according to the generalized logistic law. It is the set of the initial states of the model for which one can find a treatment protocol that guarantees that the tumor volume remains within the prescribed limits throughout the treatment. The description of the viability set's structure is based on the optimal control theory and the theory of Hamilton–Jacobi equations. An inverse problem of therapy is also considered, namely the problem of reconstruction of the treatment protocol and identification of the unknown parameter of the intensity of the tumor growth. Reconstruction is carried out by processing information about the observations of the tumor volume dynamics and the measurements of the drug concentration in the body. A solution to this problem is obtained through the use of a method based on the calculus of variations. The results of the numerical simulations are presented herein. [ABSTRACT FROM AUTHOR]

Simple Summary: As recurrence in glioblastoma is locally generated around the resection cavity, surviving glioma stem-like cells may cause recurrence. Glioma stem-like cells expressing high levels of CD44 are highly invasive and are required to change to less invasive, more proliferative types to generate a recurrent tumor. CD44 promotes both the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways show reciprocal activation of invasion and proliferation under different conditions of oxygenation. Severe hypoxia activates genes related to cell invasion, whereas moderate hypoxia activates genes related to cell proliferation. CD44 is associated with both pathways and plays a critical role in regulating the balance between the promotion of cell invasion and cell proliferation. These results may indicate that CD44 is a key molecule for executing tumor recurrence in glioblastoma. High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels of CD44 are highly invasive and resistant to radio-chemotherapy. CD44 is a multifunctional molecule that promotes the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways reciprocally activate invasion and proliferation under different hypoxic conditions. Severe hypoxia (0.5–2.5% O2) upregulates hypoxia-inducible factor (HIF)-1α, which then activates target genes, including CD44, TGF-β, and cMET, all of which are related to tumor migration and invasion. In contrast, moderate hypoxia (2.5–5% O2) upregulates HIF-2α, which activates target genes, such as vascular endothelial growth factor (VEGF)/VEGFR2, cMYC, and cyclin D1. All these genes are related to tumor proliferation. Oxygen environments around GBM can change before and after tumor resection. Before resection, the oxygen concentration at the tumor periphery is severely hypoxic. In the reparative stage after resection, the resection cavity shows moderate hypoxia. These observations suggest that upregulated CD44 under severe hypoxia may promote the migration and invasion of tumor cells. Conversely, when tumor resection leads to moderate hypoxia, upregulated HIF-2α activates HIF-2α target genes. The phenotypic transition regulated by CD44, leading to a dichotomy between invasion and proliferation according to hypoxic conditions, may play a crucial role in GBM recurrence. [ABSTRACT FROM AUTHOR]

In this research, for a given time interval, which is the general period of melanoma treatment, a bilinear control model is considered, given by a system of differential equations, which describes the interaction between drug-sensitive and drug-resistant cancer cells both during drug therapy and in the absence of it. This model also contains a control function responsible for the transition from the stage of such therapy to the stage of its absence and vice versa. To find the optimal moments of switching between these stages, the problem of minimizing the cancer cells load both during the entire period of melanoma treatment and at its final moment is stated. Such a minimization problem has a nonconvex control set, which can lead to the absence of an optimal solution to the stated minimization problem in the classes of admissible modes traditional for applications. To avoid this problem, the control set is imposed to be convex. As a result, a relaxed minimization problem arises, in which the optimal solution exists. An analytical study of this minimization problem is carried out using the Pontryagin maximum principle. The corresponding optimal solution is found in the form of synthesis and may contain a singular arc. It shows that there are values of the parameters of the bilinear control model, its initial conditions, and the time interval for which the original minimization problem does not have an optimal solution, because it has a sliding mode. Then for such values it is possible to find an approximate optimal solution to the original minimization problem in the class of piecewise constant controls with a predetermined number of switchings. This research presents the results of the analysis of the connection between such an approximate solution of the original minimization problem and the optimal solution of the relaxed minimization problem based on numerical calculations performed in the Maple environment for the specific values of the parameters of the bilinear control model, its initial conditions, and the time interval. [ABSTRACT FROM AUTHOR]

Polymers derived from natural raw materials have become of great interest due to their increased biodegradable features and possible biocompatibility. Our group has successfully synthesized and characterized polymers derived from D-mannose oligomer (M), 2-hydroxy propyl acrylate (HPA), and methacrylate (HPMA) in different weight ratios. Their biodegradation was studied in liquid media with pure Proteus mirabilis inoculum for the samples with the most sugar residue, and the results show that the methacrylate derivative M_HPMA1 lost about 50% of its weight during incubation. SEM/EDX techniques were employed to display the modifications of the samples during the biodegradation process. The glycopolymers were buried in garden soil, and the experiment proved that more than 40% of the weight of the M_HPA1 sample was lost during biodegradation, while the other samples encountered an average of about 32% weight loss. The biodegradation profile was fitted against linear and polynomial mathematical models, which enabled an estimate of about a year for the total degradation of the D-mannose glycopolymers sample in soil. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5–6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5–2-fold), the inhibition of HS biosynthetic system mainly due to the -3–3.5-fold down-regulation of N-deacetylase/N-sulfotransferases (Ndst1 and Ndst2) and sulfatase 2 (Sulf2) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes (Ext1/2, Ndst1/2, Glce, Hs2st1, Hs6st1/2), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content. [ABSTRACT FROM AUTHOR]

C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly Dullard) is a member of the newly emerging protein phosphatases and has been recognized in neuronal cell tissues in amphibians. It contains the phosphatase domain in the C-terminal, and the sequences are conserved in various taxa of organisms. CTDNEP1 has several roles in novel biological activities such as neural tube development in embryos, nuclear membrane biogenesis, regulation of bone morphogenetic protein signaling, and suppression of aggressive medulloblastoma. The three-dimensional structure of CTDNEP1 and the detailed action mechanisms of CTDNEP1's functions have yet to be determined for several reasons. Therefore, CTDNEP1 is a protein phosphatase of interest due to recent exciting and essential works. In this short review, we summarize the presented biological roles, possible substrates, interacting proteins, and research prospects of CTDNEP1. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of dense stroma that is enriched in hyaluronan (HA), with increased HA levels associated with more aggressive disease. Increased levels of the HA-degrading enzymes hyaluronidases (HYALs) are also associated with tumor progression. In this study, we evaluate the regulation of HYALs in PDAC. Methods: Using siRNA and small molecule inhibitors, we evaluated the regulation of HYALs using quantitative real-time PCR (qRT-PCR), Western blot analysis, and ELISA. The binding of BRD2 protein on the HYAL1 promoter was evaluated by chromatin immunoprecipitation (ChIP) assay. Proliferation was evaluated by WST-1 assay. Mice with xenograft tumors were treated with BET inhibitors. The expression of HYALs in tumors was analyzed by immunohistochemistry and by qRT-PCR. Results: We show that HYAL1, HYAL2, and HYAL3 are expressed in PDAC tumors and in PDAC and pancreatic stellate cell lines. We demonstrate that inhibitors targeting bromodomain and extra-terminal domain (BET) proteins, which are readers of histone acetylation marks, primarily decrease HYAL1 expression. We show that the BET family protein BRD2 regulates HYAL1 expression by binding to its promoter region and that HYAL1 downregulation decreases proliferation and enhances apoptosis of PDAC and stellate cell lines. Notably, BET inhibitors decrease the levels of HYAL1 expression in vivo without affecting the levels of HYAL2 or HYAL3. Conclusions: Our results demonstrate the pro-tumorigenic role of HYAL1 and identify the role of BRD2 in the regulation of HYAL1 in PDAC. Overall, these data enhance our understanding of the role and regulation of HYAL1 and provide the rationale for targeting HYAL1 in PDAC. [ABSTRACT FROM AUTHOR]

The proteins of extracellular vesicles (EVs) provide proteomic signatures that reflect molecular features of EV-producing cells, including cancer cells. Detection of cancer cell EV proteins is of great interest due to the development of novel predictive diagnostic approaches. Using targeted mass spectrometry with stable-isotope-labeled peptide standards (SIS), we measured in this study the levels of 34 EV-associated proteins in vesicles and whole lysate derived from the colorectal cancer (CRC) cell lines Caco-2, HT29 and HCT116. We also evaluated the abundance of 13 EV-associated proteins (FN1, TLN1, ITGB3, HSPA8, TUBA4A, CD9, CD63, HSPG2, ITGB1, GNAI2, TSG101, PACSIN2, and CDC42) in EVs isolated from blood plasma samples from 11 CRC patients and 20 healthy volunteers. Downregulation of TLN1, ITGB3, and TUBA4A with simultaneous upregulation of HSPG2 protein were observed in cancer samples compared to healthy controls. The proteomic cargo of the EVs associated with CRC represents a promising source of potential prognostic markers. [ABSTRACT FROM AUTHOR]

Chains of coupled van der Pol equations are considered. The main assumption that motivates the use of special asymptotic methods is that the number of elements in the chain is sufficiently large. This allows moving from a discrete system of equations to the use of a continuity argument and obtaining an integro-differential boundary value problem as the initial model. In the study of the behaviour of all its solutions in a neighbourhood of the equilibrium state, infinite-dimensional critical cases arise in the problem of the stability of solutions. The main results include the construction of special families of quasi-normal forms, namely non-linear boundary value problems of either Schrödinger or Ginzburg–Landau type. Their solutions make it possible to determine the main terms of the asymptotic expansion of both regular and irregular solutions to the original system. The main goal is the study of chains with diffusion- and advective-type couplings, as well as fully connected chains. [ABSTRACT FROM AUTHOR]

Countries around the world recognize the numerous social, economic and environmental advantages of promoting liquid biofuels. They invest in its development and introduce tax incentives for its manufacture and tariffs of production regulation. In most studies, the process of synthesizing fatty acid esters takes a long time from 1 to 8 h. In this work, the synthesis of fatty acid esters was carried out in the range of volumetric ratios of ethanol to linoleic type oil in order to increase the kinetics of the process. The main parameters of the synthesis were studied by use of magnetic stirred tank reactors in a parallel reactor system, H.E.L. The synthesis was carried out in the presence of a homogeneous alkaline catalyst. The volumetric ratio of ethanol to oil was maintained at 1:1, 2:1, 3:1, 4:1 and 5:1. The amount of catalyst added to the reaction mixture ranged from 0.25 to 2.5% by the weight of the reaction alcohol. The dryness of ethanol varied from 91 to 99%. Effective process conditions have been established to reduce the reaction time from 2.5 h to 5 min while maintaining a high degree of conversion. The results obtained during the study suggest the possibility of using a continuous reactor to produce fatty acid esters from linoleic raw materials containing up to 16% of free fatty acids. This also means the possibility of using second generation biofuel feedstock. [ABSTRACT FROM AUTHOR]

Versican (VCAN), also known as extracellular matrix proteoglycan 2, has been suggested as a potential biomarker in cancers. Previous research has found that VCAN is highly expressed in bladder cancer. However, its role in predicting outcomes for patients with upper urinary tract urothelial cancer (UTUC) is not well understood. In this study, we collected tissues from 10 patients with UTUC, including 6 with and 4 without lymphovascular invasion (LVI), a pathological feature that plays a significant role in determining metastasis. Results from RNA sequencing revealed that the most differentially expressed genes were involved in extracellular matrix organization. Using the TCGA database for clinical correlation, VCAN was identified as a target for study. A chromosome methylation assay showed that VCAN was hypomethylated in tumors with LVI. In our patient samples, VCAN expression was also found to be high in UTUC tumors with LVI. In vitro analysis showed that knocking down VCAN inhibited cell migration but not proliferation. A heatmap analysis also confirmed a significant correlation between VCAN and migration genes. Additionally, silencing VCAN increased the effectiveness of cisplatin, gemcitabine and epirubicin, thus providing potential opportunities for clinical application. [ABSTRACT FROM AUTHOR]

Malaria is a serious illness caused by a parasite, called Plasmodium, transmitted to humans through the bites of female Anopheles mosquitoes. The parasite infects and destroys the red blood cells in the human body leading to symptoms, such as fever, headache, and flu-like illness. Awareness campaigns that educate people about malaria prevention and control reduce transmission of the disease. In this research, a mathematical model is proposed to study the impact of awareness-based control measures on the transmission dynamics of malaria. Some basic properties of the proposed model, such as non-negativity and boundedness of the solutions, the existence of the equilibrium points, and their stability properties, have been studied using qualitative theory. Disease-free equilibrium is globally asymptotic when the basic reproduction number, R 0 , is less than the number of current cases. Finally, optimal control theory is applied to minimize the cost of disease control and solve the optimal control problem by applying Pontryagin's minimum principle. Numerical simulations have been provided for the confirmation of the analytical results. Endemic equilibrium exists for R 0 > 1 , and a forward transcritical bifurcation occurs at R 0 = 1 . The optimal profiles of the treatment process, organizing awareness campaigns, and insecticide uses are obtained for the cost-effectiveness of malaria management. This research concludes that awareness campaigns through social media with an optimal control approach are best for cost-effective malaria management. [ABSTRACT FROM AUTHOR]

Simple Summary: Normal epithelial cells in our organs are surrounded by stroma, which is an ecosystem made up of a variety of cells and proteins that support their intended functions. When normal epithelial cells go through a series of genetic steps that transform them into cancer cells, the cancer cells, in turn, change the character of the stroma. The stroma co-evolves with the cancer to become an autonomous tumor organ with its own ecosystem. Initially, stromal cells try to maintain normal epithelial cell function and suppress malignant changes. However, during their co-evolution, the cancer cells recruit supporting cells to actively promote their growth, invasion, metastasis, and treatment resistance. Here, I outline how cancer cells change the character of the most abundant cells in the stroma, called fibroblasts, and how the altered fibroblasts, in turn, make cancers more aggressive. I also outline efforts to use these changed fibroblasts as new targets for cancer treatment. Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer "wounds" the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

The well-known Van der Pol equation with delayed feedback is considered. It is assumed that the delay factor is large enough. In the study of the dynamics, the critical cases in the problem of the stability of the zero equilibrium state are identified. It is shown that they have infinite dimension. For such critical cases, special local analysis methods have been developed. The main result is the construction of nonlinear evolutionary boundary value problems, which play the role of normal forms. Such boundary value problems can be equations of the Ginzburg–Landau type, as well as equations with delay and special nonlinearity. The nonlocal dynamics of the constructed equations determines the local behavior of the solutions to the original equation. It is shown that similar normalized boundary value problems also arise for the Van der Pol equation with a large coefficient of the delay equation. The important problem of a small perturbation containing a large delay is considered separately. In addition, the Van der Pol equation, in which the cubic nonlinearity contains a large delay, is considered. One of the general conclusions is that the dynamics of the Van der Pol equation in the presence of a large delay is complex and diverse. It fundamentally differs from the dynamics of the classical Van der Pol equation. [ABSTRACT FROM AUTHOR]

Dogs can be excellent models for spontaneous studies about breast cancers, presenting similarities in clinical behavior and molecular pathways of the disease. Thus, analyses of the canine transcriptome can identify deregulated genes and pathways, contributing to the identification of biomarkers and new therapeutic targets, benefiting humans and animals. In this context, this study aimed to determine the transcriptional profile of canine mammary ductal carcinoma and contribute to the clarification of the importance of deregulated molecules in the molecular pathways involved in the disease. Therefore, we used mammary ductal carcinoma tissue samples and non-tumor mammary tissue from the radical mastectomy of six female dogs. Sequencing was performed on the NextSeq-500 System platform. A comparison of carcinoma tissue and normal tissue revealed 633 downregulated and 573 upregulated genes, which were able to differentiate the groups by principal component analysis. Gene ontology analysis indicated that inflammatory, cell differentiation and adhesion, and extracellular matrix maintenance pathways were mainly deregulated in this series. The main differentially expressed genes observed in this research can indicate greater disease aggressiveness and worse prognosis. Finally, the study of the canine transcriptome indicates that it is an excellent model to generate information relevant to oncology in both species. [ABSTRACT FROM AUTHOR]

With the rapid development of high-pressure combustible gas pipelines, it brings convenience and also buries potential safety hazards. This paper presents an in-depth exploration of the thermal radiation hazards of fireball accidents caused by leakage and provides a reference for the prevention and control of this type of accident and on-site rescue. Based on the basic principle of fluid mechanics and the calculation model of the leakage rate, a three-dimensional pipeline model was constructed by FDS software to simulate the fireballs with different positions of low, middle and high. The simulation shows that the ground temperature field of the low and middle fireballs is quite different from that of the high fireball, and the temperature level is: low position > middle position > high position. On this basis, the observation elevation angle is introduced to improve the classical fireball thermal radiation model formula, the model calculation value is compared with the numerical simulation value and the optimal threshold is determined by combining the thermal radiation flux criterion. The results show that the numerical simulation is basically consistent with the calculation results of the improved model. The smaller the observation elevation angle, the closer the target receives the thermal radiation flux to the optimal threshold and the calculated hazard range is more reliable. [ABSTRACT FROM AUTHOR]

Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 h after injection in mice. Patch clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 h after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting the key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories. [ABSTRACT FROM AUTHOR]

The authors underline the importance of these components in many aspects, characterizing tumor progression, such as tumor stiffness, angiogenesis and tumor cell invasion. This study further highlights the interconnection between ECM, the tumor microenvironment, and the immune response in addition to their reciprocal influence, which is essential in determining tumor progression and outcome. Importantly, colon cancer cell treatment with conditioned media from adipocytes isolated from obese patients enhanced the DPT expression, highlighting the importance of this ECM molecule in obesity-associated colon cancer onset. [Extracted from the article]

Characterizing geological heritage sites (geosites) available in Russia remains an urgent task. The present study focuses on two geosites from the vicinity of Kazan—a large city on the Volga River. They are attributed to the standardized geoheritage types and scored by means of several criteria. It is found out that the Pechischi geosite represents nine geoheritage types, from which the stratigraphical type (stratotype section of the Upper Kazanian regional unit of the Guadalupian) and the geohistorical type (history of the Permian System studies) are the most important. This geosite reaches 675 out of 750 maximum possible scores, and it is ranked globally. The Cheremushki geosite represents six geoheritage types, from which the stratigraphical type (reference section of the Urzhumian regional unit of the Guadalupian) and the paleontological type (locality of diverse fossils, including tetrapods) are the most important. This geosite reaches a score of 250 and is ranked nationally. The undertaken study allows for recommending several actions for the effective conservation and exploitation of these geosites. The innovative interpretation is that the presence of geosites at the urban periphery makes its general (not only geological) heritage value comparable to that of the city's center. [ABSTRACT FROM AUTHOR]

Cardiac troponins T and I are the main (most sensitive and specific) laboratory indicators of myocardial cell damage. A combination of laboratory signs of myocardial cell damage (elevated levels of cardiac troponins T and I) with clinical (severe chest pain spreading to the left side of the human body) and functional (rise or depression of the ST segment, negative T wave or emergence of the Q wave according to electrocardiography and/or decrease in the contractility of myocardial areas exposed to ischemia according to echocardiography) signs of myocardial ischemia is indicative of the ischemic damage to cardiomyocytes, which is characteristic of the development of acute coronary syndrome (ACS). Today, with early diagnostic algorithms for ACS, doctors rely on the threshold levels of cardiac troponins (99th percentile) and on the dynamic changes in the serum levels over several hours (one, two, or three) from the moment of admission to the emergency department. That said, some recently approved highly sensitive methods for determining troponins T and I show variations in 99th percentile reference levels, depending on gender. To date, there are conflicting data on the role of gender specificities in the serum levels of cardiac troponins T and I in the diagnostics of ACS, and the specific mechanisms for the formation of gender differences in the serum levels of cardiac troponins T and I are unknown. The purpose of this article is to analyze the role of gender specificities in cardiac troponins T and I in the diagnostics of ACS, and to suggest the most likely mechanisms for the formation of differences in the serum levels of cardiac troponins in men and women. [ABSTRACT FROM AUTHOR]

In this article, the transmission dynamical model of the deadly infectious disease named Ebola is investigated. This disease identified in the Democratic Republic of Congo (DRC) and Sudan (now South Sudan) and was identified in 1976. The novelty of the model under discussion is the inclusion of advection and diffusion in each compartmental equation. The addition of these two terms makes the model more general. Similar to a simple population dynamic system, the prescribed model also has two equilibrium points and an important threshold, known as the basic reproductive number. The current work comprises the existence and uniqueness of the solution, the numerical analysis of the model, and finally, the graphical simulations. In the section on the existence and uniqueness of the solutions, the optimal existence is assessed in a closed and convex subset of function space. For the numerical study, a nonstandard finite difference (NSFD) scheme is adopted to approximate the solution of the continuous mathematical model. The main reason for the adoption of this technique is delineated in the form of the positivity of the state variables, which is necessary for any population model. The positivity of the applied scheme is verified by the concept of M-matrices. Since the numerical method gives a discrete system of difference equations corresponding to a continuous system, some other relevant properties are also needed to describe it. In this respect, the consistency and stability of the designed technique are corroborated by using Taylor's series expansion and Von Neumann's stability criteria, respectively. To authenticate the proposed NSFD method, two other illustrious techniques are applied for the sake of comparison. In the end, numerical simulations are also performed that show the efficiency of the prescribed technique, while the existing techniques fail to do so. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) of the central nervous system (CNS), characterized by low stiffness and predominance of carbohydrates on protein components, mediates limited cell proliferation and migration. Pectins are polysaccharides derived from plants and could be very promising for a tunable hydrogel design that mimics the neural ECM. Aiming to regulate gel structure and viscoelastic properties, we elaborated 10 variants of pectin-based hydrogels via tuning the concentration of the polymer and the number of free carboxyl groups expressed in the degree of esterification (DE). Viscoelastic properties of hydrogels varied in the range of 3 to 900 Pa for G′ and were chosen as the first criteria for the selection of variants suitable for CNS remodeling. For extended reciprocal characterization, two pairs of hydrogels were taken to test pectins with opposite DEs close to 0% and 50%, respectively, but with a similar rheology exceeding 100 Pa (G′), which was achieved by adjusting the concentration of pectin. Hydrogel swelling properties and in vitro stability, together with structure characterization using SEM and FTIR spectroscopy, displayed some differences that may sense for biomedical application. Bioassays on C6 and U87MG glioblastoma cultures testified the potential prospects of the anti-glioma activity of hydrogels developed by decreasing cell proliferation and modulating migration but supporting the high viability of neural cells. [ABSTRACT FROM AUTHOR]

Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain. [ABSTRACT FROM AUTHOR]

Analysis of the very-low-sulfur fuel oil (VLSFO) and ultra-low-sulfur fuel oil (ULSFO) bunkered in key ports in Asia, the Middle East, North America, Western Europe, and Russia is presented. The characteristics of said fuels, including density, sulfur content, kinematic viscosity, aluminum and silicon content, vanadium and nickel content, as well as pour point are investigated. Furthermore, the main trends and correlations are also discussed. Based on the graphical and mathematical analysis of the properties, the composition of the fuels is predicted. The key fuel components in Asian ports, the most important of which is Singapore, are hydrodesulfurized atmospheric residues (AR) (50–70%) and catalytic cracker heavy cycle oil (HCO) (15–35%) with the addition of other components, which is explained by the presence of a number of large oil refining centers in the area. In the Middle East ports, the most used VLSFO compositions are based on available resources of low-sulfur components, namely hydrodesulfurized AR, the production facilities of which were recently built in the region. In European ports, due to the relatively low sulfur content in processed oils, straight-run AR is widely used as a component of low-sulfur marine fuels. In addition, fuels in Western European ports contain on average significantly more hydrotreated vacuum gas oil (21%) than in the rest of the world (4–5%). Finally, a mixture of hydrotreated (80–90%) and straight-run fuel oil (10–15%) with a sulfur content of no more than 2.0–2.5% is used as the base low-sulfur component of marine fuels in the ports of Singapore and the Middle East. [ABSTRACT FROM AUTHOR]

Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins to form proteoglycans (PGs). GAGs/PGs are major components of the cell surface and the extracellular matrix (ECM), and they display critical roles in development, normal function, and damage response in the body. Some properties (such as expression quantity, molecular weight, and sulfation pattern) of GAGs may be altered under pathological conditions. Due to the close connection between these properties and the function of GAGs/PGs, the alterations are often associated with enormous changes in the physiological/pathological status of cells and organs. Therefore, these GAGs/PGs may serve as marker molecules of disease. This review aimed to investigate the structural alterations and roles of GAGs/PGs in a range of diseases, such as atherosclerosis, cancer, diabetes, neurodegenerative disease, and virus infection. It is hoped to provide a reference for disease diagnosis, monitoring, prognosis, and drug development. [ABSTRACT FROM AUTHOR]