bluuebunny/crossref_metadata_2025_split huggingface dataset:
Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells
Authors: Zhang Yue , Ding Xiaowei , Miao Changhong , Chen Jiawei 
Published: May 2019

Abstract
Purpose: The levels of tight junction proteins (TJs), especially occludin correlate with blood-brain barrier (BBB) disruption caused by central nervous system (CNS) inflammation during perioperative period. It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of TNF-α and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms.
Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK and occludin were measured by Western blot analysis. The in vitro cell viability of hCMEC/D3 cells was measured by cell counting kit-8.
Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. In addition, the inhibitors of Hif-1α, VEGF, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression.
Conclusion: TNF-α could decrease the expression of occludin via Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, which was attenuated by propofol.
Using multi-temporal analysis to classify monthly precipitation based on maximal overlap discrete wavelet transform
Authors: Roushangar Kiyoumars , Alizadeh Farhad 
Published: May 2019

AbstractIn the present study, a hybrid methodology was proposed in which temporal pre-processing and spatial classification approaches were used in a way to take advantage of multiscale properties of precipitation series. Monthly precipitation data (1960–2010) for 31 rain gauges were used in the proposed classification approaches. Maximal overlap discrete wavelet transform (MODWT) was used to capture the time–frequency attributes of the time series and multiscale regionalization was performed by using self-organizing maps (SOM) clustering model. Daubechies 2 function was selected as mother wavelet to decompose the precipitation time series. Also, proper boundary extensions and decomposition level were applied. Different combinations of the wavelet (W) and scaling (V) coefficients were used to determine the input dataset as a basis of spatial clustering. Four input combinations were determined as single-cycle and the remaining four combinations were determined with multi-temporal dataset. These combinations were determined in a way to cover all possible scales captured from MODWT. The proposed model's efficiency in spatial clustering stage was verified using Silhouette Coefficient index. Results demonstrated superior performance of MODWT-SOM in comparison to historical-based SOM approach. It was observed that the clusters captured by MODWT-SOM approach determined homogenous precipitation areas very well (based on physical analysis).
New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations
Authors: Marques Maiara Bernardes , González-Durruthy Michael , da Silva Nornberg Bruna Félix , Oliveira Bruno Rodrigues , Almeida Daniela Volcan , de Souza Votto Ana Paula , Marins Luis Fernando 
Published: May 2019

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.
Cirrhotic Cardiomyopathy: The Interplay Between Liver and Cardiac Muscle. How Does the Cardiovascular System React When the Liver is Diseased?
Authors: Dourakis Spyros P. , Geladari Eleni , Geladari Charalampia , Vallianou Natalia 
Published: May 2019

:
It is widely known that liver cirrhosis, regardless of the etiologies is accompanied by severe
hemodynamic changes. The principal pathophysiological mechanisms are the hyperdynamic
circulation with increased cardiac output, heart rate along with reduced systemic vascular resistance.
Thus, counteractive mechanisms may develop that eventually lead to systolic as well as diastolic dysfunction
and rhythm disturbances, in order to keep a steady homeostasis in the human body.

:
Literally, blunted contractile responsiveness to physical or pharmacological stress, impaired diastolic
relaxation and electrophysiological changes, primarily QT interval prolongation, do occur
progressively in a cirrhotic patient with no known preexisting cardiac disease. This condition is
identified as cirrhotic cardiomyopathy (CCM), an entity different from that seen in alcoholic cardiac
muscle disease.

:
For the past decades, clinicians did study and attempt to understand the pathophysiology and clinical
significance of this process. Indeed, various factors have been identified acting at the molecular
and cellular level.

:
Electrocardiography, echocardiography and various serum biomarkers are the main tools that help
healthcare practitioners to point to the correct diagnosis.

:
Noteworthy, the subjects that suffer from cirrhotic cardiomyopathy may progress to heart failure
during invasive procedures such as surgery, insertion of a transjugular intrahepatic portosystemic
shunting (TIPS) and liver transplantation. Besides, several studies have illustrated that CCM is a
contributing factor, or even a precipitant, of hepatorenal syndrome (HRS), a conceivable reversible
kidney failure in patients with liver cirrhosis and ascites.

:
The treatment is the same as it is in the patients with liver cirrhosis and heart failure and there is no
particular treatment for cirrhotic cardiomyopathy. Hence, it is of utmost importance to clearly comprehend
the pathophysiology of this disease in order to design more accurate diagnostic tools and
definitive treatments in a way to prevent the complications of cirrhosis and overt heart failure.

:
The objective of this review is to describe in a comprehensive way the pathological alterations that
occur in the cardiovascular system of cirrhotic patients. It will also point the limitations that remain in
the diagnosis and treatment strategies and more importantly, this review will alert the clinicians in the
modern era to further observe and record additional pathological changes in this subset of patients.
A Marine-based Meriolin (3-Pyrimidinylazaindole) Derivative (4ab) Targets PI3K/AKT /mTOR Pathway Inducing Cell Cycle Arrest and Apoptosis in Molt-4 Cells
Authors: Chashoo Gousia , Singh Umed , Singh Parvinder P. , Mondhe Dilip M. , Vishwakarma Ram A. 
Published: May 2019

Background:
Cyclin-dependent kinases play a central role in the control of cell division
and therefore it is not surprising that cancer exhibits some features that disturb the normal controls
over the cell cycle. Previous studies related to the development of 3-Pyrimidinylazaindole (Meriolin)
derivatives as novel Cyclin dependent kinase inhibitors highlighted 4ab as the most potent inhibitor.

Objective:
The main objective of the current study was to understand the mode of cell death and the
effect of 4ab on major cellular networking pathways in cancer.

Method:
Preliminary apoptotic studies were carried out using flowcytometer and electron microscope.
The effect on cellular signalling was studied via western blotting.

Results:
4ab was found to inhibit the enzymatic activity of CDK2. The inhibition of CDK2 activity
was found to be associated with the down-regulation of P-cdc-25 and arrest of cells in G0-G1 phase of
the cell cycle in lymphoblastic leukemia cells. Further, 4ab was found to affect AKT-mToR pathway
by down-regulating the expression of major proteins including P-m-TOR (2448), P110α, P-AKT
(S473) and P-p-70S6K.

Conclusion:
Current study shows that the potent anticancer potential of 4ab is mediated via cellular
apoptosis, dysregulation of mitochondrial membrane potential and arrest of G1 phase in Molt-4 cells.
Further, target-based studies showed the effect of 4ab on one of the major cellular signalling pathways
deregulated in cancer.
SIMULATION OF ECHO SIGNALS OF TWO-POSITION SYSTEMS USING COHERENT EMITTERS
Authors: Sabitov T. I. , Kiselev A. V. 
Published: May 2019

The paper deals with the task of simulating echo signals of a radar system for two-position systems. Relations have been obtained for calculating the coordinates of the emitters of a matrix simulator in the form of a system that satisfies the conditions of in-phase conditions of signals at two receiving points. The condition of signal synchronization is achieved when the difference in distance from the emitters of the matrix to the receiving points is an integer number of wavelengths. Based on the obtained relations, an iterative algorithm for the formation of a matrix of coherent emitters has been developed, which allows synthesizing matrices of any sizes. An example of the implementation of the iterative algorithm showed that by selecting the values of the distances from the matrix emitters to the receiving points, the emitters can be located almost on one line. The obtained theoretical results are confirmed by numerical simulation data.
ALGORITHM FOR CALCULATING SURFACES OF BIFOCAL LENS ANTENNAS
Authors: Nikulina Yu. S. 
Published: May 2019

An algorithm is proposed that makes it possible to calculate the coefficients of power polynomials approximating the illuminated and shadow surfaces of bifocal lens antennas. The algorithm is based on providing equality of electrical lengths of rays passing from the focus points through lens body and its edge and on the assumption that the phase front is flat and is inclined at a determined angle relative to the main optical axis of the lens on the aperture of the lens antenna. For each of the rays an expression was written that determines its electrical length. The electrical length of the rays depends on the points coordinates of the illuminated and shadow surface of the lens, in which they are refracted. The analytical solution of the obtained equation is difficult. Therefore, it is proposed to determine the exact coordinate values by numerical methods. The proposed algorithm determines in series the three points lying on the illuminated and shadow surfaces. The coordinates of the points are used to form systems of equations whose solutions are the coefficients of power polynomials approximating the illuminated and shadow surfaces of the lens antenna. The algorithm does not impose restrictions on the relative dielectric constant of the material from which the lens antenna is made.
Examining Cost Measurements in Production and Delivery of Three Case Studies Using E-Learning for Applied Health Sciences: Cross-Case Synthesis
Authors: Meinert Edward , Alturkistani Abrar , Foley Kimberley A , Brindley David , Car Josip 
Published: May 2019

Background
The World Health Report (2006) by the World Health Organization conveys that a significant increase is needed in global health care resourcing to meet the current and future demand for health professionals. Electronic learning (e-Learning) presents a possible opportunity to change and optimize training by providing a scalable means for instruction, thus reducing the costs for training health professionals and providing patient education. Research literature often suggests that a benefit of e-Learning is its cost-effectiveness compared with face-to-face instruction, yet there is limited evidence with respect to the comparison of design and production costs with other forms of instruction or the establishment of standards pertaining to budgeting for these costs.

Objective
To determine the potential cost favorability of e-Learning in contrast to other forms of learning, there must first be an understanding of the components and elements for building an e-Learning course. Without first taking this step, studies lack the essential financial accounting rigor for course planning and have an inconsistent basis for comparison. This study aimed to (1) establish standard ingredients for the cost of e-Learning course production and (2) determine the variance instructional design has on the production costs of e-Learning courses.

Methods
This study made use of a cross-case method among 3 case studies using mixed methods, including horizontal budget variance calculation and qualitative interpretation of responses from course designers for budget variance using total quality management themes. The different implementation-specific aspects of these cases were used to establish common principles in the composition of budgets in the production and delivery of an applied health professional e-Learning course.

Results
A total of 2 case studies reported significant negative budget variances caused by issues surrounding underreporting of personnel costs, inaccurate resource task estimation, lack of contingency planning, challenges in third-party resource management, and the need to update health-related materials that became outdated during course production. The third study reported a positive budget variance because of the cost efficiency derived from previous implementation, the strong working relationship of the course project team, and the use of iterative project management methods.

Conclusions
This research suggests that the delivery costs of an e-Learning course could be underestimated or underreported and identifies factors that could be used to better control budgets. Through consistent management of factors affecting the cost of course production, further research could be undertaken using standard economic evaluation methods to evaluate the advantages of using e-Learning.
Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy
Authors: Gordin Daniel , Shah Hetal , Shinjo Takanori , St-Louis Ronald , Qi Weier , Park Kyoungmin , Paniagua Samantha M. , Pober David M. , Wu I-Hsien , Bahnam Vanessa , Brissett Megan J. , Tinsley Liane J. , Dreyfuss Jonathan M. , Pan Hui , Dong Yutong , Niewczas Monika A. , Amenta Peter , Sadowski Thorsten , Kannt Aimo , Keenan Hillary A. , King George L. 
Published: May 2019

OBJECTIVEElevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists’ plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy.RESEARCH DESIGN AND METHODSImmunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA.RESULTSGlycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD− versus CKD+ individuals with type 2 diabetes. Medalists’ plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA.CONCLUSIONSElevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.
Serum Ethylamine Levels as an Indicator of l-Theanine Consumption and the Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study
Authors: Ninomiya Toshiharu , Kanzaki Noriyuki , Hirakawa Yoichiro , Yoshinari Masahito , Higashioka Mayu , Honda Takanori , Shibata Mao , Sakata Satoko , Yoshida Daigo , Teramoto Takanori , Takemoto Susumu , Nishimoto Shozo , Hata Jun , Kitazono Takanari 
Published: May 2019

OBJECTIVE
This study investigated the association between serum ethylamine levels as an indicator of l-theanine consumption and the development of type 2 diabetes in a Japanese community.

RESEARCH DESIGN AND METHODS
A total of 2,253 community-dwelling Japanese individuals aged 40–79 years without diabetes were monitored for 7 years. Serum ethylamine levels were divided into quartiles: ≤0.86, 0.87–2.10, 2.11–5.28, and ≥5.29 ng/mL. Kinetic analysis of serum ethylamine concentrations was performed after ingestion of l-theanine–rich green tea products containing 8 mg of l-theanine by 12 healthy volunteers.

RESULTS
During follow-up, 282 subjects developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes decreased significantly with elevating levels of serum ethylamine (P for trend = 0.04). This association remained unchanged after adjusting for potential confounding factors. The multivariable-adjusted hazard ratio (HR) for type 2 diabetes was significantly lower in the fourth quartile of serum ethylamine than in the first quartile (HR 0.69, 95% CI 0.49–0.98). This trend of decrease in diabetic risk across serum ethylamine levels was more prominent in middle-aged subjects and in subjects with prediabetes, obesity, or insulin resistance. Kinetic analysis estimated that the minimum concentration at the steady state was &gt;5.90 ng/mL in the case of twice-daily ingestion with an interval of 12 h.

CONCLUSIONS
Higher serum ethylamine was significantly associated with lower risk of the development of type 2 diabetes in a general Japanese population. The measurement of serum ethylamine concentration would be a useful biomarker for the objective estimation of l-theanine consumption.
Lipoprotein(a) and Cardiovascular Outcomes in Patients With Coronary Artery Disease and Prediabetes or Diabetes
Authors: Jin Jing-Lu , Cao Ye-Xuan , Zhang Hui-Wen , Sun Di , Hua Qi , Li Yan-Fang , Guo Yuan-Lin , Wu Na-Qiong , Zhu Cheng-Gang , Gao Ying , Dong Qiu-Ting , Liu Hui-Hui , Dong Qian , Li Jian-Jun 
Published: May 2019

OBJECTIVE
The aim of the current study is to determine the impact of elevated lipoprotein(a) [Lp(a)] on cardiovascular events (CVEs) in stable coronary artery disease (CAD) patients with different glucose metabolism status.

RESEARCH DESIGN AND METHODS
In this multicenter study, we consecutively enrolled 5,143 patients from March 2011 to February 2015. Patients were categorized according to status of glucose metabolism (diabetes mellitus [DM], pre–diabetes mellitus [pre-DM], and normal glucose regulation [NGR]) levels and further classified into 12 groups by Lp(a) levels. CVE end points included nonfatal acute myocardial infarction (MI), stroke, and cardiovascular mortality. All subjects were followed up for the occurrence of the CVEs.

RESULTS
During a median of 6.1 years’ follow-up, 435 (8.5%) CVEs occurred. No significant difference in occurrence of CVEs was observed between NGR and pre-DM groups (hazard ratio 1.131 [95% CI 0.822–1.556], P &gt; 0.05). When status of glucose metabolism was incorporated in stratifying factors, 30 ≤ Lp(a) &lt; 50 mg/dL and Lp(a) ≥50 mg/dL were associated with significantly higher risk of subsequent CVEs in pre-DM (2.181 [1.099–4.327] and 2.668 [1.383–5.415], respectively; all P &lt; 0.05) and DM (3.088 [1.535–5.895] and 3.470 [1.801–6.686], all P &lt; 0.05). Moreover, adding Lp(a) to the Cox model increased the C-statistic by 0.022 and 0.029 in pre-DM and DM, respectively, while the C-statistic was not statistically improved when Lp(a) was included for CVEs prediction in NGR.

CONCLUSIONS
Our findings, for the first time, indicated that elevated Lp(a) levels might affect the prognosis in patients with pre-DM with stable CAD, suggesting that Lp(a) may help further stratify stable CAD patients with mild impaired glucose metabolism.