Based on screening in computational biology and biological in vitro assays, five natural products isolated from extracts of the herbal medicine toad skin, such as cinobufagin (CBFi), bufalin (BFi), arenobufagin (ABFi), telocinobufagin (TBFi), bufotalin (BFTi), were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (PDB 6LU7 and 7BTF) and top-scoring ligand-receptor complexes were obtained. The results showed that the binding energy of ABFi to the 3CL protein was -17.044kcal/mol, which was higher than CBFi and TBFi. However, the binding energy of ABFi to the RdRp protease was -23.250 kcal/mol, which was much lower than that of CBFi and TBFi, EVEN lower than that of ABFi to the 3CL protein. ABFi also has polar interactions with amino acids such as Glu811, Ser814, Ser681 and Thr680 of RdRp enzyme. The results revealed that ABFi had a moderate inhibitory effect on the cell proliferation of SARS-CoV-2 in vitro, with an inhibition rate of 61.12%, even weaker than Remdesivir. This new discovery provides us with new ideas for in-depth studies on the development of natural products with this class of structural generalizations as inhibitors of SARS-CoV-2, and provides an experimental basis for the next step of mechanistic studies.

Ambulatory heart rate (HR) monitors that acquire electrocardiogram (ECG) or/and photoplethysmographm (PPG) signals from the torso, wrists, or ears are notably less accurate in tasks associated with high levels of movement compared to clinical measurements. However, reliable estimation of HR can be obtained through data fusion from different sensors. These methods are especially suitable for multimodal hearable devices, where heart rate can be tracked from different modalities, including electrical ECG, optical PPG, and sounds (heart tones). Combined information from different modalities can compensate for single source limitations. In this paper, we evaluate the possible application of data fusion methods in hearables. We assess data fusion for heart rate estimation from simultaneous in-ear ECG and in-ear PPG, recorded on eight subjects while performing 5-minute sitting and walking tasks. Our findings show that data fusion methods provide a similar level of mean absolute error as the best single-source heart rate estimation but with much lower intra-subject variability, especially during walking activities. We conclude that data fusion methods provide more robust HR estimation than a single cardiovascular signal. These methods can enhance the performance of wearable devices, especially multimodal hearables, in heart rate tracking during physical activity.

Our results demonstrated that SWT stimulates osteoblastogenesis and increase the cell number of osteoblasts, suggesting positive regulatory effects on osteoblast differentiation. However, the effect of SWT on bone formation need further examination, since the expression of alp gene is downregulated. On the other hand, SWT appears to negatively regulate osteoclast differentiation and bone resorption, as number of osteoclasts and the expression of critical bone resorptive genes are all downregulated. Collectively, SWT might change the equilibrium of bone remodeling and increase the bone mass. Our data provided supportive evidences that this medicine formulation can be applied to treat osteoporosis or bone destructive diseases.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

This article utilizes the Canny edge extraction algorithm based on contour curvature and the cross-correlation template matching algorithm to extensively study the impact of high-repetition-rate CO2 pulsed Laser on the target extraction and tracking performance of the infrared imaging detector. It establishes a quantified dazzling pattern for lasers on infrared imaging systems. By conducting laser dazzling and damage experiments, a detailed analysis of the normalized correlation between target and dazzling images is performed to quantitatively describe laser dazzling effects. Simultaneously, an evaluation system, including target distance and laser power evaluation factors, is established to determine the dazzling level and whether the target is recognizable. The research results reveal that laser power and target position are crucial factors affecting the detection performance of infrared imaging-guided weapon systems under laser dazzling. Different laser powers are required to successfully interfere with the recognition algorithm of infrared imaging-guided weapons at different distances. And laser dazzling will produce a lot of false edge information, which seriously affects the performance of pattern recognition algorithm. In laser damage experiments, the detector experienced functional damage, with a quarter of the image displaying as completely black. The energy density threshold required for functional damage to the detector is approximately 3 J/cm2. The dazzling assessment conclusions also apply to evaluating damage results. Finally, the proposed evaluation formula aligns with experimental results, objectively reflecting the actual impact of laser dazzling on the target extraction and tracking performance of infrared imaging systems. This study provides an in-depth and accurate analysis for understanding the influence of lasers on the performance of infrared imaging-guided weapons.

The Food and Drug Administration’s 2011 Process Validation Guidance and International Council for Harmonization Quality Guidelines recommend continued process verification (CPV) as a mandatory requirement for pharmaceutical, biopharmaceutical, and other regulated industries. As a part of product life cycle management, after process characterization in stage 1 and process qualification and validation in stage-2, CPV is performed as stage-3 validation during commercial manufacturing. CPV ensures that the process continues to remain within a validated state. CPV requires the collection and analysis of data related to critical quality attributes, critical material attributes, and critical process parameters on a minimum basis. Data is then used to elucidate process control regarding the capability to meet predefined specifications and stability via statistical process control tools. In statistical process control, control charts and Nelson rules are commonly used throughout the industry to monitor and trend data to ensure that a process remains in control. In the control chart, the mean value is taken as the center line, and 3σ limits are placed on either side of the center line. In CPV, manufactured lots are summarized, trended, and discussed at a cross-functional level at pre-defined intervals (either weekly, bi-weekly, or even monthly) based on the batch run rate. A cross-functional team assesses details regarding 1) violation frequency, 2) statistical strength of the signal, 3) violation magnitude and its impact on process or quality, and 4) any potential root causes for out-of-expectation or out-of-trend signals. The cross-functional team must analyze whether any signal identified by the control chart is reliable and must determine whether corrective action should be taken and justify the decision in the CPV meeting minutes based on statistical strength and reliability of the signal. However, basic control charts are susceptible to false alarms and nuisance alarms. Therefore, it is imperative to understand the assumptions behind control charts and the inherent false alarm rates for different Nelson rules. In this article, the authors have detailed the assumptions behind the usage of control charts, the rate of false alarms for different Nelson rules, the impact of skewness and kurtosis of a data distribution on the false alarm rate, and methods for optimizing control chart design by reducing false alarm rates and nuisance signals.

In this work, satellite data from the Clouds and Earth’s Radiant Energy System (CERES) and Moderate Resolution Imaging Spectroradiometer (MODIS) instruments is analyzed to determine how the global absorbed sunlight and global entropy generation rate have changed during the time period from 2002 to 2023. The data is used to test hypotheses derived from the Maximum Power Principle (MPP) and Maximum Entropy Production Principle (MEP) about the evolution of earth’s surface and atmosphere. The results indicate that the amount of absorbed sunlight has increased over the last 20 years but rising surface temperatures have caused the entropy generation rate to remain approximately constant despite that decrease in albedo. The results are simpler to explain using the MPP but do not completely rule out the MEP. Given the acceptance of the MPP or MEP, some extensions and nuances are discussed.

Few studies have examined the dietary protein intake and sources in combination with the longitudinal changes in brain structure markers. Our study aimed to examine the association between dietary protein intake and different sources of dietary protein with the longitudinal rate of change in brain structural markers. A total of 2723 and 2679 participants from the UK Biobank were included in the analysis. The relative and absolute amounts of dietary protein intake were calculated through a 24-hour dietary recall questionnaire. The longitudinal change rates of brain structural biomarkers were computed using two waves of brain imaging data. We utilized multiple linear regression to examine the association between dietary protein and different sources and the longitudinal changes in brain structural biomarkers. Restrictive cubic splines were used to explore nonlinear relationships, and stratified and sensitivity analyses were conducted. Increasing the proportion of animal protein in dietary protein intake is associated with a slower reduction in the total hippocampus volume (THV, β: -0.02524, P<0.05), left hippocampus volume (LHV, β: -0.02435, P<0.01) and right hippocampus volume (RHV, β: -0.02544, P<0.05).Higher intake of animal protein relative to plant protein is linked to a lower atrophy rate in THV (β: -0.01249, P<0.05) and LHV (β: -0.01173, P<0.05) and RHV (β: -0.01193, P<0.05). Individuals with higher intake of seafood exhibit lower longitudinal rate of change in HV compared to those with no consume (THV, β: -0.004514; P<0.05; RHV, β: -0.005527, P<0.05). In subgroup and sensitivity analyses, there was not a significantly alteration. A moderate increase in the intake and proportion of animal protein in the diet, especially from seafood, is associated with a lower longitudinal change rate in hippocampus volume.

Signaling modules that integrate the diverse extra- and intracellular inputs to control cell proliferation are essential during both development and adult stages to guarantee organism homeostasis. Mobs are small adaptor proteins that participate in several of these signalling pathways. Here we review recent advances unraveling Mob4 cellular functions, a highly conserved non-catalytic protein, that plays a diversity of roles in cell proliferation, sperm cell differentiation and simultaneously is involved in synapse formation and neural development. In addition, the gene is often overexpressed in a wide range of tumors and is linked to poor clinical outcomes. Nevertheless, Mob4 molecular functions remain poorly defined, although it integrates the core structure of STRIPAK, a kinase/phosphatase protein complex, that can act upstream of the Hippo pathway. In this review we focus on the recent findings of Mob4 functions, that have begun to clarify its critical role on cell proliferation and development of tissues and individuals.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effect. Nevertheless, PC gradually develops resistance, relapses and spreads. Most patients develop, indeed, castrate-resistant PC (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, TrkA. NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its cross talk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchyme transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

The literature offers limited information on the effect of obesity on the rate of force development, a critical parameter for mobility in older adults. The objectives of this study were; to explore the influence of obesity on RFD in older adults and to examine the association between this neuromuscular parameter and walking speed. 42 older adults were classified into two groups: the control group (CG, n=22; age=81.13±4.02 years; Body mass index (BMI)=25.13±3.35 kg/m²), and the obese group (OG, n=20; age=77.71±2.95 years; BMI=34.46±3.25 kg/m²). Walking speed (m/s) was measured using the 10-meter walking test. Neuromuscular parameters of the plantar flexors were evaluated during a maximal voluntary contraction test using a dynamometer. The RFD was calculated from the linear slop of the force – time curve in two phases: from the onset of the contraction to 50 ms (RFD50-100) and from 100 to 200 ms (RFD100-200). The gait speed was lower in the OG compared to the CG (p

: To improve the efficiency of rhizobial inoculation operations and address the current situation of rhizobial inoculation being labor-intensive, a spraying and control system for variable rate application (VRA) of liquid rhizobia was developed. The system can accurately regulate the spraying rate of liquid rhizobia according to the desired rate of rhizobia by incremental Proportional Integral Derivative (PID) closed-loop control algorithm, making it particularly suitable for precise spraying with small amounts. In the laboratory experiment of precise flow control, variation coefficient of spraying nozzle from 0.10 MP to 0.20 MP pressure were no more than 1.2%. A clear linear relationship was observed between the spraying rate and pressure. The maximum response time was 1.93 seconds, while the average response time was 1.62 seconds when controlling the spraying system for small amounts. Field trial was conducted in Heilongjiang Agricultural Xianghe Farm of China. Average seeds number and 100-seed weight of soybean plant with rhizobia inoculation treatment were better than control group, and average yield of spraying liquid rhizobia agent with full base fertilizer increased by 232.5 kg/hm2, representing a significant 7.4% improvement over the control group. The results of these trails clearly showed the positive effect of the spraying and control system for liquid rhizobial inoculation, which has superior to existing inoculation manners, and provides an important technical support for the widespread adoption of rhizobia technology.

Naturally fermented dairy products are an important component of the human diet. They are a valuable source of nutrients as well as vitamins and minerals. Their importance as a source of probiotic bacterial strains should not be overlooked. A number of studies highlights the positive effects of species of the Lactobacillacea on the intestinal microbiota, the overall homeostasis of the body, as well as a complementary treatment for some diseases. However, data on the effects on intestinal epithelial cells of postmetabolites released by bacteria are incomplete. This is likely due to the fact that these effects are species and strain specific. In the present study, we investigated the effects of postmetabolites produced by a pre-selected candidate probiotic strain Limosilactobacillus fermentum on HT-29 intestinal epithelial cells. Our data showed a pronounced proliferative effect, evaluated by flow cytometry, quantification of cell population, and determination of mitotic index. This was accompanied by stabilization of the cell monolayer, measured by increase of TEER (trans epithelial electric resistance) and reorganization of actin filaments. The data obtained are a clear indication of the positive effects, that the products secreted by L. fermentum strain 53 have on the intestinal epithelial cells.

In this study the impact of terrorist attacks on exchange rate is estimated. Particularly, the study focuses on Turkish terrorist attacks and its implication on Turkish lira versus pound sterling exchange rate. In order, to find the causal effect the study employed Autoregressive distributive lag (ARDL) bound testing approach as an estimation technique. Accordingly, the analysis reveals that terrorist attack has a negative impact on the exchange rate in both short and long-run. However, the negative effect of terrorism tends to be small in both the short-run and long-run. More precisely, terrorist attack depreciates the exchange rate between Turkish lira and pound sterling by approximately 0.00072 in the next trading day. The long-term effect also shows that terrorist attack depreciates the exchange rate on average by 0.00212.

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the ex-pression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug, 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of ectoine in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA methyla-tion-related gene and marker analysis were performed. The results showed that ectoine hypo-methylation in skin cells, especially in the CpG island (CGIs) element and 5mC, was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation, but did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3i, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Igf2, Snrpn, and Mest. Overall, ectoine, an excellent DNA protectant, mildly de-methylates DNA in skin cells, modulates the expression of methylation-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

The interpretation of the local microenvironment of extracellular matrix for malignant tumor cells is in intimate relation with metastatic spread of cancer cells involving the associated issues of cellular proliferation and drug responsiveness. This study was aimed to assess the combination of both surface topographies (fiber alignments) and different stiffness of the polymeric substrates (PLLA and PCL) and collagen substrates (coat and gel) to elucidate the effect of the cellular morphology on cellular proliferation and drug sensitivities of two different types of breast cancer cells (MDA-MB-231 and MCF-7). The morphological spreading parameter of (Nuclear/Cytoplasm) induced by the anthropogenic substrates has correlated intimately with the cellular proliferation and the drug sensitivity (IC₅₀) of cancer cells. This study demonstrated the promising results of the parameter for the evaluation of cancer cell malignancy.

One of the factors in the mobility of a nation's economy is the stock exchange which plays a decisive role in sustainable economic development. Accordingly, and for the special place of the stock exchange in the economy, we decided to investigate the relationship between the interest and exchange rates and the Tehran stock exchange dividend and price index (TEDPIX). Using the autoregressive distributed lag method, the present study is conducted utilizing the annual data over the period of 1991 to 2020. The results indicate that the exchange rate has a positive long-run relationship with the TEDPIX, but no statistically significant relationship was found between the TEDPIX and the interest rate. Furthermore, the results of the estimation of the error correction model show that 30.786% of the disequilibrium in each period is adjusted to the long-run equilibrium.

Over the last two decades, a considerable amount of equipment has been acquired (spreaders, seeders, sprayers, among others) to respond to the challenges of Precision Agriculture (PA) concept. Most of this equipment has been purchased at a high cost. However, many of them, despite still being functional and equipped with sensors, actuators, and electronic processing units capable of adjusting to variations in speed, have become obsolete in terms of communication, and incompatible with new monitoring and control systems based on the “Isobus” protocol. This work aims to present a solution for updating the control system (“Ferticontrol”) of a “Vicon RS-EDW” spreader with variable rate application (VRA), making it compatible with the “InCommand” system from “Ag Leader”. The solution includes low-cost “Arduino” and “Raspberry Pi” microcontrollers and open-source software. The development shows that it is possible to implement a solution that is accessible to farmers in general. It also provides a niche business opportunity for young researchers to set up small technology-based enterprises associated with universities and research centers. These partnerships guarantee permanent innovation and represent a decisive step towards modern, technological, competitive, and sustainable agriculture.

Background: We screened key genes involved in the dedifferentiation process of thyroid cancer by analyzing differentially expressed genes in anaplastic thyroid carcinoma (ATC) using Gene Expression Omnibus (GEO) database. Methods: We analyzed differentially expressed genes in ATC from GEO database and constructed a co-expression network using Weighted Gene Co-expression Network Analysis (WGCNA) . Cytoscape was used to calculate top ten key genes based on their gene scores. DEPDC1 was selected as interest gene for further validation, including examination of its prognostic relationship with thyroid cancer, correlation analysis with thyroid differentiation markers, immune cell infiltration, and tumor microenvironment. The impact of DEPDC1 on cancer cell migration, invasion, and proliferation was validated through downregulation and overexpression of DEPDC1 gene in thyroid cancer cell lines c643 and BCPAP. Results: We identified top 10 key genes in ATC: AURKA, TPX2, RACGAP1, MELK, DLGAP5, DEPDC1, KIF2C, NCAPG, CCNB1, and PBK. DEPDC1 showed a strong correlation with the prognosis of thyroid cancer. The odds ratio (OR) for overall survival was 3.5 (P=0.016) in individuals with high DEPDC1 expression, and the OR for disease-free survival was 2.6 (P=0.003). Additionally, the analysis revealed a significant negative correlation between the expression of DEPDC1 and thyroid differentiation markers. Gene Ontology enrichment analysis demonstrated that DEPDC1 co-expressed genes were enriched in cellular processes, cell cycle pathways, and dynamic protein groups. Matrix and immune scoring indicated tumor microenvironment and immune scores were associated with DEPDC1 expression. TIMER2.0 online analysis revealed a strong correlation between DEPDC1 expression and immune cell infiltration in papillary thyroid carcinoma. After downregulation of DEPDC1 expression, the invasion, migration, and proliferation abilities of tumor cells were significantly reduced. Conversely, overexpression of DEPDC1 exhibited the opposite effect. Conclusion: DEPDC1, a newly identified dedifferentiation gene in thyroid cancer, inversely correlated with the degree of differentiation. High expression of DEPDC1 promotes cancer progression and leads to poor prognosis in thyroid cancer.

(1)Background:The purpose of the study was conducted to investigate the recovery of heart rate according to the performance level and rest interval conditions during 65%1RM bench press exercise;(2)Methods:The subjects of this study were eight healthy male college studentsin their 20 (years) attending University C. 1RM was measured before theexperiment, and the exercise sequence of six rest intervals (30sec, 1, 2, 3, 4,5min) was randomly selected and cross-distribution experiment. The experimental measurement was conducted a total of six times according to the rest interval condition (six conditions) once every 3 days to minimize the learning effect. The data was verified with repeated measures Two-way ANOVA and Contrast's repeated method was applied for post-comparison;(3)Results: First, the amount of exercise and the number of repetitions statistically substantially dropped (p<.001) as the number of sets rose, and a greater decline was shown when the rest periods got shorter. Second, the heart rate after exercise was increased significantly (p<.01) as the set progressed in the long rest interval conditions (4, 5min), and the heart rate after rest was increased statistically significantly (p<,05) as the set progressed in the short rest interval conditions (30sec, 1min). Third, the heart rate recovery rate (%) was able to perform more repetitions than in the short rest interval condition due to the relatively high physiological recovery of the neuromuscular and circulatory system under the long rest interval condition;(4)Conclusions: Therefore, according to the rest conditionduring the 65%1RM bench press exercise conducted in this study, the restinterval condition of 2~3min may be effective in improving muscular endurance,and the rest interval condition of 4~5min may be effective in improving muscular hypertrophy. As a result of this study, there was a significant difference in exercise performance (repetition) and physiological recovery depending on the rest interval condition according to the set progress during the same intensity resistance exercise. Through this, it is judged that it is possible to adjust the amount of exercise appropriate for the purpose of training by adjusting not only the intensity during resistance exercise but also the rest interval between sets.

Lung cancer is a prevalent and aggressive neoplasm worldwide, contributing to significant mortality rates. Dehydroepiandrosterone (DHEA) constitutes the bulk of the steroid hormone in human plasma, has a robust antiproliferative effect, and induces cell death in various tumor cells. However, its role in lung cancer cells remains unexplored. This study aimed to investigate the influence of DHEA on the proliferation, viability, autophagy, and migration of several lung cancer cell lines, including A549, HCC827, and NCI-H2347. Cell proliferation was assessed through crystal violet staining; cell number and viability were evaluated using trypan blue staining; viability was confirmed by MTT reduction, a method that is also an indicator of metabolic activity; migration was assessed via a wound healing assay. Autophagy was evaluated using a specific kit, while cell death was determined by annexin-V-FITC/propidium iodide staining and caspase-3/7 activity assay. The results indicate that DHEA significantly reduced proliferation, cell number, metabolic activity, and migration in all examined lung tumor cells. These effects correlate with an increased autophagy induced by DHEA. No signs of apoptosis or necrosis were observed across the range of DHEA concentrations used. Although these findings are preliminary, they suggest that DHEA could hold promise as an alternative treatment option for various subtypes of lung cancer.

Extracellular vesicles (EVs) are involved in intercellular communication during carcinogenesis and cancer cells are able to secrete EVs, in particular exosomes containing molecules, that can be transferred to recipient cells to induce pathological processes and significant modifications, as metastasis, increase of proliferation and carcinogenesis evolution. FZD proteins, a family of receptors comprised in the Wnt signaling pathway, play an important role in carcinogenesis of gastroenteric tract. Here, a still unrecognized role of Frizzled 10 (FZD10) protein was identified. In particular, the presence of FZD10 and FZD10-mRNA in exosomes extracted from culture medium of the untreated colorectal, gastric, hepatic and cholangio cancer cell lines, was detected. A substantial reduction in the FZD10 and FZD10-mRNA level was achieved in FZD10-mRNA silenced cells and in their corresponding exosomes and, concomitantly a significant decrease in viability of the silenced cells compared to their respective controls was observed. Interestingly, the incubation of silenced cells with exosomes extracted from culture medium of the same untreated cells promoted a remarkable restoration of the cell viability and, also, of the FZD10 and FZD10-mRNA level, thus indicating that the FZD10 and FZD10-mRNA delivering exosomes may be potential messengers of cancer reactivation and play an active role in long-distance metastatization

Inhalational anesthetics was previously reported to suppress glioma cell malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the effects of sevoflurane and desflurane on glioma cell malignancy changes via microRNA (miRNA) modulation. The cultured H4 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 hrs. The miR-138, -210 and -335 expression were determined with qRT-PCR. Cell proliferation and migration were assessed with wound healing assay, Ki67 staining and cell count kit 8 (CCK8) assay with/without miR-138/-210/-335 inhibitor transfections. The miRNA downstream proteins, hypoxia inducible factor-1α (HIF-1α) and matrix metalloproteinase 9 (MMP9), were also determined with immunofluorescent staining. Sevoflurane and desflurane exposure to glioma cells inhibited their proliferation and migration. Sevoflurane exposure increased miR-210 expression whereas desflurane exposure upregulated both miR-138 and miR-335 expressions. The administration of inhibitor of miR-138, -210 or -335 inhibited the suppressing effects of sevoflurane or desflurane on cell proliferation and migration, in line with the HIF-1α and MMP9 expression changes. These data indicated that inhalational anesthetics, sevoflurane and desflurane, inhibited glioma cell malignancy via miRNA upregulation and their downstream effectors, HIF-1α and MMP9, downregulation. The implication of the current study warrants further study.

The paper proposes a mechanism for the impact of changes in the key rate on the volume of newly issued loans. The volume depends on the price (interest rates on loans), and the price depends on the key rate and the actual consumption of loans in the previous period (generalized cobweb cycle). The model was estimated by a Kalman filter, adequacy was confirmed by simulation. It is possible to forecast the average rate on loans for a month in advance according to the information published by the Central Bank of the Russian Federation (CB). By playing various scenarios for changing the key rate, it was found that in quiet periods of economic development, the usual laws of supply and demand operate in the loan market and by raising the key rate, you can reduce inflation. In the turbulent (overheated) state of the economy, an increase in the key rate can, on the contrary, provoke an increase in the issuance of loans and unconventional manipulations with the key rate are required.

Average of 41,900 patients are diagnosed annually with staphylococcus bacterial infection in California, 24,089 patients have Methicillin-resistant Staphylococcus Aureus (MRSA) and 17,810 patients have Methicillin-Sensitive Staphylococcus (MSSA). This paper demonstrates that there is a difference in mortality rate due to staphylococcus infection between males and females (P-value<0.05, CI 95%). Male patient diagnosed with S. aureus has 1.3 chance of mortality incidence than female patient. In addition, MRSA infection rate is 1.4 times MSSA infection (P-value<0.05, CI 95%), but the gap of infection is decreasing; however, mortality of both infections combined are more than threefold greater compared to three decades ago.

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses, and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol, and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or Cdc37 overexpression -mechanisms that induce nuclear ERK5- induced ERK5 SUMO-2 modification at residues Lys6/Lys22 in cancer cells. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to EGF stimulation. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of transcription.

In real financial markets, the certainty equivalent rate is an important factor for investors to consider. From the value of a specific company’s certainty equivalent rate, investors can judge if this company is worth investing in. In this paper, we will explore how to obtain the value of the certainty equivalent rate so that we can evaluate a given company. First, we will introduce the theoretical support of this paper, which is put-call parity. From put-call parity, we will derive the mathematical expression for the certainty equivalent rate. Second, we will use the mathematical expression for the certainty equivalent rate to perform an empirical study. We will consider some extreme examples, including some of the best- and worst-performing stocks up to this point in 2023. Based on these stocks’ data, we will visualize the performance of these stocks and explain the meaning of the data. Finally, we will apply the results to a very popular industry—the electric vehicle industry—to explore the current electric vehicle market situation in the U.S.A.

The process of revitalising quiescent cells in order for them to proliferate plays a pivotal role in the repair of warn out tissues as well as for tissue homeostasis. This process is also crucial in the growth, development and well-being of higher multi-cellular organisms such as mammals. Deregulation of quiescent-proliferation transition is related to many diseases, in particular cancer. Recent studies have revealed that this process is regulated tightly by the Rb−E2F bistable switch mechanism. Based on experimental observations, in this study, we formulate a mathematical model to examine the effect of the growth factor concentration on the proliferation-quiescence transition in human cells. Working with a non-dimensionalised model, we prove positivity, boundedness and uniqueness of solutions. To understand model solution behaviour close to bifurcation points, we carry out bifurcation analysis, which is further verified by use of numerical bifurcation analysis, sensitivity analysis and numerical simulations. Indeed, bifurcation and numerical analysis of the model predicted a transition between stable, bistable and stable states, which are dependent on the growth factor concentration parameter (GF). The derived predictions confirm experimental observations.

Rutin has been reported as a potential anti-cancer agent for several decades. This study evaluated the effects of rutin on the proliferation, metastasis, and angiogenesis of MDA-MB-231 and MCF-7 breast cancer cell lines. Increasing concentrations of rutin significantly stimulated the proliferation of MDA-MB-231 and MCF-7 cells compared to controls. Wound scratch assay demonstrated that rutin had an inducing effect on the migration of the cells. In MDA-MB-231 and MCF-7 cells, rutin upregulated MKI67, VIM, CDH2, FN1, and VEGFA and downregulated CDH1 and THBS1 genes. It also increased N-cadherin and VEGFA and decreased E-cadherin and thrombospondin 1 protein expression. Our data indicated that rutin could stimulate proliferation, migration, and pro-angiogenic activity in two different breast cancer cell lines. This phytoestrogen induced invasion and migration of both cell lines by a mechanism involving the EMT process. This suggests that rutin may act as a breast cancer-promoting phytoestrogen.

Mitochondria are essential to cell homeostasis, and alterations in mitochondrial distribution, segregation or turnover have been linked to complex pathologies such as neurodegenerative diseases or cancer. Understanding how these functions are coordinated in specific cell types is a major challenge to discover how mitochondria globally shape cell functionality. In this review, we will first describe how mitochondrial transport and dynamics are regulated throughout the cell cycle in yeast and in mammals. Second, we will explore the functional consequences of mitochondrial transport and partitioning on cell proliferation, fate acquisition, stemness, and on the way cells adapt their metabolism. Last, we will focus on how mitochondrial clearance programs represent a further layer of complexity for cell differentiation, or in the maintenance of stemness. Defining how mitochondrial transport, dynamics and clearance are mutually orchestrated in specific cell types may help our understanding of how cells can transition from a physiological to a pathological state.

We have developed deep learning models for automatic identification of the maternal heart rate (MHR) and, more generally, false signals (FSs) on fetal heart rate (FHR) recordings. The models can be used to preprocess FHR data prior to automated analysis or as a clinical alert system to assist the practitioner. Three models were developed and used to detect (i) FSs on the MHR channel (the FSMHR model), (ii) the MHR and FSs on the Doppler FHR sensor (the FSDop model), and (iii) FSs on the scalp ECG channel (the FSScalp model). The FSDop model was the most useful because FSs are far more frequent on the Doppler FHR channel. All three models were based on a multilayer, symmetric, GRU and were trained on data recorded during the first and second stages of delivery. The FSMHR and FSDop models were also trained on antepartum recordings. The training dataset contained 1030 expert-annotated periods (mean duration: 36 min) from 635 recordings. In an initial evaluation of routine clinical practice, 30 fully annotated recordings for each sensor type (mean duration: 5 h for MHR and Doppler sensors, and 3 h for the scalp ECG sensor) were analyzed. The sensitivity, positive predictive value (PPV) and accuracy were respectively 62.20%, 87.1% and 99.90% for the FSMHR model, 93.1%, 95.6% and 99.68% for the FSDop model, and 44.6%, 87.2% and 99.93% for the FSScalp model. We built a second test dataset with a more solid ground truth by selecting 45 periods (lasting 20 min, on average) on which the Doppler FHR and scalp ECG signals were recorded simultaneously. Using scalp ECG data, the experts estimated the true FHR value more reliably and thus annotated the Doppler FHR channel more precisely. The models achieved a sensitivity of 53.3%, a PPV of 62.4%, and an accuracy of 97.29%. In comparison, two experts (blinded to the scalp ECG data) respectively achieved a sensitivity of 15.7%, a PPV of 74.3%, and an accuracy of 96.91% and a sensitivity of 60.7%, a PPV of 83.5% and an accuracy of 98.24%. Hence, the models performed at expert level (better than one expert and worse than the other), although a well-trained expert with good knowledge of FSs could probably do better in some cases. The models and datasets have been included in the Fetal Heart Rate Morphological Analysis open-source MATLAB toolbox and can be used freely for research purposes.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

Scaffolds for tissue engineering are expected to respond to a challenging combination of physical and mechanical requirements, guiding the research towards the development of novel hybrid materials. This study introduces innovative three-dimensional bioresorbable scaffolds, in which a stiff poly(lactic acid) lattice structure is meant to ensure temporary mechanical support, while a bioactive gelatin-chitosan hydrogel is incorporated to provide a better environment for cell adhesion and proliferation. The scaffolds present a core-shell structure, in which the lattice core is realized by additive manufacturing, while the shell is nested throughout the core by grafting and crosslinking a hydrogel forming solution. After subsequent freeze-drying, the hydrogel network forms a highly interconnected porous structure that completely envelops the poly(lactic acid) core. Thanks to this strategy, it is easy to tailor the scaffold properties for a specific target application, by properly designing the lattice geometry and the core/shell ratio, which are found to significantly affect the scaffold mechanical performance and its bioresorption. Compression stiffness and strength provided by poly(lactic acid) lattices are overall within the range of values displayed by human bone tissue and remain stable after prolonged immersion in water at body temperature for several weeks. On the other hand, the hydrogel undergoes gradual and homogeneous degradation over time, but the core-shell integrity and structural stability are nevertheless maintained during at least 7-week hydrolytic degradation tests. In vitro experiments with human mesenchymal stromal cells reveal that the core-shell scaffolds are biocompatible and their physical-mechanical properties and architecture are suitable to support cell growth and osteogenic differentiation, as demonstrated by hydroxyapatite formation. These results suggest that the bioresorbable core-shell scaffolds can be considered, and further studied, in view of clinically relevant endpoints in bone regenerative medicine.

Berberine (BBR) is an isoquinoline that inhibits the proliferation of transformed cells in vitro, but due to its poor solubility and bioavailability, it has only moderate therapeutic potential in vivo. Increasing evidence indicates that BBR specifically targets several metabolic, signaling and gene transcription events in transformed cells, altering their progression through the cell cycle and decreasing their metabolic rate and proliferation. In order to further develop BBR as a therapeutic, its mode of cellular internalization and localization within the cell needs to be further examined. BBR’s molecular targets and interactions with kinases, transcription factors and some enzymes are discussed in an attempt to better understand BBR’s role in these important pathways and how they may lead to changes in metabolism. Lastly, this review examines some of the benefits and challenges of using BBR as an inhibitor in cancer cell proliferation in breast cancer and glioblastoma, as two examples. BBR is a potent drug with multiple targets and it is this multiplicity of function that makes BBR such a promising drug for targeting cell metabolism and proliferation.

The proliferation and differentiation of mammalian skeletal muscle satellite cells (MuSCs) are highly complicated. Apart from the regulatory signaling cascade driven by the protein-coding genes, non-coding RNAs like microRNAs (miRNA) and circular RNAs (circRNAs) play essential roles in this biological process. However, circRNA functions in MuSCs proliferation and differentiation remain largely to be elucidated. Here, we screened for an exonic circTCF4 based on our previous RNA-Seq data, specifically expressed during the development of the longest dorsal muscle in goats. Subsequently, the circular structure and whole sequence of circTCF4 were verified using Sanger sequencing. Besides, circTCF4 was spatiotemporally expressed in multiple tissues from goats but strikingly enriched in muscles. Furthermore, circTCF4 suppressed MuSCs proliferation and differentiation, independent of AGO2 binding. Finally, we conducted Poly(A) RNA-Seq using cells treated with small interfering RNA targeting circTCF4 and found that circTCF4 would affect multiple signaling pathways, including insulin signaling pathway and AMPK signaling pathway related to muscle differentiation. Our results provide additional solid evidence for circRNA regulating skeletal muscle formation.

Transparent, flexible, biaxially oriented polyethylene terephthalate (PET) sheets were modified by bioactive polymer-fibronectin top layers for the attachment of cells and growth of muscle fibers. Towards this end, PET sheets were grafted with 4-(dimethylamino)phenyl (DMA) groups from the in situ generated corresponding diazonium compound. The arylated sheets served as macro-hydrogen donors for benzophenone and the growth of poly(2-hydroxy ethyl methacrylate) (PHEMA) top layer by surface-confined free radical photopolymerization. The PET-PHEMA sheets were further grafted with fibronectin (FBN) through the 1,1-carbonyldiimidazole coupling procedures. The bioactive PET-PHEMA-I-FBN was then employed as a platform for the attachment, proliferation and differentiation of eukaryotic cells which after a few days gave remarkable muscle fibers, of ~120 µm length and ~45 µm thickness. We demonstrate that PET-PHEMA yields a fast growth of cells followed by muscle fibers of excellent levels of differentiation compared to pristine PET or standard microscope glass slides. The positive effect is exacerbated by crosslinking PHEMA chains with ethylene glycol dimethacrylate at initial HEMA/EGDMA concentration ratio = 9/1. This works conclusively shows that in situ generated diazonium salts provide aryl layers for the efficient UV-induced grafting of biocompatible coating that beneficially serve as platform for cell attachment and growth of muscle fibers. Beyond this work, diazonium coupling agents constitute the corner stone of next generation processes for building flexible platforms for cell adhesion and uses thereof.

Few-layer graphene oxide (GO) has shown none or very weak cytotoxicity and anti-proliferative effects in a wide range of cell lines such as glyoma cells and human skin HaCaT cells, in concentrations up to 100 µg/mL However, multi-layer GO has been hardly explored in the biomedical field. Thus, multi-layer GO was examined here in human keratinocyte HaCaT cells treated with different concentrations ranging from 0.01 to 150 µg/mL during different periods of times (3, 12 and 24 hours). The results of this study showed a time-concentration dependence with two non-cytotoxic concentrations (0.01 and 0.05 µg/mL) and a median effective concentration value of 4.087 µg/mL at 24 hours of GO exposure. Contrary to what has been reported for few-layer GO, cell proliferation of the HaCaT cells in contact with the multi-layer GO at 0.01 μg/mL showed identical proliferative activity compared to an epidermal growth factor (1.6-fold greater than the control group) after 96 hours. The effects of the multi-layer GO on the expression of 13 genes (SOD1, CAT, MMP1, TGFB1, GPX1, FN1, HAS2, LAMB1, LUM, CDH1, COL4A1, FBN and VCAN) at the non-cytotoxic concentrations of GO in the HaCaT cells were analyzed after 24 hours. Thus, the lowest non-cytotoxic GO concentration was able to up-regulate the CAT, TGFB1, FN1 and CDH1 genes, which confirms the great potential of multi-layer GO in the biomedical field.

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1⁺/NKX6.1⁺), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1⁺/NKX6.1^-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

Following our previous success in identifying new steroid-based anticancer agents, we herein disclosed the structural requirements for retaining high potency against cancer cells and associated modes of action. The structurally novel steroidal dimer by001 inhibited growth of different esophageal cancer cells and colony formation at low micromolar levels, elevated cellular ROS levels and caused mitochondrial dysfunction. Mechanistic studies showed that by001 induced cell death through the mitochondria and death receptor-mediated apoptotic pathways and autophagy induction, as well as inhibited migration.

Different values of the Hubble constant for extragalactic objects are not considered here. We give a number of examples of the extreme accordance of expansion rates of different fields of knowledge with the cosmological expansion rate. The coincidence of the expansion rates means that a common cause is almost inevitable. All these examples are gravitationally bound in themselves and in this case are subject to cosmological expansion. According to standard theory, this should not happen. We therefore question the common boundary of gravity and expansion for both theoretical and observational reasons and conclude that all gravitationally dominated objects participate in cosmological expansion or scale drift, contrary to general doctrine. The space expands with its contents while numerically maintaining distance, radius, rotation time and density. What is generally interpreted as an expansion is obviously a scale drift with a drift rate that corresponds to the size of the Hubble constant. The Earth is subject to expansion and scale drift. This results in numerically constant measured values. This drift apparently also applies to distant galaxies and other objects. The cosmological red shift is not interpreted here as a Doppler effect and numerical increase in distances, but in accordance with standard theory as an expansion or drift of the space-time scale. The expansion of the radii of galaxies makes the assumption of dark matter superfluous. The continents and our everyday environment are not subject to expansion or scale drift.

Demographic and socio-economic developments couple with other requirements to satisfy human needs result in rapid urban expansion sometimes with increasing rate of surface extent greater than the rate of growth of population, that result in continuous sealing of ground surface thereby affecting ecosystem services. This study applied remote sensing toward achieving the progress of SDGs and stage to determine the ratio of the rate of land consumption to the rate of population growth of Gombe metropolis. QGIS 2.18 was used for the image processing and classification analysis for the key Landsat ETM+ (Enhanced Thematic Mapper), Impervious Surface Indices and population data to inform on the urban trend and LCR/PGR for the periods 2000-2005, 2005-2010, and 2010-2015. The result appears that the LCR/PGR for the periods of study show split trends. During 2000-2005 the result shows that the study area expanded outward with LCR/PGR of 1.2. The result also indicate that during 2005-2010, the study area densified with little expansion with the LCR/PGR of 0.8. The result further reveals that during 2010-2015 the LCR/PGR reached 1.8. Pointing that the study area expanded outward with the rate of ground sealing getting high.

Background and Objectives: A 62-year-old patient presented with significant visual reduction in the last three months. Best corrected visual acuity (BCVA) of the right eye (RE) dropped from 20/20 on both eyes to 20/200 on the RE and counting fingers (CF) on the left eye (LE); respectfully. She was diagnosed with stage 4 ovarian cancer 1 month ago. Materials and Methods: Examination revealed significant progression of cataracts and subretinal fluid on the posterior pole with choroidal thickening. Multifocal, orange-pigmented elevated choroidal lesions were observed in the RE, while the view of the left eye fundus was obstructed by cataracts. OCT revealed bilateral choroidal thickening with overlying folds and subretinal fluid and ultrasound of the choroidal lesions showed moderate homogenous internal reflectivity. Results: The patient was diagnosed with BDUMP (bilateral diffuse uveal melanocytic proliferation), a paraneoplastic syndrome characterised by simultaneous, bilateral, painless vision loss and rapidly acquired bilateral cataracts with serous retinal detachments. Cataract extraction had not obtained the expected visual recovery (RE: CF; LE 2/200, respectfully). Plasmapheresis demonstrated some success by stabilizing vision loss obtained by serous retinal detachments. Conclusion: The focus of treating BDUMP is aimed at the underlying malignancy. Vision typically deteriorates to near blindness within a year from presentation. Overall prognosis is generally poor and mean survival is reported at 12-15.7 months from the time of ocular diagnosis.

Epidemiological and clinical evidence have extensively documented the role of obesity in the develop-ment of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer, and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effec-tively reversed the effects of palmitic acid on cell proliferation, apoptosis and invasive capacity in the endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation, inva-sion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer

BMAP-27 peptide known to exert cytotoxic effects against cancer cells by membrane integrity disruption. In the current investigation, we aimed to study the role of the BMAP-27 peptide in reducing colon cancer cell proliferation and inducing apoptosis. This study utilized both primary and metastatic colon cancer cell lines (SW480 and SW620). Proliferation was measured using CCK-8, and cellular damage was analyzed by lactate dehydrogenase assay. The study assessed apoptosis, cell cycle, and proliferation by measuring the expression of CASPASE3, BAX, BCL-2, TP53, CDK-6, PCNA, Wnt11, AXIN1, and CTNNB1. Additionally, in-silico studies were conducted to determine the binding affinities of BMAP-27 with APC and β-catenin proteins. BMAP-27 peptide reduced colon cancer cell proliferation, upregulated CASPASE3, BAX, TP53, AXIN1 expression, and downregulated BCL-2, CDK-6, PCNA, WNT11, CTNNB1 in both colon cancer cell lines, however, demonstrated higher activity in primary than metastatic colon cancer cells. The molecular dynamic simulation revealed substantial binding affinity of the peptide to adenomatous polyposis coli and β-catenin proteins.BMAP-27 peptide effectively inhibited the proliferation and enhanced apoptosis in the primary than in metastatic colon cancer cells. In-silico findings suggest that BMAP-27 exhibits a strong binding affinity with APC and β-catenin, highlighting its potential role as an anti-colon cancer agent.

Microglia are resident immune cells of the central nervous system such as brain-specific macrophages and also known to regulate the innate immune functions of astrocytes through secretory molecules. This conversation plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia can cross-talk to induce microglial polarization and proliferation, which can be further regulated under the brain stroke-mimic microenvironment. Microglia in mixed glial culture increased their survival and proliferation and altered to the M2 microglia, whose role was provided by CD11b-GFAP+ astrocytes by showing approximately tenfold increase in microglia cell proliferation after the astrocyte reconstitution. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced to CCR7+ M1 microglia, whose phenotype could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and Substance-P. Also, astrocyte in the microglia co-culture revealed A2 phenotype, which could be activated to A1 astrocyte by TNFα and IFNγ under the stroke-mimic condition. Altogether, astrocyte in the mixed glial culture stimulated the microglia proliferation and M2 polarization possibly through its acquisition of A2 phenotype, both of which could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimic environment. This study demonstrated that microglia and astrocyte can be polarized to M2 microglia and A2 astrocytes respectively through the cross-talk in vitro and provided a system to explore how microglia and astrocyte may behave in the inflammatory disease milieu after in vivo transplantation.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella Sativa, has been extensively researched for its anti-cancer properties across various human cancers. Yet, its specific anticancer mechanisms and pathways in glioblastoma remain to be elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 µM and 5 µM TQ concentrations. However, at 25 µM and 50 µM, TQ significantly reduced cell viability in a dose-dependent manner. We identified 1548 DEGs at 25 µM TQ (684 upregulated, 864 downregulated) and 2797 DEGs at 50 µM TQ (1528 upregulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5), while modulating Wnt signaling and upregulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anticancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown their ability to slow aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in-silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We confirmed TKA001 binding in silico by molecular docking. TKA001 potently inhibits both TOR complex 1 and 2 downstream signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extended the lifespan of C. elegans, suggesting that TKA001 can slow aging in vivo.

Background: The present study was carried out to evaluate the roles of proliferation and angiogenesis in locally aggressive biologic behavior of ameloblastoma versus ameloblastic fibroma; Methods: 30 formalin-fixed paraffin embedded blocks (15 cases of ameloblastoma & 15 cases of ameloblastic fibroma) were used. To evaluate the proliferation, the tissue sections were stained with AgNORs stain. CD105 was used as immunohistochemical marker of angiogenesis. Quantitative evaluations of AgNORs were performed. The mean vascular density was evaluated as a measure for CD105 protein expression by using image analyzer computer system; Results: The mean number of AgNORs dots per nucleus was significantly higher in ameloblastoma as compared to ameloblastic fibroma. Also, the protein level of CD105 showed positive expression and wide distribution that the mean vascular density was significantly higher in ameloblastoma as compared to ameloblastic fibroma; Conclusion: Quantitative evaluation of AgNORs stain & the mean vascular density utilizing CD105 protein expression may reflect a higher proliferative activity and a more locally aggressive biologic behavior of ameloblastoma when compared to ameloblastic fibroma, that other factors may be involved in biologic behavior of ameloblastic fibroma.

Inflation and exchange rates have great influence on consumer prices especially on imports and exports. Exchange rate fluctuations create inefficiency and distort world prices whereas changes in inflation rates have a direct impact on consumer goods prices which incidentally include exchange rates. There is a direct interdependence between inflation and exchange rates and this paper is aimed at investigating this relationship in dynamic context. It tries to find out how changes in inflation and exchange rates impact on another by adopting the econometric and copula approaches. Both inflation and exchange rates data are susceptible to volatility clustering, possess fat tails and are skewed coupled with conditional heteroskedasticity. Hence we model the univariate distributions by using ARMA$(p,q)$-GARCH$(x,y)$ so as to capture the most important stylized features of inflation and exchange rates. A bivariate model is then constructed by coupling the marginal distributions of inflation and exchange rates using the survival Clayton copula. Empirical results from monthly inflation and exchange rates data show positive correlation between the two based on Kendall $\tau$ test which confirms that a change in inflation results in change of exchange rates an vice versa hence there is co-movement. Furthermore, by the Granger causality test, exchange rates spikes cause changes in inflation rates. The results of the study have implications on economic policy design and hedging strategies for traders on imports and exports.

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

Hepatocellular Carcinoma is one of the most predominant malignancies with high fatality rate and is rising at an alarming rate because it is quite resistant to radioand chemotherapy. The proliferation, migration and activation of endothelial cells are involved in tumor occurrence and development. Indirubin is the major active anti-tumor ingredient of a traditional Chinese herbal medicine. In this research, Td-ECs were derived from human umbilical vein endothelial cells (HUVECs) by treating HUVECs with the conditioned medium of human liver cancer cell line HepG2. The effects of indirubin on cell proliferation, migration, invasion and angiogenesis of Td-ECs were assessed. Indirubin significantly inhibited Td-EC cell proliferation in a dose- and time-dependent manner. Indirubin also inhibited Td-EC migration and angiogenesis. However, indirubin’s effects on HUVECs were weaker than on Td-ECs.

To the best of the author’s knowledge, studies of mature plasmacytoid dendritic cell proliferation associated with T lymphoblastic lymphoma were extremely rare in the literature. Here, we report a patient who underwent both mature plasmacytoid dendritic cell proliferation and T lymphoblastic lymphoma. With the findings of lymph node biopsy taken from the right cervical and inguinal regions, we identified eye-catching mature plasmacytoid dendritic cells that were considered to be responsible for this lesion at the beginning, until the immunostaining of Ki67 and TDT showed a small group of positive cells hiding in these plasmacytoid dendritic cells. Bone marrow biopsy was also performed in this patient. Microscopically, the hematopoietic tissue was almost completely replaced by lymphoblastoid cells with condensed chromatin, inconspicuous nucleoli and scanty cytoplasm, which were basically the same as those seen in the lymph nodes in morphology. However, there was no sign of plasmacytoid dendritic cells or Langerhans cells in the bone marrow biopsy. With the help of bone marrow biopsy, our final diagnosis of the lymph node was T lymphoblastic lymphoma coexisting with mature plasmacytoid dendritic cell proliferation . Although accumulations of plasmacytoid dendritic cells may occur in some infections or reactive lymphadenopathy, the presence of extensive nodules or infiltration of plasmacytoid dendritic cells strongly reminds the pathologist to carefully evaluate the bone marrow or peripheral blood status of the patient to exclude a hidden myeloid or other neoplasm.

Calcium-activated potassium channels (KCa) are the important participants in calcium signaling pathways due to their ability to be activated by increase of the intracellular free calcium concentration. KCa channels are involved in the regulation of various processes in the cells under normal, as well as pathophysiological conditions, including oncotransformation. Previously, with the use of patch-clamp method, we registered the KCa activity in the plasma membrane of human myeloid leukemia K562 cell line. Here, we performed the molecular and functional identification of KCa channels and have uncovered their role in proliferation, migration and invasion of K562 cells. Using a combined approach, we identified the functional activity of SK2, SK3 and IK channels in the plasma membrane of the cells. Selective SK and IK channel inhibitors, apamin and TRAM-34, reduced the proliferative, migratory and invasive capabilities of human myeloid leukemia cells. At the same time, the viability of K562 cells was not affected by KCa channel inhibitors. Our data imply that SK/IK channel inhibitors could be used to slow down the proliferation and spreading of leukemia cells that express functionally active KCa channels in the plasma membrane.

A technique for fabrication of bacterial cellulose-based films with CeO₂ nanofiller has been developed. The structural and morphological characteristics of the materials have been studied, their thermal and mechanical properties in dry and swollen states having been determined. The preparation methodology makes it possible to obtain composites with a uniform distribution of nanoparticles. The catalytic effect of ceria regarding the thermal oxidative destruction of cellulose has been confirmed by TGA and DTA methods. An increase in CeO₂ content led to an increase in the elastic modulus (a 1.27-fold increase caused by the introduction of 5 wt.% of the nanofiller into the polymer) and strength of the films. This effect is explained by the formation of additional links between polymer macro-chains via the nanoparticles’ surface. The materials fabricated were characterised by a limited ability to swell in water. Swelling caused a 20- to 30-fold reduction in the stiffness of the material, the mechanical properties of the films in a swollen state remaining germane to their practical use. The application of the composite films in cell engineering as substrates for the stem cells’ proliferation has been studied. The increase in CeO₂ content in the films enhanced the proliferative activity of embryonic mouse stem cells. The cells cultured on the scaffold containing 5 wt.% of ceria demonstrated increased cell survival and migration activity. An analysis of gene expression confirmed improved cultivation conditions on CeO₂-containing scaffolds.

For their clinical use Mesenchymal Stromal Cells (MSCs), isolated from bone marrow (BM-MSCs) are considered Advanced Therapy Medicinal Products (ATMP) and need to be produced according to Good Manufacturing Practice (GMP). Human platelet lysate (HPL) represents a good GMP-compliant alternative to animal serum and after pathogen inactivation with Psoralen was more efficient and safer to produce MSCs in GMP. In this study MSCs cultivated in FBS (FBS-MSC) or inactivated HPL (iHPL-MSC), were compared for their immunomodulant properties. In particular, the effects of MSCs on: 1)proliferation of total Lymphocytes (Ly) and on naïve T Ly subsets induced to differentiate versus Th1 and Th2 Ly; 2) the immunophenotype of different T cell subsets; 3)the cytokine release to verify Th1, Th2 and Th17 polarization were analyzed by using in vitro co-culture system. We observed that iHPL-MSCs showed the same immunomodulant properties observed in the FBS-MSCs co-cultures. Although, a more efficient effect on the increase of naïve T cells and, in the Th1 cytokine release related to iHPL was observed. This study confirms that iHPL, used as medium supplement, may be considered a good alternative to FBS for a GMP-compliant MSC expansion to preserve their immunomodulant proprieties.

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.

Language is an essential aspect of teaching and learning mathematics. It is necessary for communicating, transmission of concepts and ideas, and formation of meaning of mathematical concepts. In mathematics, besides symbols, which are usually common in different languages, words and expressions are used, which may invoke different concept images to students in various languages. Some words are used in mathematics and in everyday language with different meanings, while others are used only in mathematics or in mathematics and other disciplines in similar but non-identical ways. In Mathematical Analysis, the used vocabulary is gradually enhanced, and the concepts are defined in a more formal way. In the current study, the language used regarding mathematics of change is examined, focusing on rate of change and in relation to misconceptions of students.

We explored the dynamics of the two interacting information systems. We show that for the Markovian marginal systems the driving force for information dynamics is determined by both the information landscape and information flux. While the information landscape can be used to construct the driving force to describe the equilibrium time reversible information system dynamics, the information flux can be used to describe the nonequilibrium time-irreversible behaviours of the information system dynamics. The information flux explicitly breaks the detailed balance and is a direct measure of the degree of the nonequilibriumness or time irreversibility. We further demonstrate that the mutual information rate between the two subsystems can be decomposed into the equilibrium time-reversible and nonequilibrium time-irreversible parts respectively. This decomposition of the mutual information rate (MIR) corresponds to the information landscape-flux decomposition explicitly when the two subsystems behave as Markov chains. Finally, we uncover the intimate relationship between the nonequilibrium thermodynamics in terms of the entropy production rates and the time-irreversible part of the mutual information rate. We found that this relationship and MIR decomposition still hold for the more general stationary and ergodic cases. We demonstrate the above features with two examples of the bivariate Markov chains.

Development of new techniques of multimodal treatment, diagnostics of various neoplasms and improvement of these techniques can significantly increase the life expectancy of patients with carcinomas of the colon and abdominal cavity organs, since prevention of various side effects of radiation therapy is one of the main problems of oncological care. Electron irradiation is one of the most promising types of radiation therapy. There are no data on proliferation and apoptosis of the colon epithelium after irradiation with electrons, especially in different modes (single and summary). Aim of the study: Morphological evaluation of apoptosis and proliferation of colonic epithelium after local irradiation with electrons at doses 2 Gy and 25 Gy. Materials and methods. Colon fragments from sexually mature Wistar rats (n=50, body weight 200 ± 10 g) were divided into three groups: I - control (n = 10); II - experimental group (n = 20; local single electron irradiation at a dose of 2 Gy), III - experimental group (n=30), local fractional irradiation with electrons at a total dose of 25 Gy. They were studied by light microscopy using hematoxylin and eosin staining and immunohistochemical reactions with antibodies to Ki-67 and Cas3. Morphological disorders were accompanied by increased expression of pro-apoptotic molecules (caspase-3), and the period of regeneration by proliferative marker (Ki-67). Conclusions: Local fractional irradiation of the colon with electrons at a dose of 2 Gy and 25 Gy resulted in minor changes in the epithelium, a decrease in the number of goblet cells, but with preservation of regenerative potential, mild degenerative-dystrophic lesions. Intestinal crypts were damaged, leading to a decrease in Ki-67 and an increase in the number of caspase-3-positive epitheliocytes.

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that contributes to the progression of several cancers. MIF overexpression has been reported in head and neck squamous cell carcinoma (HNSCC) patients. However, the exact role of MIF in HNSCC is not fully understood. Our aim was to evaluate the amount of secreted MIF and the role of MIF in the proliferation, cell cycle, and apoptosis in HNSCC cell lines. The MIF levels in conditioned media from human primary (HN18 and HN30) and metastatic (HN17 and HN31) HNSCC cell lines were evaluated using ELISA. The HNSCC cell lines were treated with recombinant MIF and its effect on proliferation, cell cycle, and apoptotic status was determined by MTT and flow cytometry, respectively. The HNSCC-secreted MIF concentration ranged from 49.33‒860 pg/ml. Exogenous MIF (25 ng/ml) significantly increased HN18, HN30, and HN31 cell proliferation. Moreover, MIF induced cell cycle progression and inhibited apoptosis in these cells. However, MIF did not affect growth or apoptosis in HN17 cell. In conclusion, the HNSCC cell lines were evaluated secrete MIF. Exogenous MIF promotes various effects on proliferation, cell cycle, and apoptosis in HNSCC cells.

Imperatorin is a chemical compound belong to Linear furan coumarins. Imperatorin is attracting considerable attention because of its anti-tumor, antibacterial, anti-inflammatory, anticoagulant and inhibition of myocardial hypetrophy and other pharmacological efficacy. However, imperatorin has limited water solubility and preferable lipid solubility, we decided to design and synthesize imperatorin lipid microsphere, to optimize preparation conditions. The aim was to develop and formulate imperatorin lipid microsphere through nano emulsion technology and apply the response surface-central composite design to optimize the imperatorin lipid microsphere formulation. Influence of content of amount of egg lecithin(A), amount of poloxamer188(B), soybean oil for injection accounted for the total percentage of oil phase(C) were investigated. Integrated effect of dependent variables including particle size(Y₁), polydispersity index(Y₂), Zeta potentials(Y₃), drug loading(Y₄), encapsulation efficiency(Y₅). Data of overall desirabiities were fitted to a second-order polynomial equation, through which three dimensional response surface graphs were described. Optimum experimental conditions were calculated by Design-Expert 8.06. Results indicated that the optimum preparation conditions were as follows: egg lecithin amount 1.39 g, poloxamer188 amount 0.21 g, soybean oil for injection amount 10.57%. Preparation of imperatorin lipid microsphere according to the optimum experimental conditions resulted in an overall desirability of 0.7286, while the particele size (168±0.54) nm, polydispersity index (PDI) (0.138±0.02), Zeta potentials (−43.5±0.5) mV, drug loading (0.833±0.27) mg·mL⁻¹, encapsulation efficiency (90±1.27)%. The difference between observed and predicted values of the overall desirability of the optimum formulation was in range from 2.4% to 4.3%. Subsequently, using the Scanning electron microscopy to observe the micromorphology of imperatorin lipid microsphere, the result shows that round globular of relatively uniform and sizes within 200nm.The proliferation study of imperatorin lipid microsphere on MDA-MB-231 was investigated by MTT method. Furthermore, pharmacokinetics in Sprague Dawley rats were evaluated using orbital bleeding. A sensitive and reliable liquid chromatography with High Performance Liquid Chromatography (HPLC) method was established and validated for the quantification of imperatorin in rat plasma samples. The data were calculated by DAS (Drug and statistics) pharmacokinetic software version3.2.6 (China). Results demonstrated that imperatorin lipid microsphere can significantly enhance the bioavailability of imperatorin and can significantly inhibit MDA-MB-231 cell proliferating. In conclusion, our results suggersted that the response surface-central composite design is suitable for the optimized lipid microspere formulation. Imperatorin Lipid microsphere can improve the bioavailability of imperatorin and inhibit the proliferation of MDA-MB-231 than that of imperatorin.

Kaposi sarcoma is the most common neoplasm associated with Human Immunodeficiency Virus (HIV) infection. Most patients with a confirmed diagnosis experienced limited disease progression. We describe the case of a 49-year-old African American male with a rare presentation of disseminated Kaposi sarcoma as determined by multi-organ work-up. The patient’s cutaneous manifestations involved several hyperpigmented skin lesions, but the worsening of his respiratory symptoms coupled with unexplained weight loss led providers to develop a high suspicion for disseminated disease progression. This case highlights the need to increase awareness of atypical Kaposi sarcoma presentation.

The prevalent use of synthetic chemical rodenticides (both 1st or 2nd generation anticoagulants and acute rodenticides) is the primary method for managing rodents in sub-Saharan Africa. However, this practice poses substantial health and environmental risks and often fails to yield significant, sustainable reductions in rodent pest populations. In this paper, the second one of a two-part series, we advocate for a more responsible and sustainable approach to rodent management in urban and agricultural settings in sub-Saharan Africa. We propose a shift towards environmentally friendly rodent management strategies, specifically emphasizing the adoption of Ecologically-Based Rodent Management (EBRM) as a viable alternative to synthetic chemical rodenticides. EBRM relies on a comprehensive understanding of pest rodent biology, ecology, and behavior, along with the implementation of a range of community-based interventions. These actions are designed to ensure the consistent reduction of rodent pest populations to economically and hygienically acceptable levels. By embracing EBRM, we not only anticipate a reduction in the social impacts of pest rodents in a cost-effective manner but also a significant decrease in the risks posed by rodents and synthetic chemical rodenticides to human health and the environment. This paradigm shift towards EBRM promises a more sustainable and responsible approach to rodent management in sub-Saharan Africa.

Background: Interleukin (IL)-33 is a member of interleukin (IL)-1 family of cytokines which has been linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has direct effect on human gastric epithelial cells (GES-1) and on human gastric adenocarcinoma cell line (AGS) and gastric carcinoma cell line (NCI-N87), assessing its role in regulation of cell proliferation and cell cycle, apoptosis and necrosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Methods: cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assay, we also evaluated apoptosis by Caspase 3/8 Activity assay and Annexin V assays. Cell cycle were analyzed by means of Propidium Iodine assay and gene expression regulation was assessed by RT-PCR Profiling. Results: we found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell line, while it can stimulate proliferation and reduce apoptosis in normal epithelial cell line. These effects are also confirmed by the analysis of cell cycle gene expression which showed a reduced expression of proproliferative genes in cancer cells, in particular genes involved in G0/G1 and G2/M checkpoint. These results are confirmed by the gene expression analysis on surgical and bioptic specimens. Conclusions: the aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell type-dependent fashion.

Objective: Pancreatic carcinoma (PANC) is one of the important aggressive cancers, with deficiency in effective therapeutics. Studies have unveiled that miR-139-5p expression is significantly downregulated in other types of cancers. However, the functions and mechanisms of miR-139-5p in PANC remain unclear. Methods: Bioinformatic analysis was performed to analyze the differentially expressed genes in the TCGA database. PANC cell line with overexpressed miR-139-5p and Solute Carrier Family 7, Member 11 (SLC7A11) was established, and has been used to detect cell proliferation, migration, invasion and colony formation in PANC. Subsequently, bioinformatic analysis and luciferase assay were performed to confirm that SLC7A11 was a target gene of miR-139-5p. Xenograft mouse model was used to investigate the role of miR-139-5p in PANC tumorigenicity. Results: Through bioinformatic analysis, miR-139-5p was predicted to regulate phosphatidylinositol signaling pathway by targeting SLC7A11. MiR-139-5p was found to be lowly expressed in PANC tissues, while SLC7A11 was highly expressed. Low expression of miR-139-5p and high expression of SLC7A11 were positively associated with poor clinical outcomes. PANC cell proliferation, migration, and invasion could be inhibited by miR-139-5p overexpression and could be promoted by SLC7A11 overexpression. MiR-139-5p could regulate the protein expression level of PI3K and Akt associated with phosphatidylinositol signaling pathway could be by inhibiting the expression of SLC7A11. MiR-139-5p overexpression could suppress PANC tumor growth and the expression of SLC7A11, p-PI3K, p-Akt in tumor tissues. Therefore, the inhibiting effect of miR-139-5p to PANC cell proliferation, invasion and migration, at least, was partly due to its inhibiting effect on SLC7A11 expression. Conclusion: These results demonstrated a novel role of miR-139-5p/SLC7A11 in PANC and provided potential prognostic predictors for PANC patients.

In most of acute myeloid leukemia patients there is an aberrant tyrosine kinases activity. The Sprouty family proteins were originally identified in Drosophila melanogaster as antagonists of Breathless, the mammalian ortholog of fibroblast growth factor receptor. This family proteins are inhibitors of RAS signaling induced by tyrosine kinases receptors and they are implicated in negative feedback processes regulating several intracellular pathways. The present study aims to investigate the role of a member of the Sprouty family, Sprouty1, as regulator of cell proliferation and growth in patients affected by acute myeloid leukemia. Sprouty1 mRNA and protein were both significantly down-regulated in acute myeloid leukemia cells compared to the normal counterpart, but they were restored when remission is achieved after chemotherapy. Ectopic expression of Sprouty1 revealed that it plays a key role in the proliferation and apoptotic defect that represent a landmark of the leukemic cells. Our study identified Sprouty1 as negative regulator involved in the aberrant signals of acute myeloid leukemia. Furthermore, we found a correlation between Sprouty1 and FoxO3a delocalization in AML at diagnosis, suggesting a multistep regulation of RAF–MEK–ERK signaling in human cancers.

We evaluated the mono- and combination-therapy effects of valproic acid (VPA) and doxorubicin (DOX) in hepatocellular carcinoma (HCC) and identified a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.

The highly adaptable parasite Trypanosoma cruzi undergoes complex developmental stages to exploit host organisms effectively. Each stage involves the expression of specific proteins and precise intracellular structural organization. These morphological changes depend on key structures that control intracellular components’ growth and redistribution. In trypanosomatids, the flagellar attachment zone (FAZ) connects the flagellum to the cell body and plays a pivotal role in cell expansion and structural rearrangement. While FAZ proteins are well-studied in other trypanosomatids, there is limited knowledge about specific components, organization, and function in T. cruzi. This study employed the CRISPR/Cas9 system to label endogenous genes and conduct deletions to characterize FAZ-specific proteins during epimastigote cell division and metacyclogenesis. In T. cruzi, these proteins exhibited distinct organization compared to counterparts in T. brucei. TcGP72 is anchored to the flagellar membrane, while TcFLA-1BP is anchored to the membrane lining the cell body. We identified unique features in the organization and function of the FAZ in T. cruzi compared to other trypanosomatids. Deleting these proteins had varying effects on intracellular structures, cytokinesis, and metacyclogenesis. This study reveals specific variations that directly impact the success of cell division and differentiation of this parasite.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Inflation is a crucial macroeconomic indicator which measures changes in the general level of prices of goods and services. In recent years, a series of successive events affected the inflation rates. To fight this increase in inflation, governments start to take different actions through their monetary and fiscal policies. In this research 10 independent parameters were used to see their effect on inflation rates. Some are traditional like GDP, Population, and exchange rate while others are some new technology related parameters like E-money payments transactions and number of Institutions offering payment services/instruments. The dependent parameter is the consumer price index (CPI). All parameters were taken in 8 years period (2013-2020). Supervised machine learning is used to run a robust regression model. The results show that technology advancement in payments is not a catalyst for price inflation if it is used properly and under regulations and control monetary policies. The results direct regulators to have a good understanding of the situation and take the right action in their policies of adopting fintech businesses.

The seasonally adjusted civilian labor force participation rate, the sum of employed and unemployed persons as a percentage of the civilian non-institutional population, is analysed in the general to specific modelling framework with a saturating set of step indicators from January 1977 through June 2018. The results indicate that, ceteris paribus, the rise in the ratio of women to men in the labor force in addition to positive demographic movements can largely account for the rise in the labor force participation rate up to January 2000. Subsequently, the aging population helps to explain the decline. Recessions play a transitory role.

We propose an electrocardiogram (ECG) signal-based algorithm to estimate the respiratory rate is a significant informative indicator of physiological state of a patient. The consecutive ECG signals reflect the information about the respiration because inhalation and exhalation make transthoracic impedance vary. The proposed algorithm extracts the respiration-related signal by finding out the commonality between the frequency and amplitude features in the ECG pulse train. The respiration rate can be calculated from the principle components after the procedure of the singular spectrum analysis. We achieved 1.7569 breaths per min of root-mean-squared error and 1.7517 of standard deviation with a 32-seconds signal window of the Capnobase dataset, which gives notable improvement compared with the conventional Autoregressive model based estimation methods.

The Finite size Lyapunov exponent (FSLE) has been used extensively since the late 1990’s to diagnose turbulent regimes from Lagrangian experiments and to detect Lagrangian coherent structures in geophysical flows and two-dimensional turbulence. Historically, the FSLE was defined in terms of its computational method rather than via a mathematical formulation, and the behavior of the FSLE in the turbulent inertial ranges is based primarily on scaling arguments. Here we propose an exact definition of the FSLE based on conditional averaging of the finite amplitude growth rate (FAGR) of the particle pair separation. With this new definition, we show that the FSLE is a close proxy for the inverse structural time, a concept introduced a decade before the FSLE. The (in)dependence of the FSLE on initial conditions is also discussed, as well as the links between the FAGR and other relevant Lagrangian metrics, such as the finite time Lyapunov exponent and the second order velocity structure function.

Persistent organic pollutants (POPs) accumulation and hypoxia are two factors proposed to adversely alter adipose tissue (AT) functions in the context of excess adiposity. Studies have shown that preadipocytes exposure to dioxin and dioxin-like POPs have the greatest deleterious impact on rodent and immortalized human preadipocyte differentiation, but evidence on human preadipocytes is lacking. Also, hypoxia is known to strongly interfere with the dioxin-response pathway. Therefore, we tested the effects of pre-differentiation polychlorinated biphenyl (PCB)126 exposure and subsequent differentiation under hypoxia on human subcutaneous adipocytes (hSA) differentiation, glucose uptake and expression of selected metabolism- and inflammation-related genes. Pre-differentiation PCB126 exposure lowered the ATP content, glucose uptake and leptin expression of mature adipocytes but had limited effects on differentiation under normoxia (21% O2). Under hypoxia (3% O2), preadipocytes ability to differentiate was significantly reduced as reflected by significant decreased lipid accumulation and downregulation of key adipocyte genes such as PPARγ and adiponectin. Hypoxia increased glucose uptake and GLUT1 expression but abolished the adipocytes insulin response and GLUT4 expression. Expression of pro-inflammatory adipokine IL-6 was slightly increased by both PCB126 and hypoxia, while IL-8 expression was significantly increased only following the PCB126-hypoxia sequence. These observations suggest that PCB126 do not affect human preadipocyte differentiation, but do affect the subsequent adipocytes population, as reflected by lower ATP levels and absolute glucose uptake. On the other hand, PCB126 and hypoxia exert additive effects on AT inflammation, an important player in the development of chronic diseases such as type 2 diabetes and cardiovascular diseases.

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach in cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support a role of ERVs in tumor development and encourage further search for antiretroviral agents to treat malignancies in which endogenous retroviruses are active.

Traumatic brain injury represents one of the main health problems in developed countries. Growth Hormone (GH) and rehabilitation have been claimed to significantly contribute to the recovery of lost motor function after acquired brain injury, but the mechanisms by which this occurs are not well understood. In this work, we have investigated cell proliferation in the piriform cortex (PC) of adult rats with ablation of the frontal motor cortex treated with GH and rehabilitation, in order to evaluate if this region of the brain, related to the sense of smell, could be involved in benefits of GH treatment. Male rats were either ablated the frontal motor cortex in the dominant hemisphere or sham-operated and treated with GH or vehicle at 35 days post-injury (dpi) for five days. At 36 dpi, all rats received daily injections of bromodeoxyuridine (BrdU) for 4 days. We assessed motor function through the paw-reaching-for-food task. GH treatment and rehabilitation at 35 dpi significantly improved the motor deficit caused by the injury and promoted an increase of cell proliferation in the PC ipsilateral to the injury, which could be involved in the improvement observed. Cortical ablation promoted greater number of BrdU+ cells in the piriform cortex that was maintained long-term, which could be involved in the compensatory mechanisms of the brain after injury.

Background: DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B and HER2-positive Breast Cancer (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). Methods: To decipher its function, DSCAM-AS1 expression was measured by qRT-PCR in tissue samples from 93 BC patients in addition to a meta-analysis of 30 gene expression datasets, together with the evaluation of its association with clinical data. By computational analyses of our RNA-Seq in MCF-7 cells, we investigated the DSCAM-AS1 knock-down effects at both gene and isoform levels. Results: We confirmed DSCAM-AS1 overexpression in high grade Luminal A, B and HER2+ BCs and found a significant correlation with disease relapse. 908 genes were regulated by DSCAM-AS1-silencing, primarily involved in cell cycle and inflammatory response. Noteworthy, the analysis of alternative splicing and isoform regulation revealed 2,085 splicing events regulated by DSCAM-AS1, enriched in differential polyadenylation sites and 3’UTR shortening events. Finally, the DSCAM-AS1-interacting splicing factor hnRNPL was predicted as the most enriched RBP for exon skipping and 3’UTR events. Conclusion: The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer.

Activation of the EGFR pathway plays an important role in the progression of cancer and is associated with a poor prognosis in patients. The monoclonal antibody cetuximab, which displays EGFR extracellular domain-specific binding, has proven effective in the treatment of locally advanced disease and relapsed/metastatic disease. However, the effects of cetuximab are weaker than those of EGFR tyrosine kinase inhibitors (TKIs). This study investigates differences in the effects on cell growth of cetuximab and EGFR TKI AG1478 at the molecular level using oral squamous cell carcinoma (OSCC) cell lines. First, we found that there were EGFR-inhibitor sensitive (EIS) and EGFR-inhibitor resistant cell lines. The EIS cell lines expressed not only EGFR but also ErbB3, and both were clearly phosphorylated. The levels of phosphorylated ErbB3 were unaffected by cetuximab but were reduced by AG1478. EGFR ligand treatment increased the levels of phosphorylated EGFR but not phosphorylated ErbB3. Moreover, when EIS cell lines that were only capable of anchorage-dependent growth were grown in suspension, cell growth was suppressed and the levels of phosphorylated FAK, Src, and ErbB3 were significantly reduced. The levels of phosphorylated ErbB3 were unaffected by the FAK inhibitor PF573228, but were reduced by Src inhibition. Finally, combining cetuximab and a Src inhibitor produced an additive effect on the inhibition of EIS cell line growth.

The core components of regenerative medicine are stem cells with high self-renewal and tissue regeneration potentials. Adult stem cells can be obtained from many organs and tissues. NANOG, SOX2 and OCT4 represent the core regulatory network that suppresses differentiation-associated genes, maintaining the pluripotency of mesenchymal stem cells. The roles of NANOG in maintaining self-renewal and undifferentiated status of adult stem cells are still not perfectly established. In this study we define the effects of downregulation of NANOG in maintaining self-renewal and undifferentiated state in mesenchymal stem cells (MSCs) derived from subcutaneous adipose tissue (hASCs). hASCs were expanded and transfected in vitro with short hairpin Lentivirus targeting NANOG. Gene suppressions were achieved at both transcript and proteome levels. The effect of NANOG knockdown on proliferation after 10 passages and on the cell cycle was evaluated by proliferation assay, colony forming unit (CFU), qRT-PCR and cell cycle analysis by flow-cytometry. Moreover, NANOG involvement in differentiation ability was evaluated. We report that downregulation of NANOG revealed a decrease in the proliferation and differentiation rate, inducing cell cycle arrest by increasing p27/CDKN1B (Cyclin-dependent kinase inhibitor 1B) and p21/CDKN1A(Cyclin-dependent kinase inhibitor 1A) through p53 and regulate DLK1/PREF1. Furthermore, NANOG induced downregulation of DNMT1, a major DNA methyltransferase responsible for maintaining methylation status during DNA replication probably involved in cell cycle regulation. Our study confirms that NANOG regulates the complex transcription network of plasticity of the cells, inducing cell cycle arrest and reducing differentiation potential.

DNA methylation is one of the epigenetic mechanisms which have been implicated in cellular differentiation, ageing and disease development. The effect of hypomethylating drug 5-aza-2´deoxycytidine (5-aza dC) on the biosynthetic profile of caudal region chondrocytes from chick sternum was studied in detail. The chondrocytes in culture were treated with varying doses of 5-aza dC for 48h and maintained subsequently without the treatment and harvested at selected time points for analysis of growth and differentiation status. 15µg/ml of 5-aza dC showed optimum Concentration at which there was a significant increase in DNA synthesis and RNA synthesis as per cell basis. There was also a significant increase in total protein synthesis and collagen synthesis as per cell basis at this concentration. This optimal concentration also showed to up regulate the gene expression of Type X collagen and alkaline phosphatase, which are the marker of hypertrophic chondrocyte expression. These results further support the notion that methylation is the major epigenetic factor controlling the differentiation and maturation of chondrocytes.

Glioblastoma (GBM) is a major type of primary brain tumors without ideal prognosis and it’s necessary to find novel compound possessing therapeutic effect. Chrysomycin A (Chr-A) has been reported to inhibit the proliferation, migration and invasion of U251 and U87-MG cells, but the mechanism of Chr-A against glioblastoma in vivo and whether Chr-A modulates apoptosis of neuroglioma cells is unclear.The present study was to elucidate the potential of Chr-A against glioblastoma in vivo and how Chr-A modulates apoptosis of neuroglioma cells. Briefly, The an-ti-glioblastoma activity was assessed in human glioma U87 xenografts nude mice. Chr-A-related targets were identified by RNA-seq. Apoptotic ratio and caspase 3/7 activity of U251 and U87-MG cells were assayed by flow cytometry. Apoptosis-related proteins and possible molecular mecha-nism were validated via Western blotting. The results showed that Chr-A treatment significantly inhibits glioblastoma progression in xenografts nude mice, and enrichment analysis suggested that apoptosis, PI3K-Akt and Wnt signaling pathway were involved in the possible mechanism. Chr-A increased apoptotic ratio and the activity of caspase 3/7 in U251 and U87-MG cells. Western blot revealed that Chr-A broke the balance between Bax and Bcl-2 activating caspase cascade re-action and downregulated the expression of p-Akt and p-GSK-3β, suggesting that Chr-A may contribute to glioblastoma regression modulating Akt/GSK-3β signaling pathway to promote apoptosis of neuroglioma cells in vivo and in vitro. Therefore, Chr-A may hold therapeutic promise for glioblastoma.

Thalassemia is one of the most prevalent genetic disorders worldwide which has been previously found to have an association with several physiological and organ complications. Several studies found both its positive and inverse correlation with glomerular filtration rate (GFR). Therefore, in this meta-analysis, we tried to assess the accurate correlation of thalassemia with GFR. We searched in Google Scholar, PubMed, and ScienceDirect, and from the initial 96 articles we finally could include 15 studies. The quality and publication bias assessment confirmed that all the studies were of high to moderate quality with no publication bias. The main outcome of the mean difference (MD) was -6.45, 95%CI: -18.50, 5.60 (P<0.00001), which indicated a negative correlation of GFR with thalassemia. The sensitivity analyses found one study as a slight outlier and reanalyzing the data excluding that study MD was achieved as -13.90, 95%CI: -24.22, -3.59 (P<0.00001) which even strongly supports our main outcome. Our result determined that the GFR is generally higher in healthy people as compared to thalassemia patients.

Influenza A viruses (IAVs) evolve via point mutations and reassortment of viral gene segments. The patterns of reassortment in different host species differ considerably. We investigated the genetic diversity of IAVs in wild ducks and compared it with the viral diversity in gulls. The complete genomes of 38 IAVs of H1N1, H1N2, H3N1, H3N2, H3N6, H3N8, H4N6, H5N3, H6N2, H11N6 and H11N9 subtypes isolated from wild mallard duck and gull habitants of a pond in Moscow city, Russia were sequenced. The sequences were closely related to those of avian IAVs isolated in Sweden and the Netherlands. The analysis of phylogenetic trees showed that stable viral genotypes do not persist from year to year in ducks owing to frequent gene reassortment. For comparison, similar analyses were carried out using sequences of IAVs isolated in the same period from ducks and gulls in the Netherlands. Our results revealed a significant difference in diversity and rates of reassorment of IAVs in ducks and gulls.

Covid-19 fatality rates of 0.37% (Gangelt, Germany) and 0.17% (Santa Clara, USA) have been reported, estimated from serological studies. We show that the two confidence intervals strongly overlap when the uncertainty in the number of deaths is taken into account, so that the two investigations may be regarded as representative of the same population (tentatively: “Western society with no overload of the Health Care System during the pandemic”). Combining the results, the Covid-19 fatality rate is estimated to be found with 95% confidence in the range [0.1%; 0.3%].

Conventional economic theory outlines that developing countries experience economic growth through an undervalued exchange rate and that exchange rate overvaluations has negative long term effects on economic growth. This paper examined the impact of exchange rate movements as well as exchange rate misalignments on economic growth for the Trinidad and Tobago economy over the period 1960 to 2016. We find statistically significant evidence that both exchange rate appreciation and misalignments impact negatively on economic growth in the T&T economy. Drilling deeper we find interestingly that there exist no non-linear effects of exchange rate misalignments on growth. Specifically we find statistically significant evidence that both overvaluations and undervaluations hamper economic growth in the Trinidad and Tobago economy. We attribute this to T&T’s small and underdeveloped manufacturing sector that tends to be overlooked on account of its energy resources, in addition to the fact that its manufacturing sector is highly import oriented. A major policy recommendation would be for the critical reassessment of the rules governing the HSF, as government expenditure was allowed to follow energy revenues due to its current limitations.

Perfluorohexane sulfonate (PFHxS) is a widely detected replacement for legacy long-chain perfluoroalkyl substances (PFAS) in the environment and human blood samples. Its potential toxicity led to its recent classification as a global regulated persistent organic pollutant. Although animal studies have shown a positive association between PFHxS levels and hepatic steatosis and hepatocellular hypertrophy, the link with liver toxicity, including end-stage liver cancer, remains inconclusive. In this study, we examined the effects of PFHxS on the proliferation of human hepatocellular carcinoma (HCC) cells, Hep3B and SK-Hep1. Cells were exposed to different PFHxS concentrations for 24–48 hr to assess viability and 12–14 days to measure colony formation. Viability of both cell lines increased at PFHxS concentrations <200 μM, decreased at >400 μM, and were highest at 50 μM. Colony formation increased at <300 μM and decreased at 500 μM PFHxS. Consistent with the effect on HCC proliferation, PFHxS increased expression of proliferating cell nuclear antigen (PCNA) and cell-cycle molecules (CDK2, CDK4, cyclin E, and cyclin D1). In summary, PFHxS exhibited a biphasic effect on HCC cell proliferation, promoting survival and proliferation at lower concentrations and being cytotoxic at higher concentrations. This suggests that PFHxS potentially exacerbates HCC progression.

Titanium (Ti) and Ti-based alloys are commonly used in dental implants, and surface modifications of dental implants are important for achieving osseointegration (i.e., direct connection between the implant surface and bone). This study investigated the effect of an eco-friendly etching solution—a hydrogen peroxide–sodium bicarbonate mixture—on the surface properties and contact angles of and osteoblast adhesion and proliferation on Ti surfaces. Disk-shaped Ti specimens were prepared using different surface treatments (machining, sandblasting, and sandblasting/acid-etching), and they were immersed in the etching solution and then ultrasonically cleaned. Surface characterization was performed using scanning electron microscopy, digital microscopy, contact angle analysis, and X-ray photoelectron spectroscopy. MG-63 osteoblasts were cultured on the specimens, and their adhesion to the specimen surface and their proliferation were examined using staining and the MTT assay, respectively. Additional etching with the etching solution caused the formation of nano/micro hierarchical structures, increased the surface roughness, and enhanced the hydrophilicity. Osteoblast adhesion and proliferation were found to improve on the modified surfaces. The eco-friendly etching method has the potential to enhance the biological properties of Ti implant surfaces and to thereby improve the dental implant performance.

A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein we identify cyclin dependent kinase 1 (CDK1) also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7 and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in a potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.

The design of biomaterial platforms able to release bioactive molecules is mandatory in tissue repair and regenerative medicine. In this context, electrospinning is a user-friendly, versatile and low-cost technique, able to process different kinds of materials in micro- and nano-fibers with a large surface area-to-volume ratio for an optimal release of gaseous signalling molecules. Recently, the antioxidant and anti-inflammatory properties of the endogenous gasotramsmitter hydrogen sulfide (H2S), as well as its ability to stimulate relevant biochemical processes on the growth of mesenchymal stem cells (MSC), have been investigated. Therefore, in this work, new poly(lactic) acid fibrous membranes (PFM), doped and functionalized with H2S slow-releasing donors extracted from garlic, were synthetized. These innovative H2S-releasing mats were characterized for their morphological, thermal, mechanical and biological properties. Their antimicrobial activity and effects on the in vitro human cardiac MSC growth, either in the presence or in the absence of oxidative stress, were here assessed. On the basis of the results here presented, these new H2S-releasing PFM could represent promising and low-cost scaffolds or patches for biomedical applications in tissue repair.

Initial choice of Learning Rate is a key part of gradient based methods and has a great effect on the performance of the Deep Learning Model.This paper studies the behavior of multiple gradient based optimization algorithm which are commonly used in Deep Learning and compare their performance on various learning rate. As observed popular choice of optimization algorithms are highly sensitive to various choice of learning rates. Our goal is to find which optimizer has an edge over others for a specific setting. We look at two datasets namely MNIST and CIFAR10 for benchmarking. The results are quite surprising, and it will help us to choose a learning rate more efficiently.

Background: Corona virus disease was first reported in Wuhan City, Hubei province, China. Soon the corona virus disease has spread to many countries. World health organization has described the situation as Pandemic. By 12 March 2020, corona virus disease has affected 125 countries around the world. Corona virus was first confirmed in Iran on 19 February 2020. Objective: The aim of writing this small article is to determine the mortality rate of corona virus disease in different cities of Iran. This article will give readers an idea of different ways to control spread of corona virus disease in Iran. Methods: Author has collected the data of daily confirmed cases from different diagnostic centers and hospitals across the country from 19 February 2020 to 1 April 2020. Results: Mortality rate of corona virus disease is roughly 4%. Conclusions: Mortality rate could rise if COVID 19 infection is not controlled.

Regulators require financial institutions to estimate counterparty default risks from liquid CDS quotes for the valuation and risk management of OTC derivatives. However, the vast majority of counterparties do not have liquid CDS quotes and need proxy CDS rates. Existing methods cannot account for counterparty-specific default risks; we propose to construct proxy CDS rates by associating to illiquid counterparty liquid CDS Proxy based on Machine Learning Techniques. After testing 156 classifiers from 8 most popular classifier families, we found that some classifiers achieve highly satisfactory accuracy rates. Furthermore, we have rank-ordered the performances and investigated performance variations amongst and within the 8 classifier families. This paper is, to the best of our knowledge, the first systematic study of CDS Proxy construction by Machine Learning techniques, and the first systematic classifier comparison study based entirely on financial market data. Its findings both confirm and contrast existing classifier performance literature. Given the typically highly correlated nature of financial data, we investigated the impact of correlation on classifier performance. The techniques used in this paper should be of interest for financial institutions seeking a CDS Proxy method, and can serve for proxy construction for other financial variables. Some directions for future research are indicated.

To determine the fracture rate of ceramic crowns and causes of ceramic crown failure, this study used keywords—namely “endocrown,” “veneered fixed dental prosthesis,” “monolithic lithium disilicate (LS2),” and “all-ceramic single crown”—to search for articles published in English from 2005 to 2023 in the PubMed electronic database. Rather than using the Boolean logic algorithm between MESH terms and keywords, we accurately calculated the numbers of final clinically tracked cases with crown fractures from the contents of articles. The titles and abstracts of many related articles focused on implant or abutment fracture, while crown fracture was investigated and mentioned only in the main texts of the articles. Our studies included those crowns as well as having more complete data collection. Our search yielded 228, 93, 404, and 358 articles for the keywords “endocrown,” “veneered fixed dental prosthesis,” “monolithic lithium disilicate (LS2),” and “all-ceramic single crown,” respectively. We used the Newcastle–Ottawa Scale (NOS) to assess article quality, and our inclusion criteria were randomized controlled trials (RCT) and cohort study articles involving more than 3 years of follow-up and more than 20 cases. After reviewing, 16 high-quality articles were selected for analysis. The 4.4% crown fracture rate recommended on the basis of most clinical results was achieved in only 6 of the 16 articles. In these 6 articles, the researchers concluded the following reasons that may cause the crown fractures: the thickness of the veneer ceramic material; the connector dimensions; pontic span of the fixed prosthesis; the type of cement; the treatment of the ceramic surface before luting. Other articles inferred that the computer-aided design libraries that were insufficient for the creation of appropriate anatomically supported frameworks for prostheses with ceramic veneers; the thermal expansion coefficient and fracture toughness of the framework material did not match those of the veneer ceramic, resulting in an insufficient area supporting the ceramic veneer then leads to premature crown failure after a long period chewing. The future prospective for material developing could focus on solving those problems and have better clinical results.

Maximal heart rate (HRmax) is a widely used measure of cardiorespiratory fitness. Prediction of HRmax is an alternative to cardiopulmonary exercise testing (CPET), but its accuracy among endurance athletes (EA) requires evaluation. This study aimed to externally validate HRmax prediction models in the EA independently for running and cycling CPET. 4043 runners (age=33.58 (8.12) years; 83.53% males; BMI=23.66 (2.54) kg·m−2) and 1026 cyclists (age=36.88 (9.03) years; 89.67% males; BMI=24.04 (2.65) kg·m−2) underwent maximum CPET. Student t-test, mean absolute percentage error (MAPE), mean absolute error (MAE), and root mean square error (RMSE) were applied to externally validate 8 running and 5 cycling HRmax equations. HRmax was 184.60 (9.79) beats·min−1 and 182.66 (10.28) beats·min−1 respectively for running and cycling, p=0.001. Measured and predicted HRmax differed significantly (p=0.001) for 9 of 13 (69.23%) models. HRmax was overestimated by 8 (61.54%) and underestimated by 5 (38.46%) formulae. Overestimated HRmax ranged 0.08-4.94 beats·min−1 and underestimated HRmax ranged 0.03-4.90 beats·min−1. MAE and RMSE were 0.18-4.94 beats·min−1 and 9.13-10.47, respectively. MAPE ranged 3.95-4.69%. Prediction models do not allow for accurate estimation of HRmax. HRmax was more often underestimated than overestimated. Predicted HRmax can be implemented for EA as a supplemental method but CPET is the preferable approach.

This paper presents the validation of the End Point Rate (EPR) tool for QGIS (EPR4Q), a tool built-in QGIS Graphical Modeler to calculate the shoreline change by End Point Rate method. The EPR4Q tries to fill the gap of user-friendly and free open-source tool for shoreline analysis in Geographic Information System environment, since the most used software - Digital Shoreline Analysis System (DSAS) - although is a free extension, is suited for commercial software. Besides, the best free open-source option to calculate EPR called Analyzing Moving Boundaries Using R (AMBUR), since it is a robust and powerful tool, the complexity and heavy processes can restrict the accessibility and simple usage. The validation methodology consists of applying the EPR4Q, DSAS, and AMBUR on different examples of shorelines found in nature, extracted from the U.S. Geological Survey Open-File. The obtained results of each tool were compared with Pearson correlation coefficient. The validation results indicate that the EPR4Q tool created acquired high correlation values with DSAS and AMBUR, reaching a coefficient of 0.98 to 1.00 on linear, extensive, and non-extensive shorelines, guarantying that the EPR4Q tool is ready to be freely used by the academic, scientific, engineering, and coastal managers communities worldwide.

The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only 3 parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate, for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement provides strong evidence (but not proof) that the mechanism of STLIS plays an important role in the major diseases of aging (e.g., cardiovascular disease, many cancers, and diabetes mellitus) which dominate human mortality. This result represents significant progress in our understanding the factors behind the cause of aging.

This paper studies the impact of agricultural subsidies and product certification on the use rate of green pesticides based on experimental economics. We found that agricultural subsidies effectively increased the utilization rate of green pesticides. If the agricultural subsidies raised from 20% to 100%, the green pesticides’ using rate increased by 438.51%. We also found that product certification increased the utilization rate of green pesticides by 376.16%%.The increase of agricultural subsidies is more effective than the product certification. Under a higher proportion of agricultural subsidies, farmers’ behavior will maintain “status bias”. Therefore, there are three suggestions proposed. Firstly, because of high price of green pesticides and lower production, the subsidies for agricultural materials should raise greatly to effectively improve the utilization rate of green pesticides. It is recommended that green pesticide provided free of charge in some wealthy areas. Secondly, both subsidies and product certification can improve the use rate of green pesticides. However, since the effect of agricultural subsidies is better than product certification, and farmers may have status bias. Therefore, it is recommended to give priority to the substantial increase on the proportion of agricultural subsidies, and then to product certification.

The use of machine learning techniques in predictive health care is on the rise with minimal data used for training machine-learning models to derive high accuracy predictions. In this paper, we propose such a system, which utilizes Heart Rate Variability (HRV) as features for training machine learning models. This paper further benchmarks the usefulness of HRV as features calculated from basic heart-rate data using a window shifting method. The benchmarking has been conducted using different machine-learning classifiers such as artificial neural network, decision tree, k-nearest neighbour and naive bays classifier. Empirical results using MIT-BIH Arrhythmia database shows that the proposed system can be used for highly efficient predictability of abnormality in heartbeat data series.

Licochalcone H (LCH), a regioisomer of licochalcone C derived from the root of Glycyrrhiza inflata. CRC treatment has always been challenged by the development of resistance. We investigated the antiproliferative activity of LCH in oxaliplatin (Ox)-sensitive and -resistant CRC cells. LCH significantly inhibited cell viability and colony growth in both Ox-sensitive and Ox-resistant CRC cells. We found that LCH decreased epidermal growth factor receptor (EGFR) and AKT kinase activities and related activating signaling proteins including phospho (p)-EGFR and pAKT. A computational docking model indicated that LCH may interact with EGFR, AKT1, and AKT2 at the ATP-binding sites. LCH induced ROS generation, as verified by N-acetyl-L-cysteine (NAC) treatment, and increased the expression of the ER stress markers. LCH treatment of CRC cells induced depolarization of MMP and increased. Multi-caspase activity was induced by LCH treatment and confirmed by Z-VAD-FMK treatment. LCH increased the number of subG1 cells and arrested the cell cycle at the G1 phase. LCH inhibits the growth of Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, and inducing ROS generation and ER stress-mediated apoptosis. Therefore, LCH could be a potential therapeutic agent for improving not only Ox-sensitive but also Ox-resistant CRC treatment.

Choline and choline metabolites are essential for all cellular functions. They have also been reported to be crucial for neural development. In this work, we studied the functional characteristics of the choline uptake system in human neural stem cells (hNSCs). Additionally, we investigated the effect of extracellular choline uptake inhibition on the cellular activities in hNSCs. We found that the mRNAs and proteins of choline transporter-like protein 1 (CTL1) and CTL2 were expressed at high levels. Immunostaining showed that CTL1 and CTL2 were localized in the cell membrane and partly in the mitochondria, respectively. The uptake of extracellular choline was saturable and performed by a single uptake mechanism, which was Na+-independent and pH-dependent. We conclude that CTL1 is responsible for extracellular choline uptake, and CTL2 may uptake choline in the mitochondria and be involved in DNA methylation via choline oxidation. Extracellular choline uptake inhibition caused intracellular choline deficiency in hNSCs, which suppressed cell proliferation, cell viability, and neurite outgrowth. Our findings contribute to the understanding of the role of choline in neural development as well as the pathogenesis of various neurological diseases caused by choline deficiency or choline uptake impairment.