Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor ß and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor ß and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor ß after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor ß-STAT3 and PDGF-PDGF receptor ß-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.

Reduced IFN-γ levels along with changes in hematologic and immunologic parameters are key to COVID-19 severity in Bangladeshi patients.

The manifestation of coronavirus disease 2019 (COVID-19) severity and mortality has been associated with dysregulation of the immune response, often influenced by racial disparities and conferred by changes in hematologic and immunologic parameters. These biological and hematologic parameters as well as cytokine profiles were investigated in a cohort of 61 COVID-19-positive patients (categorized into mild, moderate, and severe groups) from Bangladesh using standard analytical methods. The data reported that the interleukin (IL)-4 and IL-6 levels were significantly increased, whereas the levels of interferon (IFN)-γ were significantly reduced in patients with severe COVID-19 (p < 0.05) compared with those in patients with mild and/or moderate COVID-19. The extent of erythrocyte sedimentation rate (ESR); neutrophil count; and levels of ferritin, C-reactive protein (CRP), and D-dimer (p < 0.05) were found to be significantly increased, whereas the white blood cell (WBC), lymphocyte, eosinophil, and platelet counts (p < 0.05) were observed to be significantly reduced in patients with severe COVID-19 compared with those in the patients in other 2 groups. Our study exhibited a significantly higher IL-6-to-lymphocyte ratio in patients with severe COVID-19 than in those with mild and moderate COVID-19. The calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and ferritin-to-ESR ratio were significantly increased in patients with severe COVID-19. The increase in the IL-4 and IL-6 levels along with CRP and D-dimer levels may envisage a hyperinflammatory environment and immune dysregulation, which contribute to prolonged viral persistence, leading to severe disease. However, the reduced level of IFN-γ can be attributed to a less fatality toll in Bangladesh compared with that in the rest of the world.

Forecasting e-waste recovery scale driven by seasonal data characteristics: A decomposition-ensemble approach.

Forecasting the scale of e-waste recycling is the basis for the government to formulate the development plan of circular economy and relevant subsidy policies and enterprises to evaluate resource recovery and optimise production capacity. In this article, the CH-X12 /STL-X framework for e-waste recycling scale prediction is proposed based on the idea of 'decomposition-integration', considering that the seasonal data characteristics of quarterly e-waste recycling scale data may lead to large forecasting errors and inconsistent forecasting results of a traditional single model. First, the seasonal data characteristics of the time series of e-waste recovery scale are identified based on Canova-Hansen (CH) test, and then the time series suitable for seasonal decomposition is extracted with X12 or seasonal-trend decomposition procedure based on loess (STL) model for seasonal components. Then, the Holt-Winters model was used to predict the seasonal component, and the support vector regression (SVR) model was used to predict the other components. Finally, the linear sum of the prediction results of each component is used to obtain the final prediction result. The empirical results show that the proposed CH-X12/STL-X forecasting framework can better meet the modelling requirements for time-series forecasting driven by different seasonal data characteristics and has better and more stable forecasting performance than traditional single models (Holt-Winters model, seasonal autoregressive integrated moving average model and SVR model).

Artificial neural network for the prediction model of glomerular filtration rate to estimate the normal or abnormal stages of kidney using gamma camera.

OBJECTIVE: Chronic kidney disease (CKD) is evaluated based on glomerular filtration rate (GFR) using a gamma camera in the nuclear medicine center or hospital in a routine procedure, but the gamma camera does not provide the accurate stages of the diseases. Therefore, this research aimed to find out the normal or abnormal stages of CKD based on the value of GFR using an artificial neural network (ANN). METHODS: Two hundred fifty (Training 188, Testing 62) kidney patients who underwent the ultrasonography test to diagnose the renal test in our nuclear medical centre were scanned using gamma camera. The patients were injected with 99mTc-DTPA before the scanning procedure. After pushing the syringe into the patient's vein, the pre-syringe and post syringe radioactive counts were calculated using the gamma camera. The artificial neural network uses the softmax function with cross-entropy loss to diagnose CKD normal or abnormal labels depending on the value of GFR in the output layer. RESULTS: The results showed that the accuracy of the proposed ANN model was 99.20% for K-fold cross-validation. The sensitivity and specificity were 99.10% and 99.20%, respectively. The Area under the curve (AUC) was 0.9994. CONCLUSION: The proposed model using an artificial neural network can classify the normal or abnormal stages of CKD. After implementing the proposed model clinically, it may upgrade the gamma camera to diagnose the normal or abnormal stages of the CKD with an appropriate GFR value.

Differential game model and coordination model for green supply chain based on green technology research and development.

The purpose of this paper is to establish a green supply chain differential game model for green technology research and development based on a secondary green supply chain composed of a single manufacturer and a single retailer. It compares the differential game equilibrium solutions under centralized and decentralized decision-making. The green supply chain members are coordinated through the dynamic wholesale price mechanism, and numerical simulation is used as a methodology, to verify and explain the results. The study found that compared to decentralized decision-making, the level of green technology and the total profit of green channels are higher under centralized decision-making. When the coordination parameters are within a certain range, the dynamic wholesale price mechanism can coordinate the behavior of manufacturers and retailers. The result also discovers that under the dynamic wholesale price mechanism, with the increase of investment cost coefficient, or the increase of price sensitivity or the decrease of consumer's environmental awareness, the green technology level, product green degree, price, retailer's profit, and the total profit of green channel is decreased. In contrast, the wholesale price and manufacturer's profits are increased.

Molecular Docking, Drug-Likeness and ADMET Analysis, Application of Density Functional Theory (DFT) and Molecular Dynamics (MD) Simulation to the Phytochemicals from Withania Somnifera as Potential Antagonists of Estrogen Receptor Alpha (ER- α).

INTRODUCTION: Breast cancer is one of the leading causes of death of women every year. Estrogen receptor alpha (ER- α) is an important pathway that is responsible for the development of breast cancer. Tamoxifen is the most commonly used drug to treat breast cancer. But the main drawback of using this drug is that it increases the risk of uterine cancer, stroke, and pulmonary embolism. METHODS: In this research, the in-silico approach was followed to get the anticancer agent from Withania somnifera as the root extract of the plant is active against breast cancer. For this, 15 bioactive molecules were subjected to molecular docking and 9 molecules were obtained comparing the consensus binding affinity of H3B-9224. RESULTS: After rescoring, drug-likeness analysis and ADMET analysis of the molecules were carried out and 3 molecules remained. These 3 molecules showed good ADMET properties, which are crucial requirements in the drug discovery process. Their activity was checked by applying density functional theory (DFT) and all of them showed good reactivity. Their binding interaction was also evaluated. CONCLUSION: Finally, the stability of those molecules was evaluated by applying molecular dynamics (MD) simulation. After this simulation, 2 molecules remained that had good stability with the protein during the simulation period.

Exploring the mediation effect of awareness and quarantine in affecting rate: A study on COVID-19.

COVID-19 is a very smash and apprehensive health issue in the current world which broke the medical system of whole earth originated in the wholesale sea market of Wuhan city, Hubei province, China on December 12, 2019. One key technique as lockdown has been followed by almost every country to protect the transmission of the virus. Comprehensive research is needed to explore the techniques for preventing the virus besides the innovation of vaccines and medicine. This study explores the awareness and quarantine strategy whether the technique is effective or not to monitor the affecting rate of COVID-19. In addition to explore the awareness and quarantine, the effectiveness of knowledge regarding the symptoms of SARS CoV-2 to reducing the affecting rate is also examined. A total of 264 samples were used by a self-administered questionnaire. The findings of the study indicate that cough, fever, diarrhea and weakness are the common symptoms of the disease which knowledge on them significantly influences to control the affecting rate of COVID-19. The study also indicates that awareness and quarantine mediate the significant positive relationship between the symptoms of the disease and its affecting rate. The results of the study could contribute as a guideline for the patient, community, decision-maker of a particular country to monitoring the affecting rate and for a researcher as an opportunity for further study.

Automated approach for estimation of grade groups for prostate cancer based on histological image feature analysis.

BACKGROUND: There is a low reproducibility of the Gleason scores that determine the grade group of prostate cancer given the intra- and interobserver variability among pathologists. This study aimed to develop an automated approach for estimating prostate cancer grade groups based on features obtained from histological image analysis. METHODS: Fifty-nine patients who underwent radical prostatectomy were selected under the approval of the institutional review board of our university hospital. For estimation, we followed the grade group criteria provided by the International Society of Urological Pathology in 2014. One hundred eight specimen slides obtained from the patients were digitized to extract 110 regions of interest (ROI) from hematoxylin and eosin-stained histological images using a digital whole slide scanner at ×20 magnification with a pixel size of 0.4 µm. Each color pixel value in the ROI was decomposed into six intensities corresponding to the RGB (red, green, and blue) and HSV (hue, saturation, and value) color models. Image features were extracted by histological image analysis, obtaining 54 features from the ROI based on histogram and texture analyses in the six types of decomposed histological images. Then, 40 representative features were selected from the 324 histological image features based on statistically significant differences (P < .05) between the mean image feature values for high (≥3, Gleason score ≥4 + 3) and low (≤2, Gleason score ≤3 + 4) grade groups. The relationship between grade groups and the most representative image feature (ie, complexity) was approximated using regression to estimate real-number grade groups defined by continuous numerical grading. Finally, the grade groups were expressed as the conventional grade groups (ie, integers from 1 to 5) using a piecewise step function. RESULTS: The grade groups were correctly estimated by the proposed approach without errors on training (70 ROIs) and validation (40 ROIs) data. CONCLUSIONS: Our results suggest that the proposed approach may support pathologists during the evaluation of grade groups for prostate cancer, thus mitigating intra- and interobserver variability.

Effects of Noninhibitory Serpin Maspin on the Actin Cytoskeleton: A Quantitative Image Modeling Approach.

Recent developments in quantitative image analysis allow us to interrogate confocal microscopy images to answer biological questions. Clumped and layered cell nuclei and cytoplasm in confocal images challenges the ability to identify subcellular compartments. To date, there is no perfect image analysis method to identify cytoskeletal changes in confocal images. Here, we present a multidisciplinary study where an image analysis model was developed to allow quantitative measurements of changes in the cytoskeleton of cells with different maspin exposure. Maspin, a noninhibitory serpin influences cell migration, adhesion, invasion, proliferation, and apoptosis in ways that are consistent with its identification as a tumor metastasis suppressor. Using different cell types, we tested the hypothesis that reduction in cell migration by maspin would be reflected in the architecture of the actin cytoskeleton. A hybrid marker-controlled watershed segmentation technique was used to segment the nuclei, cytoplasm, and ruffling regions before measuring cytoskeletal changes. This was informed by immunohistochemical staining of cells transfected stably or transiently with maspin proteins, or with added bioactive peptides or protein. Image analysis results showed that the effects of maspin were mirrored by effects on cell architecture, in a way that could be described quantitatively.

Colorimetric and Optical Discrimination of Halides by a Simple Chemosensor.

A thiophene-based tripodal copper(II) complex has been synthesized as a new colorimetric and optical chemosensor for naked-eye discrimination of halides in acetonitrile and an acetonitrile-water mixture. The binding interactions of the new receptor with several anions were analyzed by UV-Vis titrations, electrospray ionization mass spectrometric (ESI-MS) experiments and density functional theory (DFT) calculations. The results from UV-Vis titrations indicate that the coordinative unsaturated copper(II) complex strongly binds a halide at its vacant copper(II) centre via a metal-ligand bond forming a 1:1 complex, exhibiting binding affinities in the order of fluoride > chloride > bromide > iodide. The interactions of the receptor with halides were further confirmed by ESI-MS, showing a distinct signal corresponding to a 1:1 complex for each halide, suggesting that the noncovalent interactions also exist in the gas phase. In addition, time-dependent DFT (TD-DFT) calculations were also carried out to understand the excited-state properties of the chemosensor complexes. A detailed analysis of the TD-DFT calculations shows a consistent red-shift in the first optically-allowed transition, consistent with the observed colorimetric experiments.

An exclusive fluoride receptor: Fluoride-induced proton transfer to a quinoline-based thiourea.

A new quinoline-based tripodal thiourea has been synthesized, which exclusively binds fluoride anion in DMSO, showing no affinity for other anions including, chloride, bromide, iodide, perchlorate, nitrate and hydrogen sulfate. As investigated by 1H NMR, the receptor forms both 1:1 and 1:2 complex yielding the binding constants of 2.32(3) (in log ß1 ) and 4.39(4) (in log ß2 ), respectively; where quinoline groups are protonated by the fluoride-induced proton transfer from the solution to the host molecule. The 1:2 binding is due to the interactions of one fluoride with NH binding sites of urea sites and another fluoride with secondary +NH binding sites within the tripodal pocket. The formation of both 1:1 and 1:2 complexes has been confirmed by the theoretical calculations based on density functional theory (DFT).

Nuclear localization signals in prototype foamy viral integrase for successive infection and replication in dividing cells.

We identified four basic amino acid residues as nuclear localization signals (NLS) in the C-terminal domain of the prototype foamy viral (PFV) integrase (IN) protein that were essential for viral replication. We constructed seven point mutants in the C-terminal domain by changing the lysine and arginine at residues 305, 308, 313, 315, 318, 324, and 329 to threonine or proline, respectively, to identify residues conferring NLS activity. Our results showed that mutation of these residues had no effect on expression assembly, release of viral particles, or in vitro recombinant IN enzymatic activity. However, mutations at residues 305 (R → T), 313(R → T), 315(R → P), and 329(R → T) lead to the production of defective viral particles with loss of infectivity, whereas non-defective mutations at residues 308(R → T), 318(K → T), and 324(K → T) did not show any adverse effects on subsequent production or release of viral particles. Sub-cellular fractionation and immunostaining for viral protein PFV-IN and PFV-Gag localization revealed predominant cytoplasmic localization of PFV-IN in defective mutants, whereas cytoplasmic and nuclear localization of PFV-IN was observed in wild type and non-defective mutants. However sub-cellular localization of PFV-Gag resulted in predominant nuclear localization and less presence in the cytoplasm of the wild type and non-defective mutants. But defective mutants showed only nuclear localization of Gag. Therefore, we postulate that four basic arginine residues at 305, 313, 315 and 329 confer the karyoplilic properties of PFV-IN and are essential for successful viral integration and replication.

Physiological and growth responses of six turfgrass species relative to salinity tolerance.

The demand for salinity-tolerant turfgrasses is increasing due to augmented use of effluent or low-quality water (sea water) for turf irrigation and the growing turfgrass industry in coastal areas. Experimental plants, grown in plastic pots filled with a mixture of river sand and KOSAS(R) peat (9 : 1), were irrigated with sea water at different dilutions imparting salinity levels of 0, 8, 16, 24, 32, 40, or 48 dS m⁻¹. Salinity tolerance was evaluated on the basis of leaf firing, shoot and root growth reduction, proline content, and relative water content. Paspalum vaginatum was found to be most salt tolerant followed by Zoysia japonica and Zoysia matrella, while Digitaria didactyla, Cynodon dactylon "Tifdwarf," and Cynodon dactylon "Satiri" were moderately tolerant. The results indicate the importance of turfgrass varietal selection for saline environments.

Discectomy for primary and recurrent prolapse of lumbar intervertebral discs.

PURPOSE: To reviewed 416 patients who underwent discectomy for primary or recurrent prolapse of lumbar intervertebral discs (PLID). METHODS: Records of 296 men and 102 women aged 19 to 60 (mean, 39) years who underwent discectomy for a primary PLID, and 14 men and 4 women aged 28 to 50 (mean, 40) years who underwent revision discectomy for a recurrent ipsilateral (n=14) or contralateral (n=4) PLID at L4-5 (n=14), L5-S1 (n=3), or L3-4 (n=1) were reviewed. The pain-free interval, side and degree of herniation, operating time, length of hospital stay, and pre- and post-operative visual analogue score (VAS) for pain were recorded. Clinical outcomes were evaluated using the modified Macnab criteria and the Oswestry Disability Index. RESULTS: Patients were followed up for one to 4 years. The mean operating time was significantly longer in revision discectomy (65 vs. 141 minutes, p<0.001, unpaired t-test). There was no significant difference between revision and primary discectomy in terms of length of hospital stay or clinical improvement rates. Age, gender, smoking, profession, level and extent of herniation, and pain-free interval did not affect clinical outcomes. In the 18 revision cases, the mean pain-free interval until recurrence was 31 (range, 1-42) months. At the one-year follow-up, results were excellent in 8, good in 6, fair in 3, and poor in one. Three of the patients had persistent pain despite taking analgesics. 14 of the patients had returned to their normal daily activities. Complications included foot drop (n=1), dural tear (n=3), and superficial wound infection (n=1). CONCLUSION: Discectomy achieved satisfactory results for both primary and recurrent PLIDs.

Pharmacological evaluation of Antidesma ghaesembilla Gaertn fruits for central nervous system depressant activity / Evaluación farmacológica de frutos de Antidesma ghaesembilla Gaertncomo depresores del sistema nervioso central

The objective of this study is to investigate the anxiolytic and sedative activities of the methanol and chloroform extracts of Antidesma ghaesembilla fruits at the dose of 400 mg/kg bw using rodent behavioral models such as thiopental sodium-induced sleeping time, hole cross method and open field process for sedative and its anxiolytic activity was evaluated using the elevated plus maze (EPM) methods. In case of thiopental sodium-induced sleeping time, both extracts exhibited dose dependent suppression of motor activity, exploratory behavior (in open field and hole cross method) and prolongation of thiopental sodium-induced sleeping time in mice, where maximum effect was shown by the methanol extract. In EPM test, the methanolic extract significantly increased exploration to and time spent by the treated mice in EPM open arms in a way similar to that of diazepam, but the chloroform extract was found to produce moderate activity. These significant results may justify the scientific basis for use of this plant in traditional medicine as a modality for anxiety and related disorders.

El objetivo de este estudio fue la investigación de las actividades ansiolíticas y sedantes de los extractos clorofórmicos y metabólicos de los frutos de Antidesma ghaesembilla a las dosis de 400 mg/kg pp utilizando modelos de comportamiento de roedores, tales como el tiempo de sueño inducido por tiopental sódico, el método de “hole cross” (cruce de un agujero) y el campo abierto para evaluar sedación, y la actividad ansiolítica fue evaluada utilizando el método del laberinto elevado (elevated plus maze, EPM). En el caso del sueño inducido por tiopental sódico, ambos extractos exhibieron una supresión dosis dependiente de la actividad motora, de la actividad exploratoria (en el método de campo abierto y “hole cross”) y prolongación del tiempo de inducción de sueño inducido por tiopental en ratones, con efectos máximos mostrados para el extracto metabólico. En el ensayo de EPM, el extracto metabólico aumentó significativamente el tiempo de exploración y el tiempo consumido en el laberinto de una manera similar al diazepam, pero el extracto clorofórmico se encontró que produjo solo una moderada actividad. Estos resultados significativos pueden justificar una base científica para el uso de plantas en medicina tradicional para tratar la ansiedad y desórdenes relacionados.

A C Symmetric Nitrate Complex with a Thiophene-Based Tripodal Receptor.

A thiophene-based tripodal receptor has been synthesized and its complexes with nitrate and iodide have determined by single-crystal X-ray analysis. In the nitrate complex, one nitrate is encapsulated in a selective orientation forming a C(3) symmetric complex, which is bonded to three protonated secondary amines with six NH···O bonds. The anion is coordinated in a plane perpendicular to the principal rotation axis passing through the tertiary nitrogen of the receptor and the nitrogen of the encapsulated nitrate. High-level DFT calculations support the crystallographic results demonstrating that an adduct with trigonal binding of three oxygen atoms is more stable than that of one oxygen atom of the encapsulate nitrate. On the other hand, in the structure of the iodide complex, all three iodides lie outside the cavity. (1)H NMR titration studies indicate that the receptor forms a 1:1 complex with nitrate with a binding constant of K = 315 M(-1) in chloroform, showing a moderate selectivity over halides and perchlorate.