In cell signaling pathways, proteins interact with each other to determine cell fate in response to either cell-extrinsic (micro-environmental) or intrinsic cues. One of the well-studied pathways, ...the mitogen-activated protein kinase (MAPK) signaling pathway, regulates cell processes such as differentiation, proliferation, apoptosis, and survival in response to various micro-environmental stimuli in eukaryotes. Upon micro-environmental stimulus, receptors on the cell membrane become activated. Activated receptors initiate a cascade of protein activation in the MAPK pathway. This activation involves protein binding, creating scaffold proteins, which are known to facilitate effective MAPK signaling transduction.
This paper presents a novel mathematical model of a cell signaling pathway coordinated by protein scaffolding. The model is based on the extended Boolean network approach with stochastic processes. Protein production or decay in a cell was modeled considering the stochastic process, whereas the protein-protein interactions were modeled based on the extended Boolean network approach. Our model fills a gap in the binary set applied to previous models. The model simultaneously considers the stochastic process directly. Using the model, we simulated a simplified mitogen-activated protein kinase (MAPK) signaling pathway upon stimulation of both a single receptor at the initial time and multiple receptors at several time points. Our simulations showed that the signal is amplified as it travels down to the pathway from the receptor, generating substantially amplified downstream ERK activity. The noise generated by the stochastic process of protein self-activity in the model was also amplified as the signaling propagated through the pathway.
The signaling transduction in a simplified MAPK signaling pathway could be explained by a mathematical model based on the extended Boolean network model with a stochastic process. The model simulations demonstrated signaling amplifications when it travels downstream, which was already observed in experimental settings. We also highlight the importance of stochastic activity in regulating protein inactivation.
The incidence of colorectal cancer (CRC) is rapidly increasing in developing countries, especially among populations that are adopting Western-style diets. Several, but not all, epidemiological and ...experimental studies suggest that a high intake of meat, especially red and processed meat, is associated with increased CRC risk. Potential reasons for the association between high red and processed meat intake and CRC risk include the content of the meat (e.g. protein, heme) and compounds generated by the cooking process (e.g. N-nitroso compounds, heterocyclic amines). These factors can affect the large intestine mucosa with genotoxicity and metabolic disturbances. Increased bacterial fermentation (putrefaction) of undigested protein and production of bacterial metabolites derived from amino acids may affect colon epithelial homeostasis and renewal. This correlates with the fact that most colonic cancers are detected in the distal colon and rectum where protein fermentation actively occurs. However, there are still large controversies on the relationship between red meat consumption and CRC risk. Therefore, the purpose of this review is to enhance the current understanding on the association between high red and processed meat intakes with CRC risk. A principal focus of this review will be to discuss the meat-related components, such as proteins in the meat, heme, N-nitroso compounds, and heterocyclic amines, and the effects they have upon the large intestine mucosa and the intestinal gut microbiota.
In Korea, the prevalence rate of hypertension among people aged over 30 is on an upward trend, which increased from 26.2% in 2008 to 28.3% in 2018. This hovers above the global morbidity rate of ...hypertension. As hypertension is the cause of cerebrovascular or cardiovascular diseases, early treatment and management are critical. Also, while there has been numerous research conducted on exercise intervention, the number of studies done on hypertension and physical fitness falls far below. To identify the relationship between health and physical fitness depending on the blood pressure levels of Korean seniors, the physical fitness test results of the National Fitness Award 100 conducted in 2017 were used, and blood pressure level, physique, and physical fitness data of 17,110 elderly population aged above 65 were analyzed. IBM Statistics SPSS 25.0 was used to process the collected data. Due to the gender difference in blood pressure levels, physique, and physical strength, the analysis was conducted by each gender, and the analysis of variance (ANOVA) was performed to identify the differences in physique and physical strength depending on the blood pressure level. Also, Tukey's HDS test was conducted if such differences were found. All analyzes were tested at the significance level (α) of 0.05. As a result of comparing the physique factors by blood pressure level, only males showed a significant difference between groups in terms of height(p = .019), and higher blood pressure implied greater height. Also, for both genders, those with high blood pressure appeared to have greater body weight(p < .001), body fat percentage(p < .001), BMI(p < .001), waist circumference(p < .001), and waist-to-height ratio(p < .001),. In addition, as the result of comparing health-related physical strength and skill-related physical strength by blood pressure level, males showed a significant difference only in muscular strength(p = .026) and flexibility(p < .001), while females showed a significant difference between groups in terms of cardiovascular endurance(p < .001), muscular strength(p = .025), muscular endurance(p < .001), balance, and motor coordination except for flexibility. Holistically, males only showed a significant difference in muscular strength and flexibility while females appeared to have a significant difference between groups in all categories except flexibility, which can be considered that physical fitness factors influence the blood pressure of females more than males.
Introduction Data on omega-3 polyunsaturated fatty acids in relation to cardiovascular disease are limited in women. The aim of this study was to examine longitudinal relations of tuna and dark fish, ...α-linolenic acid, and marine omega-3 fatty acid intake with incident major cardiovascular disease in women. Methods This was a prospective cohort study of U.S. women participating in the Women’s Health Study from 1993 to 2014, during which the data were collected and analyzed. A total of 39,876 women who were aged ≥45 years and free of cardiovascular disease at baseline provided dietary data on food frequency questionnaires. Analyses used Cox proportional hazards models to evaluate the association between fish and energy-adjusted omega-3 polyunsaturated fatty acid intake and the risk of major cardiovascular disease, defined as a composite outcome of myocardial infarction, stroke, and cardiovascular death, in 38,392 women in the final analytic sample (96%). Results During 713,559 person years of follow-up, 1,941 cases of incident major cardiovascular disease were confirmed. Tuna and dark fish intake was not associated with the risk of incident major cardiovascular disease ( p -trend >0.05). Neither α-linolenic acid nor marine omega-3 fatty acid intake was associated with major cardiovascular disease or with individual cardiovascular outcomes (all p -trend >0.05). There was no effect modification by age, BMI, or baseline history of hypertension. Conclusions In this cohort of women without history of cardiovascular disease, intakes of tuna and dark fish, α-linolenic acid, and marine omega-3 fatty acids were not associated with risk of major cardiovascular disease.
TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the ...identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Expression of constitutively active (GTP-bound) Rag in mammalian cells activated TORC1 in the absence of amino acids, whereas expression of dominant-negative Rag blocked the stimulatory effects of amino acids on TORC1. Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals.
A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading ...to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor's volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. To this end, we simulated the impact of different fibroblast distributions on treatment outcomes. As a proof of principle, we focused on five types of distribution of fibroblasts characterized by different locations, shapes, and orientations of the fibroblast region with respect to the resistant cells. Our simulation shows that the spatial architecture of fibroblasts modulates tumor progression in both continuous and adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy of a virtual patient with four metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations. Our simulation highlights the importance of undetected metastatic lesions on adaptive therapy outcomes.
Frailty is highly prevalent in older adults. Malnutrition is a common problem in older adults and is related to frailty.
The aim was to investigate a structural frailty model, to verify the factors ...which affect the frailty of older adults, and to evaluate the moderating effects of nutritional status on frailty through multi-group analysis.
Secondary analysis as a descriptive survey.
Data were prospectively collected from 1,374 older adults (age ≥ 70) from the Korean Frailty and Aging Cohort Study in 2017.
Frailty was measured by the FRAIL scale robust (score 0), pre-frailty (score 1–2), frailty (score 3–5), and nutritional status was evaluated by the Mini Nutritional Assessment (MNA) well-nourished (score ≥ 24), risk of malnutrition (score 17–23.5), malnourished (score < 17). Other domains were evaluated with the hand grip strength test, Short Physical Performance Battery (SPPB), short form of the Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), and ENRICHD Social Support Instrument (ESSI). The frailty model was developed by confirming the relationship among the influencing factors of frailty. To evaluate the different frailty pathways according to nutritional status in multi-group analysis, participants were divided into two subgroups according to the mean MNA score. Subgroups were classified into a well-nourished group (n = 851) for scores equal to or higher than the average score, and a malnourished group (n = 523) for scores lower than the average score. The path analysis was performed using the AMOS 23.0 program.
The frailty model's fit indices were adequate. In the model, the most influential factor for frailty was depression, followed by SPPB, age, polypharmacy, cognitive function, and female sex. In the multi-group analysis according to nutritional status, the malnourished group significantly increased in frailty as SPPB scores decreased. In addition, SPPB scores and cognitive function significantly decreased with increasing age in the malnourished group when compared to the well-nourished group.
Depression, SPPB, age, polypharmacy, cognitive function, and female sex were found to be important factors that affect frailty. Malnourished older adults are more likely to suffer from physical impairment, lower cognitive function, and frailty. Vigorous efforts are needed to improve nutritional status in older adults, which ultimately might improve functional outcomes and frailty.
While the coronavirus disease (COVID‐19) accounts for the current global pandemic, the emergence of other unknown pathogens, named “Disease X,” remains a serious concern in the future. Emerging or ...re‐emerging pathogens continue to pose significant challenges to global public health. In response, the scientific community has been urged to create advanced platform technologies to meet the ever‐increasing needs presented by these devastating diseases with pandemic potential. This review aims to bring new insights to allow for the application of advanced nanomaterials in future diagnostics, vaccines, and antiviral therapies, thereby addressing the challenges associated with the current preparedness strategies in clinical settings against viruses. The application of nanomaterials has advanced medicine and provided cutting‐edge solutions for unmet needs. Herein, an overview of the currently available nanotechnologies is presented, highlighting the significant features that enable them to control infectious diseases, and identifying the challenges that remain to be addressed for the commercial production of nano‐based products is presented. Finally, to conclude, the development of a nanomaterial‐based system using a “One Health” approach is suggested. This strategy would require a transdisciplinary collaboration and communication between all stakeholders throughout the entire process spanning across research and development, as well as the preclinical, clinical, and manufacturing phases.
Nanomaterials have a significant potential for creating sophisticated complexes, mimicking the natural size and structures of viruses without the complications of toxicity. New approaches for applying advanced nanomaterial‐based platform technologies to future diagnostics, vaccines, and antiviral treatments against emerging infectious diseases are reviewed. The unmet needs and future directions of current nanomaterial‐based tools in the clinical settings are also addressed.
Infiltrate and destroy: In an environment rich in protonating or oxidative species, such as the intracellular milieu of cancer cells, the main absorption band of spherical, water‐soluble polyaniline ...nanoparticles was red‐shifted to a near‐infrared (NIR) wavelength as a result of the formation of the emeraldine salt (see picture). The doped nanoparticles caused photothermal ablation of cancer cells upon NIR laser irradiation in vitro and in vivo.
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