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The present paper deals with a weakly nonlinear stability problem under an imposed time-periodic thermal modulation. The temperature has two parts: a constant part and an externally imposed time-dependent part. We focus on stationary convection using the slow time scale and quantify convective amplitude through the real Ginzburg-Landau equation (GLE). We have used the classical fourth order Runge-Kutta method to solve the real Ginzburg-Landau equation. The effect of various parameters on heat transport is discussed through GLE. It is found that heat transport analysis is controlled by suitably adjusting the frequency and amplitude of modulation. The applied magnetic field (effect of Ha) is to diminish the heat transfer in the system. Three different types of modulations thermal, gravity, and magnetic field have been compared. It is concluded that thermal modulation is more effective than gravity and magnetic modulation. The magnetic modulation stabilizes more and gravity modulation stabilizes partially than thermal modulation.

In this paper we investigate an oscillatory mode of nonlinear magneto-convection under time dependant magnetic field. The time dependant magnetic field consists steady and oscillatory parts. The oscillatory part of the imposed magnetic field is assumed to be of third order. An externally imposed vertical magnetic field in an electrically conducting horizontal fluid layer is considered. The finite amplitude analysis is discussed while perturbing the system. The complex Ginzburg-Landau model is used to derive an amplitude of oscillatory convection for weakly nonlinear mode. Heat transfer is quantified in terms of the Nusselt number, which is governed by the Landau equation. The variation of the modulation excitation of the magnetic field alternates heat transfer in the layer. The modulation excitation of the magnetic field is used either to enhance or diminish the heat transfer in the system. Further, it is found that, oscillatory mode of convection enhances the heat transfer and than stationary convection. The results have possible technological applications in magnetic fluid based systems involving energy transmission. Keywords: Weakly nonlinear theory, Oscillatory convection, Complex Ginzburg Landau model, Magnetic modulation

We evaluated the feasibility of DEXA (Norland XR-26 mark II) for quantitative measurements of bone mineral density (BMD) in the lateral plane of the distal femur after total knee arthroplasty (TKA). BMD was measured in 5-6 regions of interest (ROI) in close relation to the femoral component. In an in vitro study using 3 different distal femur phantoms, we found that the precision was affected by rotation of the distal femur. When BMD measurements were repeated within a range of motion of 40°, 20°, and 0°, the coefficient of variation (CV) was approximately 15%, 10%, and 0.6%, respectively. We found that the use of bone cement for implant fixation had no effect on the level of BMD. Double measurements performed in 28 patients gave average CV values of 3.3%, 3.0%, and 2.6% for the uncemented Duracon, and Interax femoral components and the cemented AGC components, respectively. Our in vivo average CV measurements of BMD of the distal femur after TKA were on a level, suitable for repeated BMD measurements in prospective studies, wich evaluate adaptive bone remodeling of the distal femur after cemented and uncemented TKA. [ABSTRACT FROM AUTHOR]

The effect of vertical throughflow and internal heating effects on fluid saturated porous medium under gravity modulation is investigated. The amplitude of modulation is considered to be very small and the disturbances are expanded in terms of power series of amplitude of convection. A weakly nonlinear stability analysis is proposed to study stationary convection. The Nusselt number is obtained numerically to present the results of heat transfer while using Ginzburg–Landau equation. The vertical throughflow has dual effect either to destabilize or to stabilize the system for downward or upward directions. The effect of internal heat source (Ri>0) enhances or sink (Ri

This paper carried out a nonlinear thermal convection in a porous medium saturated with viscoelastic nanofluid under vibrations. The Darcy model has been used for the porous medium, while the nanofluid layer incorporates the effect of Brownian motion along with thermophoresis. An Oldroyd-B type constitutive equation was used to describe the rheological behavior of viscoelastic nanofluids. The non-uniform vertical vibrations of the system, which can be realized by oscillating the system vertically, is considered to vary sinusoidally with time. In order to find the heat and mass transports for unsteady state, a nonlinear analysis, using a minimal representation of the truncated Fourier series of two terms, has been performed. Effect of various parameters has been investigated on heat and mass transport and then presented graphically. It is found that gravity modulation can be used effectively to regulate either heat or mass transports in the system.

A weak nonlinear oscillatory mode of thermal instability is investigated while deriving a non autonomous complex Ginzburg–Landau equation. Darcy porous medium is considered in the presence of vertical throughflow and time periodic thermal boundaries. Only infinitesimal disturbances are considered. The disturbances in velocity, temperature and solutal fields are treated by a perturbation expansion in powers of amplitude of applied temperature field. The effect of throughflow has either to stabilize or to destabilize the system for stress free and isothermal boundary conditions. Nusselt and Sherwood numbers are obtained numerically and presented the results on heat and mass transfer. It is found that, throughflow and thermal modulation can be used alternatively to control the heat and mass transfer. Further, it is also found that oscillatory flow enhances the heat and mass transfer than stationary flow. Effect of modulation frequency and phase angle on mean Nusselt number is also discussed.

Effect of vertical throughflow on Darcy convection has been investigated subject to time-periodic temperature modulation of the boundaries. The amplitudes of temperature modulation at the lower and upper surfaces are considered to be very small, and the disturbances are expanded in terms of power series of amplitude of convection. A weak nonlinear stability analysis has been performed for the stationary mode of convection, and heat transport in terms of the Nusselt number, which is governed by the non-autonomous Ginzburg–Landau equation, is calculated. The effect of vertical throughflow is found to be either to destabilize or stabilize the system for downward or upward throughflows in the case of impermeable boundary conditions. The effect of amplitude and frequency of modulation, Prandtl–Darcy number on heat transport has been analyzed and depicted graphically. Further, the study establishes that the heat transport can be controlled effectively by a mechanism that is external to the system.

The effect of vertical throughflow and time-periodic gravity field has been investigated on Darcy convection. The amplitude of gravity modulation is considered to be very small and the disturbances are expanded in terms of power series of amplitude of convection. A weak nonlinear stability analysis has been performed for the stationary mode of convection. As a consequence heat transport evaluated in terms of the Nusselt number, which is governed by the non-autonomous Ginzburg-Landau equation. Throughflow can stabilize or destabilize the system for stress free and isothermal boundary conditions. The amplitude and frequency of modulation, Prandtl Darcy number on heat transport have been analyzed and depicted graphically. Further, the study establishes that the heat transport can be controlled effectively by a mechanism that is external to the system. Finally flow patterns are presented in terms of streamlines and isotherms.

A theoretical analysis of thermo-convective instability in an electrically conducting two component fluid layer is carried out when the gravity field vary with time in a sinusoidal manner. Newtonian liquid is considered between two horizontal surfaces, under a constant vertical magnetic field. The disturbance is expanded in terms of power series of amplitude of convection, which is assumed to be small. We use the linear matrix differential operator method to find the Ginzburg–Landau amplitude equation for the modulated problem. Use the solution of the Ginzburg–Landau equation in quantifying the amount of heat and mass transports in terms of Nusselt and Sherwood numbers. It is found that, the effect of magnetic field is to stabilize the system. Effect of various parameters on the heat and mass transport is also discussed. Further, it is found that the heat and mass transports can be controlled by suitably adjusting frequency and amplitude of gravity modulation.

In this paper, a theoretical investigation has been carried out to study the combined effect of rotation speed modulation and internal heating on thermal instability in a temperature dependent viscous horizontal fluid layer. Rayleigh–Bénard momentum equation with Coriolis term has been considered to describe the convective flow. The system is rotating about it is own axis with non-uniform rotational speed. In particular, a time-periodic and sinusoidally varying rotational speed has been considered. A weak nonlinear stability analysis is performed to find the effect of modulation on heat transport. Nusselt number is obtained in terms of amplitude of convection and internal Rayleigh number, and depicted graphically for showing the effects of various parameters of the system. The effect of modulated rotation speed is found to have a stabilizing effect for different values of modulation frequency. Further, internal heating and thermo-rheological parameters are found to destabilize the system.

Background: Alzheimer's disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities., Objective: The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas., Methods: Statistical methods such as Pearson's chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors., Results: Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60-69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60-69) had a higher likelihood ( p  = 0.002) of cognitive impairment than Parmer ( p  = 0.067) and Cochran counties ( p  = 0.064). The risk of females ( p  = 0.033) in Parmer County was 78.3% lower compared to males in developing AD., Conclusions: Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD + levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD + dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD + levels. These decreased NAD + levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD + to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD + -dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC., (© 2024. The Author(s).)

Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.

Background/aim: Telmisartan is an angiotensin II receptor type 1 (AT1) antagonist with anticancer properties against solid and hematological cancer cell lines. Using telmisartan as a template, we developed alkylamine derivatives with reduced AT1 activity but increased anticancer activity., Materials and Methods: Synthesis of candidate compounds was carried out via hexafluorophosphate benzotriazole tetramethyl uronium coupling reaction, then their inhibition of cell proliferation was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and colony-formation assay was carried out on the lead candidate compound 8 Cell death via apoptosis or necrosis by compound 8 was determined by flow cytometry using annexin V and propidium iodide, tolerability dosing was carried out in ICR mice, and tumor-reduction properties were determined in an MDA-MB-231 xenograft model., Results: Some of the synthesized candidates exhibited good inhibition of cell proliferation with low micromolar half maximal effective concentrations in triple-negative breast cancer cell lines MDA-MB-231 and 4T1. Compound 8 exhibited lower affinity towards AT1 than parent telmisartan, inhibition of colony formation, and cell-cycle analysis revealed apoptosis as potentially important in causing cell death. In vivo evaluation with compound 8 indicated that it was well tolerated at high concentrations in healthy mice. Additionally, compound 8 showed higher growth inhibition in the MDA-MB-231 tumor xenograft mouse model compared to telmisartan., Conclusion: Our study indicated that alkylamine derivatives of telmisartan exhibited good solubility and higher inhibition of cancer cell proliferation than telmisartan. Compound 8 was found to be a good lead compound, with potential for development as an anticancer agent., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Using the melt quenching technique, a lithium zinc borate glass (LZB) system with trivalent dysprosium ions (Dy 3+ ) was synthesized, and the luminescence and lasing properties of these materials were examined for the generation of white light. Structural investigation through X-ray diffraction revealed that the prepared glass had an amorphous nature. The optimized glass containing 0.5 Dy 3+ had a direct optical band gap of 2.782 eV and an indirect optical band gap of 3.110 eV. A strong excitation band at 386 nm ( 6 H 15/2 → 4 I 13/2 ) was recognized in the ultraviolet (UV) light region of its excitation spectrum. Emission bands could be seen in the photoluminescence spectrum at 659, 573, and 480 nm under the 386 nm excitation. These transitions of emission resembled electronic transitions such as ( 4 F 9/2 → 6 H 11/2 ), ( 4 F 9/2 → 6 H 13/2 ), and ( 4 F 9/2 → 6 H 15/2 ). In a pristine glass matrix, the higher intensity ratio of yellow to blue can result in the production of white light. The optimized Dy 3+ ion concentration was observed to be 0.5 mol%. In addition, an analysis of lifetime decay was conducted for all synthesized glasses, and their decay trends were systematically investigated. Noticeably, we assessed the photometric parameters and found that they were close to the white light standard. Furthermore, a cytotoxicity study was carried out using lung fibroblast (WI-38) cell lines for the optimized 0.5Dy 3+ -doped LZB glass and it appeared to be noncytotoxic. It is clear from the results that the noncytotoxic LZB glass doped with 0.5 Dy 3+ ions could be a suggestive choice for the manufacture of white light-emitting diodes and lasers using near-UVs., (© 2023 John Wiley & Sons Ltd.)

This work describes about the synthesis and evaluation of substituted benzofuran piperazines as potential anticancer agents. The synthesized candidates have been evaluated for their cell proliferation inhibition properties in six murine and human cancer cell lines. In vitro evaluation of apoptosis and cell cycle analysis with the lead candidate 1.19 reveals that necrosis might be an important pathway for the candidate compounds to cause cell death. Further, in vivo evaluation of the lead compound shows that this candidate is well tolerated in healthy mice. Additionally, an in vivo anticancer efficacy study in mice using a MDA-MB-231 xenograft model with the lead compound provides good anti-cancer efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Triple-negative breast cancer (TNBC) affects young women and is the most aggressive subtype of breast cancer (BC). TNBCs disproportionally affect women of African-American (AA) descent compared to other ethnicities. We have identified DNA repair gene RAD51 as a poor prognosis marker in TNBC and its posttranscriptional regulation through microRNAs (miRNAs). This study aims to delineate the mechanisms leading to RAD51 upregulation and develop novel therapeutic combinations to effectively treat TNBCs and reduce disparity in clinical outcomes., Methods: Analysis of TCGA data for BC cohorts using the UALCAN portal and PrognoScan identified the overexpression of RAD51 in TNBCs. miRNA sequencing identified significant downregulation of RAD51-targeting miRNAs miR-214-5P and miR-142-3P. RT-PCR assays were used to validate the levels of miRNAs and RAD51, and immunohistochemical and immunoblotting techniques were used similarly for RAD51 protein levels in TNBC tissues and cell lines. Luciferase assays were performed under the control of RAD51 3'-UTR to confirm that miR-214-5P regulates RAD51 expression. To examine the effect of miR-214-5P-mediated downregulation of RAD51 on homologous recombination (HR) in TNBC cells, Dr-GFP reporter assays were performed. To assess the levels of olaparib-induced DNA damage responses in miR-214-5P, transfected cells, immunoblots, and immunofluorescence assays were used. Furthermore, COMET assays were used to measure DNA lesions and colony assays were performed to assess the sensitivity of BRCA-proficient TNBC cells to olaparib., Results: In-silico analysis identified upregulation of RAD51 as a poor prognostic marker in TNBCs. miRNA-seq data showed significant downregulation of miR-214-5P and miR-142-3P in TNBC cell lines derived from AA women compared to Caucasian-American (CA) women. miR-214-5P mimics downregulated RAD51 expression and induces HR deficiency as measured by Dr-GFP assays in these cell lines. Based on these results, we designed a combination treatment of miR-214-5P and olaparib in HR-proficient AA TNBC cell lines using clonogenic survival assays. The combination of miR-214-5P and olaparib showed synergistic lethality compared to individual treatments in these cell lines., Conclusions: Our studies identified a novel epigenetic regulation of RAD51 in TNBCs by miR-214-5P suggesting a novel combination therapies involving miR-214-5P and olaparib to treat HR-proficient TNBCs and to reduce racial disparity in therapeutic outcomes., (© 2023. The Author(s).)

Triple negative breast cancer (TNBC), an aggressive and highly metastatic subtype of breast cancer. Glioma-associated oncogene 1 (GLI1) is a transcription factor and effector of the Hedgehog (Hh) signaling pathway, and is predictive of poor survival for TNBC patients. A nanostring DNA Damage Response (DDR) mRNA panel was used to identify GLI1-induced regulation of DDR genes. Western blots, immunohistochemistry and immunofluorescence were used to evaluate protein expression. Colony assays and mammosphere formation assays were utilized to assess survival of cancer cells. Flow cytometry analyses were employed to evaluate changes in the cell cycle profile, and DNA fiber assays were used to analyze alterations in replication dynamics in TNBC cells. The UALCAN portal and Ensemble programs were used for computational analysis of TCGA data. CompuSyn software was used to calculate combination index (CI) values to assess synergism in drug combination experiments. Inhibition of GLI1 in TNBC cells transcriptionally downregulate expression of FANCD2 and its foci formation, and causes a homologous recombination repair (HR) deficiency. As HR-deficient cancer cells are sensitive to PARP-targeted therapies, we evaluated a combination of the GLI1 inhibitor, GANT61, and a PARP inhibitor (olaparib) in TNBC cells. Combination of GANT61 and olaparib elevated DNA damage levels and these drug combinations caused synergistic lethality to TNBC cells. Aberrantly activated GLI1 regulates HR-mediated DNA repair by transcriptionally regulating FANCD2 to overcome chemotherapy-induced replication stress and DNA damage, and it contributes to resistance of TNBC cells to therapeutics., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer's disease. BRCA1 interacting protein 1 or BRIP1 is a 5' to 3' DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity., Objective: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases., Methods: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability., Results: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells., Conclusion: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress.

Clear cell renal cell carcinoma is the most common and deadly type of cancer affecting the kidney, and is characterized histologically by large intracellular lipid deposits. These deposits are thought to result from lipid metabolic reprogramming occurring in tumor cells, but the exact mechanisms and implications of these metabolic alterations are incompletely understood. Obesity is an independent risk factor for clear cell renal cell carcinoma, and is also associated with lipid accumulation in noncancerous epithelial cells of the proximal tubule, where clear cell renal cell carcinoma originates. This article explores the potential link between obesity-associated renal lipid metabolic disturbances and lipid metabolic reprogramming in clear cell renal cell carcinoma, and discusses potential implications for future research.

Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)