Cycle Profile Research Articles

Function‐Valued Marked Spatial Point Processes on Linear Networks: Application to Urban Cycling Profiles

ABSTRACTIn the literature on spatial point processes, there is an emerging challenge in studying marked point processes with points being labelled by functions. In this paper, we focus on point processes living on linear networks and, from distinct points of view, propose several mark summary characteristics that are of great use in studying the average association and dispersion of the function‐valued marks. Through a simulation study, we evaluate the performance of our proposed mark summary characteristics, both when marks are independent and when some sort of spatial dependence is evident among them. Finally, we employ our proposed mark summary characteristics to study the spatial structure of urban cycling profiles in Vancouver, Canada.

Relaxometric properties and biocompatibility of a novel nanostructured fluorinated gadolinium metal-organic framework.

A novel Gd-MOF based on tetrafluoro-terephthalic acid has been synthesized and its structure has been solved using X-ray single crystal diffraction data. The compound, with the formula [Gd2(F4BDC)3·H2O]·DMF, is isostructural with other Ln-MOFs based on the same ligand and has been recently reported. Its crystals were also reduced to nanometer size by employing acetic acid or cetyltrimethylammonium bromide (CTAB) as a modulator. The relaxometric properties of the nanoparticles were evaluated in solution by measuring 1H T1 and T2 as a function of the applied magnetic field and temperature. The biocompatibility of Gd-MOFs was evaluated on murine microglial BV-2 and human glioblastoma U251 cell lines. In both cell lines, Gd-MOFs do not modify the cell cycle profile or the activation levels of ERK1/2 and Akt, which are protein-serine/threonine kinases that participate in many signal transduction pathways. These pathways are fundamental in the regulation of a large variety of processes such as cell migration, cell cycle progression, differentiation, cell survival, metabolism, transcription, tumour progression and others. These data indicate that Gd-MOF nanoparticles exhibit high biocompatibility, making them potentially valuable for diagnostic and biomedical applications.

Transcriptome-wide profiling for melanocytes derived from newborn and adult human epidermis with enhanced proliferation.

The senescence-associated protein p16INK4A acts as a limiter element in cell-cycle progression. The loss of p16INK4A function is causally related to cellular immortalization. The increase in p16INK4A levels with advancing age was demonstrated in melanocytes. However, the characteristic difference between young and senescent melanocytes affecting immortalization of melanocytes remains unclear. In this study, we generated 10 different cell lines in total from newborn (NB) and adult (AD) primary normal human epidermal melanocytes (NHEM) using four different methods, transduction of CDK4R24C and cyclin D1 (K4D), K4D with TERT (K4DT), SV40 T-antigen (SV40T), and HPV16 E6 and E7 (E6/E7) and performed whole transcriptome sequencing analysis (RNA-Seq) to elucidate the differences of genome-wide expression profiles among cell lines. The analysis data revealed distinct differences in expression pattern between cell lines from NB and AD although no distinct biological differences were detected in analyses such as comparison of cell morphology, evaluation of cell proliferation, and cell cycle profiles. This study may provide useful in vitro models to benefit the understanding of skin-related diseases.

The motivations for a women's series

The sources often speak of the world of women in an indirect, cross-cutting way, since over the centuries women have played social, legal, economic and cultural roles that are not always evident. Only in a few cases can gender studies boast of archives and libraries of exclusively female provenance: even with reference to recent periods, their number is small, either because of conservative conduct anchored in outdated historiographical hierarchies or as a result of women's lesser aptitude for documenting their existence and their role in society, expressing a difficulty in considering themselves as agent subjects in history. It is precisely on this side that the organization of the cycle Profiles of Women among Papers and Books was oriented, with which the aim was to illustrate to a wide audience the lives of some female figures and institutions that represent, or have represented, at several levels’ Italian society and culture through the cognitive lens of their papers and books.

Predicting cell cycle stage from 3D single-cell nuclear-stained images.

The cell cycle governs the proliferation, differentiation, and regeneration of all eukaryotic cells. Profiling cell cycle dynamics is therefore central to basic and biomedical research spanning development, health, aging, and disease. However, current approaches to cell cycle profiling involve complex interventions that may confound experimental interpretation. To facilitate more efficient cell cycle annotation of microscopy data, we developed CellCycleNet, a machine learning (ML) workflow designed to simplify cell cycle staging with minimal experimenter intervention and cost. CellCycleNet accurately predicts cell cycle phase using only a fluorescent nuclear stain (DAPI) in fixed interphase cells. Using the Fucci2a cell cycle reporter system as ground truth, we collected two benchmarking image datasets and trained two ML models-a support vector machine (SVM) and a deep neural network-to classify nuclei as being in either the G1 or S/G2 phases of the cell cycle. Our results suggest that CellCycleNet outperforms state-of-the-art SVM models on each dataset individually. When trained on two image datasets simultaneously, CellCycleNet achieves the highest classification accuracy, with an improvement in AUROC of 0.08-0.09. The model also demonstrates excellent generalization across different microscopes, achieving an AUROC of 0.95. Overall, using features derived from 3D images, rather than 2D projections of those same images, significantly improves classification performance. We have released our image data, trained models, and software as a community resource.

Peanut–cotton intercropping to enhance soil ecosystem multifunctionality: Roles of microbial keystone taxa, assembly processes, and C-cycling profiles

Legume-based intercropping, such as the peanut–cotton system, stands out as a promising strategy for enhancing soil ecosystem multifunctionality (EMF); however, the underlying microbial mechanisms driving these enhancements remain inadequately explored. In this study, after implementing peanut–cotton intercropping for six consecutive years, a data set of 13 ecosystem functional indicators including 41 soil variables, was obtained and used to quantify the average EMF index. We investigated changes in microbial keystone taxa in co-occurrence networks, community assembly processes, carbon (C) cycling profiles, and their collective impacts on soil EMF. Soil EMF increased by an average of 140.0 % in the peanut–cotton intercropping system, compared with monoculture systems of both peanut and cotton, driven by significant increases in C-cycling (159.9 %), nutrient provisioning (91.2 %), and microbial growth efficiency functions (53.9 %). The peanut–cotton intercropping system significantly increased the average well-color developments (AWCD), abundance of C-fixation and C-degradation genes, and related pathways, resulting in a highly vigorous microbial C-cycling profile. The microbial community assembly processes shifted from a balance of stochastic and deterministic processes in monocultures to predominantly deterministic processes (> 70 %) in the intercropping system. Additionally, the peanut–cotton intercropping system fostered a more efficient and stable bacterial–fungal cross-kingdom network than the monocultures, characterized by a higher average clustering coefficient, higher robustness, and shorter average path length. This intercropping system also recruited a group of keystone taxa affiliated with Proteobacteria, Actinobacteria, and Ascomycota phyla. The enhancement of EMF in the peanut–cotton intercropping system resulted from the positive impact of key microbial community members and their assembly, C/N ratios, AWCD, and C-fixation and C-degradation genes. Our study provides insights into the complex ecological linkages between microbial communities, C-cycling profiles, and soil ecosystem functions, providing valuable insights into the microbial mechanisms underlying the benefits of intercropping systems.

Discovery of Potent Isoquinolinequinone N-Oxides to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.

In silico and experimental potentials of 6-shogaol and meglumine antimoniate on Leishmania major: multiple synergistic combinations through modulation of biological properties.

Conventional therapeutic agents are no longer adequate against leishmaniasis. This complex condition continues to have a high mortality rate and public health impact. The present study aimed to explore an extensive array of experiments to monitor the biological activities of 6-shogaol, a major component of ginger, and meglumine antimoniate (MA or Glucantime®). The binding affinity of 6-shogaol and inducible nitric oxide synthase (iNOS), a major enzyme catalyzing nitric oxide (NO) from L-arginine was the source for the docking outline. The inhibitory effects of 6-shogaol, MA, and mixture were assessed using colorimetric and macrophage assays. Antioxidant activity was inferred by UV-visible spectrophotometry. Variably expressed genes were measured by quantifiable real-time polymerase chain reaction. Apoptotic and cell cycle profiles were analyzed by flow cytometry. Moreover, a DNA fragmentation assay was performed by electrophoresis and antioxidant metabolites include superoxide dismutase (SOD), catalase (CAT), and also nitric oxide (NO) by enzyme-linked immunosorbent assay. 6-shogaol and MA exhibited multiple synergistic mechanisms of action. These included a remarkable leishmanicidal effect, potent antioxidative activity, a high safety index, upregulation of M1 macrophages/Th1-associated cytokines (including, γ-interferon, interleukin-12p40, tumor necrotizing factor-alpha, and associated iNOS), significant cell division capture at the sub-G0/G1 phase, a high profile of apoptosis through DNA fragmentation of the nuclear components. In addition, the activity of NO was substantially elevated by treated intracellular amastigotes, while SOD and CAT activities were significantly diminished. This study is exclusive because no similar investigation has inclusively been conducted before. These comprehensive mechanistic actions form a logical foundation for additional advanced study.

Green Hydrogen Production Using Manganese – Vanadium Redox Flow Batteries

The redox flow batteries (RFBs) can be tuned to allow mining of surplus energy capacity and supplement green hydrogen economy as a one-stop station [1, 2].With this concept, an RFB can undergo two sequential discharging modes: i) electrochemical discharge of redox active species, and ii) chemical discharge to produce hydrogen gas, when surplus electricity is available, on the surface of electrocatalysts contained in additional external tanks (i.e., dual circuit RFB) [3, 4]. Herein, electrolytes with Mn3+/Mn2+ (RFB catholyte ~ 1.5 V vs. SHE) and V3+/V2+ (RFB anolyte ~ −0.26 V vs. SHE) redox species are flown to spatially separated external catalytic reactors to drive redox mediated water electrolysis. The fully charged V2+ redox mediator in the anolyte provides electrons to achieve hydrogen evolution reaction (HER) and thereby itself gets discharged to V3+ redox state before circulating back to flow battery tanks.Considering the additional layer of redox-mediated water electrolysis, it is imperative to identify benchmark cycling performance for a robust dual circuit RFB operation. In the first phase of our study, electrochemical behavior of Mn3+/Mn2+ redox couple in the favorable presence of V5+ as an additive was elucidated using ultramicroelectrode voltammograms. Despite significant performance enhancement, capacity fade during galvanostatic cycling could not be fully eliminated owing to Mn3+ disproportionation reaction and manganese crossover. Also, charge/discharge cycling profiles suggest that the inevitable Mn3+ disproportionation affects the true state-of-charge in electrolytes which in turn hinders their potential to generate hydrogen gas. Working towards hydrogen generation, our recent efforts have been to evaluate kinetics for hydrogen evolution reaction (HER) on different carbon substrate – electrocatalyst combinations in acidic V3+/V2+ environment. Overall, this study aims to provide a profound understanding of reliable operating conditions to establish a synergy between Mn3+ disproportionation during the conventional energy storage mode and the total volume of hydrogen gas produced during the secondary mode. References Reynard, D. and H. Girault, Combined hydrogen production and electricity storage using a vanadium-manganese redox dual-flow battery. Cell Reports Physical Science, 2021. 2(9): p. 100556. Amstutz, V., et al., Renewable hydrogen generation from a dual-circuit redox flow battery. Energy & Environmental Science, 2014. 7(7): p. 2350-2358. Peljo, P., et al., All-vanadium dual circuit redox flow battery for renewable hydrogen generation and desulfurisation. Green Chemistry, 2016. 18(6): p. 1785-1797. Piwek, J., et al., Vanadium-oxygen cell for positive electrolyte discharge in dual-circuit vanadium redox flow battery. Journal of Power Sources, 2019. 439: p. 227075.

Synthesis and biological evaluation of imidazolium conjugated with dimethylcardamonin (DMC) as a novel potential agent against MDA-MB-231 triple-negative breast cancer cells

A new imidazolium ionic liquid (IL) halide conjugated with dimethylcardamonin (DMC, 1), namely [Bbim]Br-DMC (3), was synthesised to improve the biological activity of the natural chalcone. DMC was isolated from seeds of Syzygium nervosum A. Cunn. ex DC. which was an effective anti-breast cancer agent. The compound 1 and 3 showed anticancer activity in MDA-MB-231 cells with IC50 values of 14.54 ± 0.99 μM and 7.40 ± 0.15 μM, respectively. MTT assay showed that compound 3 had cytotoxic effect at least two-fold greater than compound 1 but was low toxic to normal cells of Hs 578Bst. After 48 h, compound 3 at concentration of IC50 value inhibited the proliferation and induced morphological changes of MDA-MB-231 cells in a time-dependent manner. The cell cycle profile also showed that compound 3 exerted anti-proliferation activity with the cell cycle arrest at G0/G1 phase and compound 3 also induced apoptosis and reduced mitochondrial membrane potential in MDA-MB-231 cells in a dose-dependent manner. In gene expression assay, compound 3 up-regulated pro-apoptotic genes such as Bax and p53 and suppressed anti-apoptotic Bcl-2 whereas there was no effect on DNA repair gene such as PARP1. The Bax/Bcl-2 ratio was significantly increased after treated with compound 3. In the molecular docking study, the interactions between compound 3 and B-DNA structure in the minor groove region via hydrogen bonds was reported. In conclusion, [Bbim]Br-DMC or compound 3 is a potential candidate to induce apoptosis and inhibits proliferation via cell cycle arrest and decreases mitochondrial membrane of triple-negative breast cancer MDA-MB-231 cells.

PGV-1 Causes Disarrangement of Spindle Microtubule Organization Resulting in Aberrant Mitosis in HLF and HuH6 Cells Associated with Altered MYCN Status.

The HLF and HuH-6 cell lines represent hepatocellular carcinoma (HCC) with different characteristics in chromosome content that may give different drug responses. Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib. We applied MTT cytotoxic assay, colony forming assay, flow cytometry analysis, immunofluorescence assay and western blot assay. PGV-1 exhibited cytotoxic effects on HLF and HuH-6 with IC-50 values of 1 µM and 2 µM, respectively, whereas sorafenib showed less cytotoxicity with IC-50 values of 5 µM and 8 µM respectively. PGV-1 suppressed the cell growth permanently but not for sorafenib. Sorafenib did not change the cell cycle profiles on both cells, but PGV-1 arrested the cells at G2/M with the characteristic of senescent cells and mitotic disarrangement. PGV-1 and sorafenib showed the same effect in downregulating p-EGFR, indicating that both compounds have the same target on EGFR activation or as Tyrosine kinase inhibitors. PGV-1 suppressed the MYCN expression in HuH-6 and HLF cells but stabilized cMYC-T58 indicating that even though the MYCN was downregulated, the cells maintained the active form of cMYC. In this regard, PGV-1 also stabilized the expression of PLK-1 and AurA. PGV-1 elicits stronger cytotoxic properties compared to sorafenib. The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

Reciprocal Interactions of Human Monocytes and Cancer Cells in Co-Cultures In Vitro.

The tumor microenvironment (TME) includes immune and stromal cells and noncellular extracellular matrix (ECM) components. Tumor-associated macrophages (TAMs) are the most important immune cells in TME and are crucial for carcinomas' progression. The purpose was to analyze direct and indirect interactions in co-culture of tumor cells with monocytes/macrophages and, additionally, to indicate which interactions are more important for cancer development. Cytokines, reactive oxygen species, nitric oxide level, tumor cell cycle and changes in tumor cell morphology after human tumor cells (Hep-2 and RK33 cell lines) with human monocyte/macrophage (THP-1 cell line) interactions were tested. Morphology and cytoskeleton organization of tumor cells did not change after co-culture with macrophages. In co-culture of tumor cells with human monocyte, changes in the percentage of tumor cells in cell cycle phases was observed. No significant changes in reactive oxygen species (ROS) were found in the co-culture as compared to the tumor cell mono-culture. Monocytes produced about three times higher ROS than tumor cells. In co-cultures, a lower nitric oxide (NOx) level was found as compared to the sum of the production by both mono-cultures. Co-culture conditions limited the production of cytokines (IL-4, IL-10 and IL-13) as compared to the sum of their level in mono-cultures. In conclusion, macrophages influence tumor cell growth and functions. Mutual (direct and paracrine) interactions between tumor cells and macrophages changed cytokine production and tumor cell cycle profile. The data obtained may allow us to initially indicate which kind of interactions may have a greater impact on cancer development processes.

Progerin Can Induce DNA Damage in the Absence of Global Changes in Replication or Cell Proliferation.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also expressed at low levels in healthy individuals and appears to play a role in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs) and alterations in the nature of DSB repair. The source of DSBs in HGPS is often attributed to stalling and subsequent collapse of replication forks in conjunction with faulty recruitment of repair factors to damage sites. In this work, we used a model system involving immortalized human cell lines to investigate progerin-induced genomic damage. Using an immunofluorescence approach to visualize phosphorylated histone H2AX foci which mark sites of genomic damage, we report that cells engineered to express progerin displayed a significant elevation of endogenous damage in the absence of any change in the cell cycle profile or doubling time of cells. Genomic damage was enhanced and persistent in progerin-expressing cells treated with hydroxyurea. Overexpression of wild-type lamin A did not elicit the outcomes associated with progerin expression. Our results show that DNA damage caused by progerin can occur independently from global changes in replication or cell proliferation.

PhosphoLipidome Alteration Induced by Clostridioides difficile Toxin B in Enteric Glial Cells.

Clostridioides difficile (C. difficile) is responsible for a spectrum of nosocomial/antibiotic-associated gastrointestinal diseases that are increasing in global incidence and mortality rates. The C. difficile pathogenesis is due to toxin A and B (TcdA/TcdB), both causing cytopathic and cytotoxic effects and inflammation. Recently, we demonstrated that TcdB induces cytopathic and cytotoxic (apoptosis and necrosis) effects in enteric glial cells (EGCs) in a dose/time-dependent manner and described the underlying signaling. Despite the role played by lipids in host processes activated by pathogens, to counter infection and/or induce cell death, to date no studies have investigated lipid changes induced by TcdB/TcdA. Here, we evaluated the modification of lipid composition in our in vitro model of TcdB infection. Apoptosis, cell cycle, cell viability, and lipidomic profiles were evaluated in EGCs treated for 24 h with two concentrations of TcdB (0.1 ng/mL; 10 ng/mL). In EGCs treated with the highest concentration of TcdB, not only an increased content of total lipids was observed, but also lipidome changes, allowing the separation of TcdB-treated cells and controls into different clusters. The statistical analyses also allowed us to ascertain which lipid classes and lipid molecular species determine the clusterization. Changes in lipid species containing inositol as polar head and plasmalogen phosphatidylethanolamine emerged as key indicators of altered lipid metabolism in TcdB-treated EGCs. These results not only provide a picture of the phospholipid profile changes but also give information regarding the lipid metabolism pathways altered by TcdB, and this might represent an important step for developing strategies against C. difficile infection.

DIPG-38. VAL-083 IN COMBINATION WITH AZD1775 FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are malignant pediatric brain tumors characterized by H3K27M mutation and global genome hypomethylation. This results in enhanced transcription of MGMT, a DNA-repair enzyme, rendering alkylating chemotherapeutics ineffective. Therefore, we investigated the efficacy of a functionally different DNA damaging agent, Val-083, that induces double strand breaks and triggers S/G2 phase cell cycle arrest for homologous DNA repair. We further evaluated its combined efficacy with Wee1 (G2/M checkpoint) inhibitor, AZD1775, to override cell cycle arrest and propel cells with DNA damage into premature mitosis and apoptosis. METHODS DMG cells were treated with increasing concentration of Val-083 and/or AZD1775 and their viability was evaluated using CellTiter-Glo luminescent assay. Next, the drugs’ mechanisms of action were investigated by immunoblotting for biomarkers involved in DNA damage response and cell cycle arrest. Flow cytometry was used to investigate cell cycle profile and apoptosis. Additionally, in vivo tumor growth inhibition and survival benefit were evaluated using zebrafish and mouse xenograft DMG models. RESULTS The IC50 values of Val-083 range between 0.69 and 4.38 µM while the IC50 values of AZD1775 range between 0.22 to 0.98 µM. Combination of both drugs showed high areas of synergy on multiple DMG lines, DNA double strand breaks and significant increase in cell population at the S (p<0.01) and G2/M (p<0.05) phases. Importantly, on zebrafish xenograft tumor model, combination treatment significantly (p<0.001) inhibited tumor growth in comparison to control and single treatment groups. Furthermore, the combined treatment demonstrated significant (p<0.01) survival benefit (median survival (MS) = 62 days) on tumor-bearing nude mice models, in comparison to vehicle (MS= 44 days), Val-083 (MS= 54.5 days) and AZD1775 (MS= 47 days) treatment groups. CONCLUSION Val-083 in combination with AZD1775 demonstrate promising efficacy in DMG preclinical models, providing a strong rationale for positioning these arms for clinical testing.

Anticancer activity of the ethylacetate fraction of Vernonia amygdalina Delile towards overexpression of HER-2 breast cancer cell lines

Vernonia amygdalina Delile, coming from the Asteraceae tribe, contains active compounds that can treat breast cancer. This study examines the anticancer activity of Vernonia amygdalina Delile leaves, an active fraction of MCF-7/HER-2 breast cancer cells. Thin-layer chromatography determines the phytochemical screening. Cytotoxic and proliferation analyses were determined using the MTT method for the MCF-7/HER-2 breast cancer cell line. The cell cycle and apoptosis profiles were examined using flow cytometry. The results can be summarized in this study: Vernonia amygdalina Delile fraction contains a flavonoid with great potential for pharmacological activities, for instance, inhibiting the growth of cancer cells. The ethyl acetate fraction was more potent and cytotoxic on MCF-7/HER-2 cells (IC50 = 66 μg/mL) than extract ethanol (IC50 = 130 μg/mL). The ethylacetate fraction of Vernonia amygdalina Delile has been proven to inhibit cell proliferation by decreasing cell viability with an IC50 of 66 μg/mL concentration incubated for 24, 48, and 72 hrs with cell viability values of 64.46%, 61.67%, and 53.89%, respectively, compared to the ethanol extract IC50 of 130 μg/mL concentration with cell viability values of 56.0%, 50.19%, and 58.67%, respectively, which induced apoptosis and inhibited the cell cycle in the G2-M phase. To conclude, the ethyl acetate fraction of Vernonia amygdalina Delile can be used as an anticancer against the MCF-7/HER-2 cell line with an IC50 of 66 μg/mL, inhibiting cell proliferation and the cell cycle and inducing apoptosis activity in the MCF-7/HER-2 cell.

Cellular mechanisms mediating the anti-cancer effects of carnosol on gingiva carcinoma

Carnosol, a rosemary polyphenol, displays anticancer properties and is suggested as a safer alternative to conventional surgery, radiotherapy, and chemotherapy. Given that its effects on gingiva carcinoma have not yet been investigated, the aim of this study was to explore its anti-tumor selectivity and to unravel its underlying mechanisms of action. Hence, oral tongue and gingiva carcinoma cell lines exposed to carnosol were analyzed to estimate cytotoxicity, cell viability, cell proliferation, and colony formation potential as compared with those of normal cells. Key cell cycle and apoptotic markers were also measured. Finally, cell migration, oxidative stress, and crucial cell signaling pathways were assessed. Selective anti-gingiva carcinoma activity was disclosed. Overall, carnosol mediated colony formation and proliferation suppression in addition to cytotoxicity induction. Cell cycle arrest was highlighted by the disruption of the c-myc oncogene/p53 tumor suppressor balance. Carnosol also increased apoptosis, oxidative stress, and antioxidant activity. On a larger scale, the alteration of cell cycle and apoptotic profiles was also demonstrated by QPCR array. This was most likely achieved by controlling the STAT5, ERK1/2, p38, and NF-ĸB signaling pathways. Lastly, carnosol reduced inflammation and invasion ability by modulating IL-6 and MMP9/TIMP-1 axes. This study establishes a robust foundation, urging extensive inquiry both in vivo and in clinical settings, to substantiate the efficacy of carnosol in managing gingiva carcinoma.

Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells.

Aim: Multidrug resistance (MDR) is frequent in non-small cell lung cancer (NSCLC) patients, which can be due to its fibrotic stroma. This work explores the combination of pentoxifylline, an anti-fibrotic and chitinase 3-like-1 (CHI3L1) inhibitor drug, with conventional chemotherapy to improve NSCLC treatment. Methods: The effect of pentoxifylline in the expression levels of P-glycoprotein (P-gp), CHI3L1 and its main downstream proteins, as well as on cell death, cell cycle profile, and P-gp activity was studied in two pairs of sensitive and MDR counterpart NSCLC cell lines (NCI-H460/NCI-H460/R and A549/A549-CDR2). Association studies between CHI3L1 gene expression and NSCLC patients' survival were performed using The Cancer Genome Atlas (TCGA) analysis. The sensitizing effect of pentoxifylline to different drug regimens was evaluated in both sensitive and MDR NSCLC cell lines. The cytotoxicity of the drug combinations was assessed in MCF10A non-tumorigenic cells. Results: Pentoxifylline slightly decreased the expression levels of CHI3L1, β-catenin and signal transducer and activator of transcription 3 (STAT3), and caused a significant increase in the G1 phase of the cell cycle in both pairs of NSCLC cell lines. A significant increase in the % of cell death was observed in the sensitive NCI-H460 cell line. TCGA analysis revealed that high levels of CHI3L1 are associated with low overall survival (OS) in NSCLC patients treated with vinorelbine. Moreover, pentoxifylline sensitized both pairs of sensitive and MDR NSCLC cell lines to the different drug regimens, without causing significant toxicity to non-tumorigenic cells. Conclusion: This study suggests the possibility of combining pentoxifylline with chemotherapy to increase NSCLC therapeutic response, even in cases of MDR.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

Deep machine learning approaches for battery health monitoring

The performance and longevity of batteries can be measured through battery parameters, like: state of charge, state of health, and remaining useful life. Therefore, accurate estimation of these parameters is essential for developing efficient battery management systems. Recently, a variety of smart model-based and data-driven artificial neural network methods have been evolved for efficient management of battery systems. However, there is space for improving the accuracy and reliability of the proposed methods, particularly in the prediction and forecasting of battery performance metrics. In this study, a deep machine learning based forecasting technique has been proposed to better estimate the battery performance parameters. Available open source data-sets on three distinct battery technologies comprising of battery cycling profiles and environmental conditions, are adopted to construct and validate models for predicting battery health. A common data-set is developed by combining the open source data, which is later supplied as input to the predictive analytics and time series analysis. Encoders and decoders are employed for the extraction of important and relevant feature information from the data-set. Three different network model-based architectures are developed to predict the state of charge of Lithium-ion batteries. The proposed models are observed to accurately capture the dynamic behavior of the battery during discharge, which is confirmed by the analysis of the recorded voltage, current, and temperature data, and the precise estimation of state of charge. Furthermore, a novel forecasting method based on the time-series analysis is also introduced. Mean average error values less than 0.2% are observed when neural basis expansion analysis for interpretable time series architecture in conjunction with encoder–decoder-based feature extraction is employed.