Search Results (206)

Diosgenin is a phytosteroid sapogenin with reported antitumoral activity. Despite the evidence indicating a lower incidence of prostate cancer (PCa) associated with a higher consumption of phytosteroids and the beneficial role of these compounds, only a few studies have investigated the effects of diosgenin in PCa, and its mechanisms of action remain to be disclosed. The present study investigated the effect of diosgenin in modulating PCa cell fate and glycolytic metabolism and explored its potential interplay with G protein-coupled oestrogen receptor (GPER). Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145, and PC3) human prostate cell lines were stimulated with diosgenin in the presence or absence of the GPER agonist G1 and upon GPER knockdown. Diosgenin decreased the cell viability, as indicated by the MTT assay results, which also demonstrated that castrate-resistant PCa cells were the most sensitive to treatment (PC3 > DU145 > LNCaP > PNT1A; IC50 values of 14.02, 23.21, 56.12, and 66.10 µM, respectively). Apoptosis was enhanced in diosgenin-treated cells, based on the increased caspase-3-like activity, underpinned by the altered expression of apoptosis regulators evaluated by Western blot analysis, which indicated the activation of the extrinsic pathway. Exposure to diosgenin also altered glucose metabolism. Overall, the effects of diosgenin were potentiated in the presence of G1. Moreover, diosgenin treatment augmented GPER expression, and the knockdown of the GPER gene suppressed the proapoptotic effects of diosgenin in PC3 cells. Our results support the antitumorigenic role of diosgenin and its interest in PCa therapy, alone or in combination with G1, mainly targeting the more aggressive stages of the disease. Full article

The global increase in the population of Visually Impaired People (VIPs) underscores the rapidly growing demand for a robust navigation system to provide safe navigation in diverse environments. State-of-the-art VIP navigation systems cannot achieve the required performance (accuracy, integrity, availability, and integrity) because of insufficient positioning capabilities and unreliable investigations of transition areas and complex environments (indoor, outdoor, and urban). The primary reason for these challenges lies in the segregation of Visual Impairment (VI) research within medical and engineering disciplines, impeding technology developers’ access to comprehensive user requirements. To bridge this gap, this paper conducts a comprehensive review covering global classifications of VI, international and regional standards for VIP navigation, fundamental VIP requirements, experimentation on VIP behavior, an evaluation of state-of-the-art positioning systems for VIP navigation and wayfinding, and ways to overcome difficulties during exceptional times such as COVID-19. This review identifies current research gaps, offering insights into areas requiring advancements. Future work and recommendations are presented to enhance VIP mobility, enable daily activities, and promote societal integration. This paper addresses the urgent need for high-performance navigation systems for the growing population of VIPs, highlighting the limitations of current technologies in complex environments. Through a comprehensive review of VI classifications, VIPs’ navigation standards, user requirements, and positioning systems, this paper identifies research gaps and offers recommendations to improve VIP mobility and societal integration. Full article

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1^T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Full article

Ionospheric scintillation is a pressing issue in space weather studies due to its diverse effects on positioning, navigation, and timing (PNT) systems. Developing an accurate and timely prediction model for this event is crucial. In this work, we developed two machine learning models for the prediction of ionospheric scintillation events at the equatorial anomaly during the maximum and minimum phases of solar cycle 24. The models developed in this study are the Random Forest (RF) algorithm and the eXtreme Gradient Boosting (XGBoost) algorithm. The models take inputs based on the solar wind parameters obtained from the OMNI Web database from the years 2010–2017 and Pc5 wave power obtained from the Bear Island (BJN) magnetometer station. We retrieved data from the Scintillation Network and Decision Aid (SCINDA) receiver in Egypt from which the S4 index was computed to quantify amplitude scintillations that were utilized as the target in the model development. Out-of-sample model testing was performed to evaluate the prediction accuracy of the models on unseen data after training. The similarity between the observed and predicted scintillation events, quantified by the R² score, was 0.66 and 0.74 for the RF and XGBoost models, respectively. The corresponding Root Mean Square Errors (RMSEs) associated with the models were 0.01 and 0.01 for the RF and XGBoost models, respectively. The similarity in error shows that the XGBoost model is a good and preferred choice for the prediction of ionospheric scintillation events at the equatorial anomaly. With these results, we recommend the use of ensemble learning techniques for the study of the ionospheric scintillation phenomenon. Full article

Research on augmentation and supplement systems for navigation systems has become a significant aspect in comprehensive positioning, navigation and timing (PNT) studies. The BeiDou-3 navigation satellite system (BDS-3) has constructed a dynamic inter-satellite network to gain more observation data than ground monitoring stations. Low Earth orbit (LEO) satellites have advantages in their kinematic velocity and information carrying rate and can be used as satellite-based monitoring stations for navigation satellites to make up for the distribution limitation of ground monitoring stations. This study constructs multi-source observation links with satellite-to-ground, inter-satellite and satellite-based observation data, proposes an orbit synchronization method for navigation satellites and LEO satellites and verifies the influence thereof on orbit accuracy with different observation data. The experimental results under conditions of real and simulated observation data showed the following: (1) With the support of satellite-based observation links, the orbit accuracy of the BDS-3 MEO satellites could be improved significantly, with a 78% improvement with the simulation data and a 76% improvement with the real data. When the navigation satellites leave the monitoring area of the ground monitoring stations, the accuracy reduction tendency of the orbit prediction could also be slowed down with the support of the LEO satellites and the accuracy could be maintained within centimeters. (2) Comparing the orbit accuracy with the support of the satellite-to-ground observation links, the orbit accuracy of the MEO satellites could be improved by 65.5%, 73.7% and 79.4% with the support of the 6, 12 and 60 LEO satellites, respectively. When the observation geometry and the covering multiplicity meet the basic requirement of orbit determination, the improvements to the orbit accuracy decrease with the growth of LEO satellite numbers. (3) The accuracy of orbit determination with the support of the LEO satellites or the inter-satellite links was at the centimeter level for both, verifying that inter-satellite links and satellite-based links can be used as each other’s backups for navigation satellites. (4) The accuracy of orbit determination with the multi-source observation links was also at the centimeter level, which was not better than the results with the support of the satellite-to-ground and inter-satellite links or the satellite-to-ground and satellite-based links. Full article

Volatile organic compounds (VOCs) are one of significant contributors to air pollution and have profound effects on human health and the environment. This study introduces a detailed analysis of VOC emissions from various industries within an industrial complex using a high-resolution measurement instrument. This study aimed to identify the VOC profiles and their concentrations across 12 industries. Sampling was conducted across 99 facilities in an industrial complex in South Korea, and VOC analysis was performed based on measurement data using a Proton-Transfer-Reaction Time-of-Flight Mass Spectrometry (PTR-ToF-MS). The results indicated that the emission of oxygenated VOCs (OVOCs) was dominant in most industries. Aromatic hydrocarbons were also dominant in most industries, except in screen printing (SP), lubricating oil and grease manufacturing (LOG), and industrial laundry services (ILS) industries. Chlorinated VOCs (Cl-VOCs) showed a relatively higher level in the metal plating (MP) industry than those in other industries and nitrogen-containing VOCs (N-VOCs) showed high levels in general paints and similar product manufacturing (PNT), MP, and ILS industries, respectively. The gravure printing industry was identified as the highest emitter of VOCs, with the highest daily emissions reaching 5934 mg day⁻¹, primarily consisting of ethyl acetate, toluene, butyl acetate, and propene. The findings suggest that the VOC emissions from the gravure printing and plastic synthetic leather industries should be primarily reduced, and it would be the most cost-effective approach to improving air quality. This study can provide the fundamental data for developing effective reduction technologies and policies of VOC, ultimately contributing to enhanced atmospheric models and regulatory measures. Full article

Prostate cancer is the second most common neoplasia and fifth-leading cause of cancer death in men worldwide. Electromagnetic and magnetic fields have been classified as possible human carcinogens, but current understanding of molecular and cellular pathways involved is very limited. Effects due to extremely low magnetic/hypomagnetic fields (LMF) are furthermore poorly understood. Extracellular vesicles (EVs) are crucial mediators of cellular communication with multifaceted roles in cancer progression, including via transport and uptake of various protein and microRNA (miRNA) EV-cargoes. miRNAs regulate gene expression and are implicated in cancer-related processes such as proliferation, metastasis, and chemoresistance. This study investigated the effects of LMF exposure (20 nT) by magnetic shielding on the prostate cancer cell line PC3 compared to the prostate epithelial cell line PNT2 under short-term (4 h) conditions. We examined EV profiles following a 4 h LMF exposure alongside associated functional enrichment KEGG and GO pathways for the EV proteomes. The 4 h LMF exposure significantly reduced cellular EV release and modified PC3 EV cargoes to a more inflammatory and metastatic profile, with 16 Disease Pathways and 95 Human Phenotypes associated specifically with the LMF-treated PC3 EV proteomes. These included cancerous, metabolic, blood, skin, cardiac and skeletal Disease Pathways, as well as pain and developmental disorders. In the normal PNT2 cells, less EV protein cargo was observed following LMF exposure compared with cells not exposed to LMF, and fewer associated functional enrichment pathways were identified. This pointed to some differences in various cellular functions, ageing, defence responses, oxidative stress, and disease phenotypes, including respiratory, digestive, immune, and developmental pathways. Furthermore, we analysed alterations in matrix metalloproteinases (MMPs) and miRNAs linked to metastasis, as this is crucial in cancer aggressiveness. The 4 h LMF exposure caused a significant increase in MMP2 and MMP9, as well as in onco-miRs miR-155, miR-210, miR-21, but a significant reduction in tumour-suppressor miRs (miR-200c and miR-126) in the metastatic PC3 cells, compared with normal PNT2 cells. In addition, 4 h LMF exposure significantly induced cellular invasion of PC3 cells. Overall, our findings suggest that changes in magnetic field exposures modulate EV-mediated and miR-regulatory processes in PCa metastasis, providing a basis for exploring novel therapeutic strategies. Full article

mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein complexes, mTORC1 and mTORC2. We have identified a rapamycin-resistant mTOR complex, called mTORC3, which is different from the canonical mTORC1 and mTORC2 complexes in that it does not contain the Raptor, Rictor, or mLST8 mTORC1/2 components. mTORC3 phosphorylates mTORC1 and mTORC2 targets and contains the ETS transcription factor ETV7, which binds to mTOR and is essential for mTORC3 assembly in the cytoplasm. Tumor cells that assemble mTORC3 have a proliferative advantage and become resistant to rapamycin, indicating that inhibiting mTORC3 may have a therapeutic impact on cancer. Here, we investigate which domains or amino acid residues of ETV7 and mTOR are involved in their mutual binding. We found that the mTOR FRB and LBE sequences in the kinase domain interact with the pointed (PNT) and ETS domains of ETV7, respectively. We also found that forced expression of the mTOR FRB domain in the mTORC3-expressing, rapamycin-resistant cell line Karpas-299 out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo. Our data provide useful information for the development of molecules that prevent the assembly of mTORC3, which may have therapeutic value in the treatment of mTORC3-positive cancer. Full article

Modern systems and devices, including unmanned aerial systems (UASs), autonomous vehicles, and other unmanned and autonomous systems, commonly rely on the Global Positioning System (GPS) for positioning, navigation, and timing (PNT). Cellular mobile devices rely on GPS for PNT and location-based services. Many of these systems cannot function correctly without GPS; however, GPS signals are susceptible to a wide variety of signal-related disruptions and cyberattacks. GPS threat detection and mitigation have received significant attention recently. There are many surveys and systematic reviews in the literature related to GPS security; however, many existing reviews only briefly discuss GPS security within a larger discussion of cybersecurity. Other reviews focus on niche topics related to GPS security. There are no existing comprehensive reviews of GPS security issues in the literature. This paper fills that gap by providing a comprehensive treatment of GPS security, with an emphasis on UAS applications. This paper provides an overview of the threats to GPS and the state-of-the-art techniques for attack detection and countermeasures. Detection and mitigation approaches are categorized, and the strengths and weaknesses of existing approaches are identified. This paper also provides a comprehensive overview of the state-of-the-art on alternative positioning and navigation techniques in GPS-disrupted environments, discussing the strengths and weaknesses of existing approaches. Finally, this paper identifies gaps in existing research and future research directions. Full article

Satellite navigation is an essential component of the national infrastructure. Space weather and ionospheric conditions are the prime sources of GNSS (global navigation satellite system) positioning, navigation, and timing (PNT) service disruptions and degradations. Protection, toughening, and augmentation (PTA) of GNSS PNT services require novel approaches in ionospheric effects mitigation. Standard global ionospheric correction models fail in the mitigation of high-dynamics and local ionospheric disturbances. Here, we demonstrate that in the case of the short-term fast-developing geomagnetic storm, a machine learning-based environment-aware GNSS ionospheric correction model for sub-equatorial regions may provide a substantial improvement over the existing global Klobuchar model, considered a benchmark. The proposed machine learning-based model utilises just the geomagnetic field density component observations as a predictor to estimate TEC/GNSS ionospheric delay as the prediction model target. Further research is needed to refine the methodology of machine learning model development selection and validation and to establish an architecture-agnostic framework for GNSS PTA development. Full article

A high-precision time reference is fundamental to the positioning, navigation, and timing (PNT) of global navigation satellite systems (GNSS). The precision of clock steering determines the accuracy of practical applications that rely on the time–frequency reference. With the invention of direct digital synthesizer (DDS) technology, digital clock steering (DCS) has gradually become a mainstream technology. However, the key factor limiting DCS accuracy is the system quantization noise, which leads to a low frequency and phase adjustment accuracy. Here we propose a DCS method based on $\Sigma$-$\Delta$ modulation to address the issue of low resolution of DAC through shaping the quantization noise. A simulated GNSS time–frequency reference system experimental platform is constructed to validate the effectiveness of the proposed method. The experimental results demonstrate that this method achieves a phase adjustment accuracy of 0.48 ps and a frequency adjustment accuracy better than 0.48 pHz, which is two orders of magnitude higher than that of existing GNSS time–frequency reference systems. Thus, the proposed method offers a significant improvement in time–frequency reference systems, leading to better performance, reliability, and accuracy in a wide range of practical applications. Full article

Obesity stands out as a primary risk factor for diabetes. Attaining healthy weight loss, especially reducing body fat, is important in managing prediabetes and preventing progression to full diabetes and its co-morbidities. This study examined the effects of personalized nutrition therapy (PNT) combined with continuous glucose monitoring (CGM) on body weight and composition in individuals with prediabetes. A total of 30 individuals with prediabetes who were overweight or obese were assigned randomly to either the treatment, observed CGM data plus PNT, or the control group which was blinded to their blood glucose results throughout the study. Both groups were provided with dietary recommendations for calorie intake and macronutrient distribution, coupled with personalized goal setting for glucose control and healthy eating, without any specific emphasis on weight reduction or changes in physical activity. Regular visits were scheduled every 10 days to perform measurements and replace CGMs. Data were analyzed using General Linear Model with repeated measures. Over the 30-day follow-up period, both groups experienced significant reductions in weight and fat mass. The treatment group exhibited two-fold greater reductions in both weight and fat mass, a significant decrease in carbohydrate intake, and a significant increase in time spent on physical activitycompared to the control group. In addition, compliance was notably higher in the treatment group. These findings indicate that overweight or obese individuals with prediabetes can achieve weight loss and improved body composition through personalized education for glucose control, without exclusively emphasizing weight loss as the primary objective. Additionally, the real-time feedback provided by CGM enhances these improvements. Full article

Establishing a national comprehensive PNT (Positioning, Navigation, and Timing) system has become a consensus among major countries worldwide. As a crucial component in completing the entire PNT system, the 5G NR (new radio) time service signal plays a vital role. This paper proposes a 5G NR time service signal that uses a spread spectrum system, shares the 5G signal frequency band, but does not occupy the bandwidth of the 5G communication signal. This timing service signal has relatively low power, making it appear “submerged” within the power of the 5G communication signal. The spread spectrum code for this timing signal employs the chaotic orthogonal composite sequence proposed in this paper. Compared to traditional spread spectrum sequences, this sequence offers better security than m-sequences, improved autocorrelation than Walsh sequences, and an effective suppression of the short-period characteristics exhibited when the Skew Tent-Map chaotic sequence takes special values. This paper simulates the capture of the 5G NR time service signal in an environment with a signal-to-noise ratio of 10 dB using an FFT-based parallel code phase search algorithm, successfully capturing the 5G NR time service signal and verifying the feasibility of the proposed chaotic orthogonal composite sequence as a spread spectrum code. Full article

Glyphosate, the active ingredient of several broad-spectrum herbicides, is widely used throughout the world, although many adverse effects are known. Among these, it has been recognized as an endocrine disruptor. This work aimed to test the effects and potential endocrine disrupting action of glyphosate on PNT1A human prostate cells, an immortalized non-tumor epithelial cell line, possessing both ERα and ERβ estrogen receptors. The results showed that glyphosate induces cytotoxicity, mitochondrial dysfunction, and rapid activation of ERα and ERβ via nuclear translocation. Molecular analysis indicated a possible involvement of apoptosis in glyphosate-induced cytotoxicology. The apoptotic process could be attributed to alterations in mitochondrial metabolism; therefore, the main parameters of mitochondrial functionality were investigated using the Seahorse analyzer. Impaired mitochondrial function was observed in glyphosate-treated cells, with reductions in ATP production, spare respiratory capacity, and proton leakage, along with increased efficiency of mitochondrial coupling. Finally, the results of immunofluorescence analysis demonstrated that glyphosate acts as an estrogen disruptor determining the nuclear translocation of both ERs. Nuclear translocation occurred independent of dose, faster than the specific hormone, and persisted throughout treatment. In conclusion, the results collected show that in non-tumor prostate cells glyphosate can cause cell death and acts as a xenoestrogen, activating estrogen receptors. The consequent alteration of hormonal functions can have negative effects on the reproductive health of exposed animals, compromising their fertility. Full article

The evaluation of coronavirus disease 2019 (COVID-19) vaccine immunogenicity remains essential as the severe acute respiratory syncytial virus 2 (SARS-CoV-2) pandemic continues to evolve and as additional variants emerge. Neutralizing antibodies are a known correlate of protection for SARS-CoV-2 vaccines. A pseudovirus neutralization (PNT) assay was developed and validated at Novavax Clinical Immunology Laboratories to allow for the detection of neutralizing antibodies in vaccine clinical trial sera. The PNT assay was precise, accurate, linear, and specific in measuring SARS-CoV-2 neutralization titers in human serum for ancestral strain and the Omicron subvariants BA.5 and XBB.1.5, with an overall geometric coefficient of variation of ≤43.4%, a percent relative bias within the expected range of −60% to 150%, and a linearity value of R² > 0.98 for all three strains. This pseudovirus assay will be useful for the analysis of vaccine clinical trial samples to assess vaccine immunogenicity. Future work will focus on modifying the assay for emerging variants, including XBB.1.16, EG.5.1, BA.2.86, and any other variants that emerge in the ongoing pandemic. Full article