Search Results (2,564)

p27^Kip1 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. p27^Kip1, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27^Kip1 for specific interactions/functions. Several germline or somatic CDKN1B (the p27^Kip1 encoding gene) mutations have been demonstrated to be associated with multiple endocrine neoplasia type 4 (MEN4), hairy cell leukemia, small-intestine neuroendocrine tumors, and breast and prostate cancers. Here, we analyzed the effect of four CDKN1B missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C>T, p.P117S; c.397C>A, p.P133T; c.487C>T, p.Q163*; and c.511G>T, p.E171*. By transfecting breast cancer cell lines, we observed increased growth and cell motility for all the investigated mutants compared to wild-type p27^Kip1 transfected cells. Furthermore, we discovered that the mutant forms exhibited altered phosphorylation on key residues and different localization or degradation mechanisms in comparison to the wild-type protein and suggested a possible region as crucial for the lysosome-dependent degradation of the protein. Finally, the loss of p27^Kip1 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27^Kip1 forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT. Full article

The cellular stress response (CSR) is a conserved mechanism that protects cells from -environmental and physiological stressors. The heat shock response (HSR), a critical component of the CSR, utilizes molecular chaperones to mitigate proteotoxic stress caused by elevated temperatures. We hypothesized that while the canonical HSR pathways are conserved across cell types, specific cell lines may exhibit unique transcriptional responses to heat shock. To test this, we compared the transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately following heat shock and after an 8-h recovery period. RNA sequencing revealed the conserved activation of canonical HSR pathways, including the unfolded protein response, alongside the -enrichment of the non-canonical “Receptor Ligand Activity” pathway across all cell lines. Cell-line-specific variations were observed, with HepG2 cells exhibiting significantly higher ex-pression levels of certain genes compared to other cell lines under stress conditions, as well as greater fold changes in gene expression relative to its control conditions. Validation by qPCR confirmed the activation of key genes within the “Receptor Ligand Activity” pathway across time points. These findings provide insights into conserved and context-specific aspects of the HSR, contributing to a more comprehensive understanding of stress response mechanisms across mammalian cells. Full article

Signal conditioning circuits, in particle energy spectrum determination systems, introduce shaping characteristics that affect pulse integrity. This study explores algorithms to compensate for these effects, focusing on digital signal processing for pole-zero cancellation (PZC) and unfolding techniques. The PZC algorithm successfully corrects baseline shift and pulse amplitude loss, providing significant improvements in signal fidelity. Although a digital PZC applied in streaming for high event rates was previously not feasible, this work proposes its implementation on FPGA, combining it with the unfolding method to enable online compensation and enhanced performance under various experimental conditions. Full article

Background: The hypoglycemic activity of mulberry leaf polyphenols has been widely studied, while its mechanism of action needs further elucidation. Methods: The inhibitory activity mechanism of astragalin on α-glucosidase was investigated with a combination of multispectroscopic techniques and molecular docking. The hypoglycemic pathway was further revealed with a high-glucose human hepatocellular carcinomas (HepG2) cell model. Results: The results indicated that astragalin inhibited α-glucosidase with IC₅₀ of 154.5 µM, which was the highest in potency among the main polyphenols from mulberry leaves. Astragalin could bind to α-glucosidase with a single inhibition site and quench its endofluorescence with a static quenching mechanism. Astragalin changed the secondary structure of α-glucosidase, and the decreased α-helix content, representing the un-folding conformation, resulted in the decreased activity. The molecular docking further indicated that two sustainable hydrogen bonds were generated between astragalin and α-glucosidase residue Ser-88 and Tyr-133. The main driving forces to form the astragalin-α-glucosidase complex were the van der Waals force and hydrogen bond. Astragalin at a concentration of 80 µg/mL obtained the best hypoglycemic effect by activating the Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Conclusions: This study provides new insights into the potential utilization of astragalin-rich foods in the improvement of diabetes mellitus. Full article

The intention of this paper is to develop an original notion of self-as-mediation, where a reimagining of the function of art as a phenomenological/epistemological praxis will be the methodological vehicle. The argument here will unfold over four moments. Firstly, I argue that through the elevation of art into a valid form of inquiry—one that engages our collective and individual being-in—a relation coupling art with science can be established. Secondly, by means of a further reflection on the linguistic aspects of the complementary domains of science and art—in part inspired by the standpoint of Carl Otto Apel—a unified transcendental–pragmatic interpretation of this art–science relationship will be determined. In the third moment, I make the argument that through a phenomenological reflection derived from the apodictic assertion of self-as-mediation, a trifold relation situating self-as-mediation is revealed as dynamically engaged in a continual exchange, or interchange, between what can be considered to be an “attitude” and a “doing”, referred to here as relation and action. Thus, the fourth moment is revealed as a weird dynamic relational movement, out of which a radical ethic may be developed. It is argued that along with an implied recasting of religious consciousness, a complementary and positive vision for humanity at this time of ecological and social tragedy may also be offered by this approach. Full article

Variability and relationship between phenological traits and leaf, acorn, and tree size morphometric traits were examined in early and late bud-flushing groups of the pedunculate oak population in the vicinity of Sremska Mitrovica, Serbia. According to the obtained three-year results, there were no significant differences in tree size and leaf morphometric characteristics between the early and late group. The effect of trees within phenological groups was statistically significant and considerable, especially in leaf blade width (lbw) and leaf area (la). Acorn length (acl) and acorn index (acinx) were significantly influenced by phenological group, achieving moderate contribution of phenological group to the total variation. There was a clear effect of phenological group on variation of examined phenological traits. The effect of year of monitoring on the same traits was not significant, but there was a clear effect of interaction between phenological group and year, especially in case of traits describing the period from bud swelling until the emergence of wrinkled leaves (f12a), unfolded leaves (f12b), and fully developed leaves (f12g) and their ratio with the period from 8 March until the emergence of wrinkled leaves: f12b/f02a and f12g/f02a ratio. Earlier phenology in warmer years is clearer in the early bud-flushing group than in the late one. Periods between different bud swelling and f12a, f12b, and f12g phenological phases were significantly shorter in 2017 (with a warm April) than in 2015 (with moderate temperatures in March and April) in the early group, but significantly longer in the late group. Examined traits were classified in six groups based on their factorial loadings with the first six principal components rotated by Varimax method, revealing strict distinction between traits by their original nature. In that sense, all examined groups of traits could be considered as informative in variability studies of pedunculate oak. The tree size traits (tree height and diameter at breast height) formed the separate, fifth group, suggesting no close relationship of these traits with any other examined characteristic. Both cluster analysis and PCA suggest distinct classification by trees’ phenology, but also considerable differences by the second principal component which is closely related to leaf size characteristics. The research should be continued on variability between populations and progenies, especially with respect to phenological and acorn morphometric traits. Understanding the phenological variations between early and late oaks could be essential for designing robust forest adaptation management strategies. Full article

Propolis is a highly complex, resinous natural product collected by honeybees from tree leaves and buds and mixed with pollen and enzymes. Due to its antimicrobial properties, it has various medical and industrial applications. As a nonconventional strategy, the use of propolis was suggested to control contaminating yeast growth in ethanol fermentations, without significantly affecting the starter yeast of the fermentation, Saccharomyces cerevisiae. In this study, we have developed a highly propolis-resistant S. cerevisiae strain using evolutionary engineering. The evolved strain FD11 had a higher growth rate (µ_max = 0.21 h⁻¹) than the reference strain (µ_max = 0.17 h⁻¹) under propolis stress and showed cross-resistance against caffeine stress. Moreover, it had significantly lower reactive oxygen species levels and higher cell wall integrity than the reference strain. Comparative transcriptomic analysis results revealed that the genes involved in oxidoreductase activity, transmembrane transporter activity, unfolded protein binding and pleiotropic drug resistance were upregulated in FD11. Whole genome re-sequencing analysis revealed mutations in multiple genes including PDR1, encoding a transcription factor regulating pleiotropic drug response. The results imply the importance of pleiotropic drug response and cell wall integrity in propolis resistance and the potential of using propolis-resistant, robust yeast strains in industrial applications. Full article

As advancements in autonomous underwater vehicle (AUV) technology unfold, the role of underwater wireless sensor networks (UWSNs) is becoming increasingly pivotal. However, the high energy consumption in these networks can significantly reduce their operational lifespan, while latency issues can impair overall network performance. To address these challenges, a novel mixed packet forwarding strategy is developed, which incorporates a wakeup threshold and a dynamically adjusted access probability for the cluster head (CH). This approach aims to conserve energy while maintaining acceptable network latency levels. The wakeup threshold restricts the frequency of state switching for the CH, thereby reducing energy consumption. Meanwhile, the dynamic access probability regulates the influx of packets to mitigate system congestion based on current network conditions. Furthermore, to accommodate the network’s varied transmission demands, packets generated by sensor nodes (SNs) are categorized into two types according to their sensitivity to latency. A discrete−time queueing model with preemptive priority is then established to evaluate the performance of different packets and the CH. Numerical results show how different parameters affect network performance and demonstrate that the proposed mixed packet forwarding mechanism can effectively manage the trade−off between latency and energy consumption, outperforming the traditional mechanism within a specific range of parameters. Full article

The effect of polyphenols on the texture and flavor of egg yolk hot gel (EY) was studied. Tea polyphenols (TP), rosmarinic acid (RE), and curcumin (CC) showed significant antioxidant properties during egg yolk processing and could effectively reduce lipid oxidation products (decreased by 68.9%, 76.4%, and 58.61%, respectively) and protein oxidation products (decreased by 47.49%, 37.47%, and 52.51%, respectively) and volatile odor components (styrene, nonanal and 1-octene-3-ol). In addition, these polyphenols enhanced the hot gel properties of the yolk, but did not significantly change the taste of the yolk. This improvement could be attributed to hydrophobic interactions, hydrogen bonds and ionic bonds formed between polyphenols and egg yolk proteins. These interactions produced a more stable structure that was less likely to unfold during heat treatment. As a result, exposure to free sulfhydryl groups, free amino acids and free fatty acids was minimized, thus reducing oxidation reactions. Full article

The betacoronavirus genus contains five of the seven human coronaviruses, making it a particularly critical area of research to prepare for future viral emergence. We utilized three human betacoronaviruses, one from each subgenus—HCoV-OC43 (embecovirus), SARS-CoV-2 (sarbecovirus), and MERS-CoV (merbecovirus)—, to study betacoronavirus interactions with the PKR-like ER kinase (PERK) pathway of the integrated stress response (ISR)/unfolded protein response (UPR). The PERK pathway becomes activated by an abundance of unfolded proteins within the endoplasmic reticulum (ER), leading to phosphorylation of eIF2α and translational attenuation. We demonstrate that MERS-CoV, HCoV-OC43, and SARS-CoV-2 all activate PERK and induce responses downstream of p-eIF2α, while only SARS-CoV-2 induces detectable p-eIF2α during infection. Using a small molecule inhibitor of eIF2α dephosphorylation, we provide evidence that MERS-CoV and HCoV-OC43 maximize viral replication through p-eIF2α dephosphorylation. Interestingly, genetic ablation of growth arrest and DNA damage-inducible protein (GADD34) expression, an inducible protein phosphatase 1 (PP1)-interacting partner targeting eIF2α for dephosphorylation, did not significantly alter HCoV-OC43 or SARS-CoV-2 replication, while siRNA knockdown of the constitutive PP1 partner, constitutive repressor of eIF2α phosphorylation (CReP), dramatically reduced HCoV-OC43 replication. Combining GADD34 knockout with CReP knockdown had the maximum impact on HCoV-OC43 replication, while SARS-CoV-2 replication was unaffected. Overall, we conclude that eIF2α dephosphorylation is critical for efficient protein production and replication during MERS-CoV and HCoV-OC43 infection. SARS-CoV-2, however, appears to be insensitive to p-eIF2α and, during infection, may even downregulate dephosphorylation to limit host translation. Full article

Reducing carbon dioxide (CO₂) emissions is vital at both global and national levels, given their significant role in exacerbating climate change. CO₂ emissions, stemming from a variety of industrial and economic activities, are major contributors to the greenhouse effect and global warming, posing substantial obstacles in addressing climate issues. It is imperative to forecast CO₂ emissions trends and classify countries based on their emission patterns to effectively mitigate worldwide carbon emissions. This paper presents an in-depth comparative study on the determinants of CO₂ emissions in twenty countries with high Human Development Index (HDI), exploring factors related to economy, environment, energy use, and renewable resources over a span of 25 years. The study unfolds in two distinct phases: initially, statistical techniques such as Ordinary Least Squares (OLS), fixed effects, and random effects models are applied to pinpoint significant determinants of CO₂ emissions. Following this, the study leverages supervised and unsupervised time series approaches to further scrutinize and understand the factors influencing CO₂ emissions. Seasonal AutoRegressive Integrated Moving Average with eXogenous variables (SARIMAX), a statistical time series forecasting model, is first used to predict emission trends from historical data, offering practical insights for policy formulation. Subsequently, Dynamic Time Warping (DTW), an unsupervised time series clustering approach, is used to group countries by similar emission patterns. The dual-phase approach utilized in this study significantly improves the accuracy of CO₂ emissions predictions while also providing a deeper insight into global emission trends. By adopting this thorough analytical framework, nations can develop more focused and effective carbon reduction policies, playing a vital role in the global initiative to combat climate change. Full article

The thermodynamic study of protein folding shows the generation of a narrow range of ΔG° values, as a net result of large changes in the ΔH° and TΔS° values of the folding process. The obvious consequence of this narrow range of values is that a linear enthalpy–entropy relationship, showing apparent enthalpy–entropy compensation (EEC), is clearly observed to be associated with the study of protein folding. Herein, we show the ΔH°, TΔS°, and ΔG° values for a set of 583 data from protein folding processes, at various temperatures, as calculated by using the Gibbs–Helmholtz equations. This set of thermodynamic data was calculated from the melting temperature (Tm), the melting enthalpy (ΔHm), and the change in heat capacity (ΔCp°) values, all of them associated with the heat-induced protein unfolding processes and included in the ProTherm Data Base. The average values of enthalpy (ΔH°av), entropy (TΔS°av), and free energy (ΔG°av) for the folding process were calculated within the range of temperature from 0 °C to the average value of Tm. The values and temperature dependency of TΔS°av within this temperature range are practically equal to those corresponding to ΔH°av, while ΔG°av remains small and displaying a curve with a minimum at about 10 °C and a value of ΔG° = −30.9 kJ/mol at the particular temperature of 25 °C. The large negative value of TΔS°av, together with the also large and negative value of ΔCp°av, suggests large conformational changes and important EEC, thus causing the small average value of ΔG° for protein folding, which is enough to guarantee both protein stability and molecular flexibility to allow for adaptation to the chemical potentials of the environment. Our analysis suggests that EEC may be the quantum-mechanical evolutive mechanism to make functional proteins adaptative to environmental temperature and metabolite concentrations. The analysis of protein folding data, compared with those of protein–ligand interaction, allows us to suggest strategies to overcome EEC in the design of new drugs. Full article

Afghan refugees are at the forefront of international attention amidst the unfolding global refugee crisis. Having borne witnesses to the horrors of war, fled their homeland, and endured the tragic loss of loved ones, they suffered a psychological trauma that reshaped their cognitive and emotional frameworks. This cross-sectional survey explores the prevalence and comorbidity of posttraumatic stress disorder and posttraumatic obsessive-compulsive disorder among Afghan refugees living in Haripur, Pakistan, and the intergenerational transmission of PTSD across their three generations. Researchers collected data from 48 male participants representing three generations of 16 Afghan refugee families using the Obsessive-Compulsive Inventory-Revised and the Posttraumatic Diagnostic Scale for DSM-5-TR. The findings revealed a significant positive correlation between posttraumatic obsessive-compulsive disorder and posttraumatic stress disorder, indicating a substantial co-occurrence of posttraumatic obsessive-compulsive disorder and posttraumatic stress disorder. About 79.20% of total participants were diagnosed with posttraumatic obsessive-compulsive disorder, and it was more prevalent among the first generation (87.5%) than in the second and third generations (75.0%) each—additionally, significant variability across generations in the prevalence of PTSD. The first-generation refugees experienced severe and very severe symptoms (12.5%), the second-generation experienced moderate symptoms, and the third-generation experienced mild symptoms (16.6%). These results emphasize the importance of addressing the comorbidity of both disorders in refugee communities to underscore their intergenerational adverse mental health outcomes. Full article

In the present work, we performed calculations of the kinetic isotope effect (KIE) on H/D, ¹⁴N/¹⁵N, ¹⁶O/¹⁸O, and ¹²C/¹³C isotopic substitution in the dissociation of beta-sheet polyglycine dimers of different lengths into two monomer chains. This dissociation reaction, proceeding via breaking of the interchain hydrogen bonds (H-bonds), is considered to be a model of unfolding of the secondary structure of proteins. The calculated strengthening of the interchain hydrogen bonds $N-H\cdots O=C$ due to heavy isotope substitution decreases in the row H/D >> ¹⁴N/¹⁵N > ¹⁶O/¹⁸O > ¹²C/¹³C. The KIE for H/D substitution, defined as the ratio of the rate constants ${\displaystyle \frac{k\left(H\right)}{k\left(D\right)}}$, was calculated with the use of a “completely loose” transition state model. The results of the calculations show that a very high H/D isotope effect can be achieved for proteins even with moderately long chains connected by dozens of interchain H-bonds. The results obtained also indicate that the heavy isotope substitution in the internal (interchain) and external H-bonds, located on the periphery of a dimer, can provide comparable effects on secondary structure stabilization. Full article

Oxidative stress, endoplasmic reticulum (ER) stress, and alterations in autophagy activity have been described as prominent factors mediating many pathological processes in chronic kidney disease (CKD). The accumulation of misfolded proteins in the ER may stimulate the unfolded protein response (UPR). The interplay between autophagy and UPR in hemodialysis (HD) patients remains unclear. The aim of the present study was to explore the associations between serum oxidative stress markers, autophagy activity, and ER stress markers in the peripheral blood mononuclear cells (PBMCs) of patients on HD. Autophagy and ER stress-related protein expression levels in PBMCs were measured using western blotting. The redox state of human serum albumin was measured via high-performance liquid chromatography. Levels of the microtubule associated protein light chain 3 (LC3)-II, BECLIN1, and p62/SQSTM1 proteins were significantly increased in PBMCs of HD patients compared to healthy subjects. The PBMCs in HD patients also displayed augmented glucose-regulated protein 78 kDa (GRP78), phosphorylated eukaryotic translation initiation factor 2, subunit 1 alpha (p-eIF2α), and activating transcription factor 6 (ATF6) levels (p < 0.05). Additionally, nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) levels were elevated in the PBMCs of HD patients, compared to those of healthy subjects. Correlation analysis showed that the redox status of albumin was significantly correlated with the p62 protein level in PBMCs. Compared to healthy controls, we found elevated autophagosome formation in HD patients. Increased expression of ER stress markers was also observed in HD patients. Furthermore, increased p62 expression was positively correlated with the protein expression of NRF2, as well as a reduced form of serum albumin (human mercaptalbumin; HMA), in HD patients. Full article