Search Results (64)

Experimental data on the folding and unfolding of small globular proteins are often well described assuming a two-state equilibrium process. It means that after careful analysis by a combination of experimental techniques, only folded and unfolded states of the protein are found to be populated under various external conditions with no detectable intermediates. One of the consequences of the two-state behavior is that the equilibrium ratio of the folded to unfolded protein states follows a simple thermodynamic relation, and the enthalpy difference between states can be obtained from the temperature dependence of the equilibrium constant. In this paper, we theoretically investigate the criteria for the two-state equilibrium behavior and discuss the thermodynamic constraint on the properties of the “hidden” folding intermediates. The literature data on the folding mechanism of lysozyme in water and glycerol, which follows a two-state equilibrium behavior but includes kinetic intermediates, is analysed in light of this constraint. Full article

Trachinotus ovatus is a euryhaline, warm-water pelagic fish species with strong adaptability, rapid growth, and a high survival rate, making it one of the most important marine aquaculture species in China. In recent years, extensive experience has been accumulated in the cage farming of T. ovatus, but whether it can adapt to deep-sea environments and grow normally remains a current research focus. This study used RNA-Seq sequencing technology to analyze the gene expression changes in the liver of T. ovatus under three conditions: rest (0 cm/s), medium flow velocity (54 cm/s), and high flow velocity (90 cm/s). Through differential expression analysis, Short Time-series Expression Miner (STEM) analysis and protein–protein interaction (PPI) network analysis, a total of 5107 differentially expressed genes (DEGs), three significantly expressed gene profiles (profile6, profile1, and profile5), and 15 hub genes were identified. The results showed that changes in flow speed significantly impacted key biological processes such as energy metabolism, protein homeostasis, and endoplasmic reticulum (ER) stress response. Under moderate and high flow conditions, glycolysis-related genes were upregulated to meet the energy demands of swimming, while the downregulation of the PPARγ-RXRG complex and its downstream genes in the lipid metabolism pathway suggested a limitation in its fatty acid β-oxidation capacity. At the same time, protein synthesis was enhanced, and the unfolded protein response (UPR) was activated to help cope with ER stress. Furthermore, when the flow speed reached 90 cm/s, the expression of UPR- related genes and the anti-apoptotic factor JNK significantly decreased, suggesting that the stress response was nearing its limit and could potentially trigger cell apoptosis. These findings provide new insights into the molecular adaptation mechanisms of T. ovatus to flow speed stress and offer theoretical support for its rational farming in deep-sea cages, suggesting that the water flow speed in farming should not exceed 90 cm/s. Full article

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H₂S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H₂S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants. Full article

Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER–mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)—characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity—the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration. Full article

Two new Co(II) coordination compounds viz. [Co(H₂O)(bz)₂(μ-3-Ampy)₂]_n (1) and [Co(4-Mebz)₂(2-Ampy)₂] (2) (wherebz = benzoate, 4-Mebz = 4-Methylbenzoate and Ampy = Aminopyridine) were synthesized and characterized via elemental (CHN), electronic spectroscopy, FT-IR spectroscopy, and thermogravimetric analysis (TGA). The molecular structures were determined by single-crystal X-ray diffraction analysis, inferring that compound 1 crystallizes as a 3-Ampy bridged Co(II) coordination polymer, whereas compound 2 crystallizes as a mononuclear Co(II) compound. Compound 1 unfolds the presence of N–H⋯O, C–H⋯O, O–H⋯O, C–H⋯N and aromatic π⋯π interactions, while for compound 2, N–H⋯O, C–H⋯O, C–H⋯C and C–H⋯π interactions are observed. Both the compounds showcase scarcely reported chelate ring interactions involving the benzoate moiety (chelate ring⋯π in 1 and N–H⋯chelate ring in 2). We also conducted theoretical evaluations comprising of combined QTAIM/NCI plot analysis, DFT energy calculation and MEP surface analysis to analyze the supramolecular interactions present in the crystal structures. As per QTAIM parameters, the predominance of π-stacking interactions over hydrogen bonds in stabilizing the assembly in compound 1 is affirmed. Likewise, in compound 2, both hydrogen bonding (HBs) and C–H⋯π interactions are deemed pivotal in stabilizing the dimeric assemblies. The in vitro antiproliferative activities of compounds 1 and 2 were performed against Dalton’s lymphoma (DL) cancer cell lines through cytotoxicity and apoptosis assays, showcasing higher cytotoxicity of compound 1 (IC₅₀ = 28 μM) over compound 2 (IC₅₀ = 34 μM). Additionally, a molecular docking study investigated the structure–activity relationship of these compounds and allowed an understanding of the molecular behaviour after treatment. 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 purpose of this conceptual and explorative study is to document the advantages of health-promoting self-leadership practice. Professional certification programs are criticized due to a lack of practice among participants, involvement, and short duration. This study is based on self-leadership practices over several weeks of two executive MBA student classes from spring 2020 and 2021. A preliminary theoretical framework is developed suggesting that health-promoting self-leadership, which includes three orientations, has an impact on self-efficacy, mental fitness, and performance. Two different self-leadership classes with managers from the public and private sectors went through a self-development process as a semester project. The content analyses of 112 student reports unfolded students’ self-development processes and results identified in diaries, notes, tables, training schedules, and reflections. The findings, based on two different samples and aggregated data, support the theoretical framework. Moreover, the processes of self-development and self-leadership seem to be advantageous for almost all managers. The health-promoting self-leadership practice improved managers’ mental and physical fitness, energy balance, self-efficacy beliefs, and performance. These outcomes were achieved through physical activity, self-talk, meditative exercises, reward systems, visualizing, diet programs, and routines. The findings underscore the importance of self-development processes amongst managers, and that health-promoting self-leadership courses should last over several weeks. Full article

In the relentless pursuit of sustainable energy solutions, the petroleum industry faces the imperative challenge of mitigating sulfur emissions. This comprehensive review scrutinizes Titanium Dioxide (TiO₂) as an extraordinary catalyst, pushing the boundaries of desulfurization performance in petroleum refining. The abstract begins by underscoring the urgent need for advanced desulfurization technologies, driven by stringent environmental mandates and escalating global energy demands. The spotlight then shifts to the unparalleled physicochemical attributes of TiO₂, showcasing its inherent advantages such as exceptional surface area, stability, and photocatalytic process. A profound exploration of TiO₂’s catalytic mechanisms follows, unraveling its capacity to disintegrate stubborn sulfur–carbon bonds, thereby elevating desulfurization efficiency to unprecedented levels. This review meticulously dissects diverse forms of TiO₂, ranging from nanoparticles to mesoporous structures, and provides a critical analysis of their respective strengths and limitations in catalyzing sulfur removal. Delving into operational nuances, this review examines the impact of temperature, pressure, and catalyst loading on TiO₂ performance, offering crucial insights for optimizing desulfurization processes. The narrative then unfolds to explore cutting-edge developments in TiO₂-based catalysts, encompassing ingenious modifications, composites, and hybrid materials designed to augment catalytic activity and selectivity. Anticipating the road ahead, this review contemplates the challenges and prospects of deploying TiO₂ on an industrial scale, pointing toward avenues for future research and development. This abstract encapsulates a wealth of knowledge, serving as an indispensable resource for researchers, engineers, and policymakers navigating the dynamic landscape of sustainable petroleum refining. TiO₂ emerges as a transformative force, propelling the industry toward cleaner, greener, and more efficient energy production. Full article

Land use conflicts are intensifying in Northern Sweden due to the increasing global demand for resources coupled with the green transition. In line with this, a thorough understanding of land use conflicts in the area is becoming necessary as economic activities expand and newer ones are developed. Hence, this paper aims to provide a systematic literature review of research on land use conflicts specific to Northern Sweden, focusing on various economic activities such as forestry, mining, tourism, energy sector and reindeer husbandry. Additionally, we aim to determine lessons learned and suggested ways forward based on a systematic review. We used Scopus and Web of Science on June 2023 and through descriptive statistical analysis of 33 articles, we summarized research trends and gaps. We found three main typologies of conflicts and five main themes of suggested ways forward. Recommendations agree that there should be a broader understanding of the underlying interests of the stakeholders; and there should be an inclusive, more participatory approach to discussing potential solutions, not to create an agreement but to come to an understanding. Beyond academic insights, the findings hold practical relevance for shaping effective land use policies. This paper offers valuable lessons that extend beyond the local context, informing broader discussions and policy considerations for sustainable land management in the larger Arctic setting, where similar challenges and resource demands are unfolding. Full article

L-theanine, a unique non-protein amino acid, is an important bioactive component of green tea. Previous studies have shown that L-theanine has many potent health benefits, such as anti-anxiety effects, regulation of the immune response, relaxing neural tension, and reducing oxidative damage. However, little is known concerning whether L-theanine can improve the clearance of mitochondrial DNA (mtDNA) damage in organisms. Here, we reported that L-theanine treatment increased ATP production and improved mitochondrial morphology to extend the lifespan of UVC-exposed nematodes. Mechanistic investigations showed that L-theanine treatment enhanced the removal of mtDNA damage and extended lifespan by activating autophagy, mitophagy, mitochondrial dynamics, and mitochondrial unfolded protein response (UPR^mt) in UVC-exposed nematodes. In addition, L-theanine treatment also upregulated the expression of genes related to mitochondrial energy metabolism in UVC-exposed nematodes. Our study provides a theoretical basis for the possibility that tea drinking may prevent mitochondrial-related diseases. Full article

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5–20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30–40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival. Full article

With rapid global economic growth and a rise in disposable household income, particularly within a progressively warming planet, the escalating demand for energy to achieve thermal comfort has become a salient concern in the Global South, notably in emerging economies like India. This burgeoning need for cooling solutions has not only underscored the vital role of energy consumption but has also accentuated the imperative of comprehending the ensuing implications for electricity policy and strategic planning, particularly within the ambit of the Global South. This study explored the nuanced landscape of active cooling within an intentional community, Auroville, in southern India, aiming to discern the factors underpinning household preferences and practices in the pursuit of thermal comfort. Employing a mixed-methods approach, this study contributed empirically and methodologically to the interdisciplinary discourse by analysing residential electricity consumption patterns and cooling practices within selected households in the specified community. The study unfolded in three methodological stages: firstly, an analysis of climatic data coupled with an environmental stress index (ESI) assessment; secondly, the monitoring of end-user electricity consumption followed by rigorous data analysis; and lastly, the utilisation of qualitative in-depth interviews and observational techniques. This study’s outcome yielded empirical insights into the unprecedented shifts in the ESI for Auroville since 2014. Furthermore, the study unravelled the intricate complexities inherent in occupant behaviour within residential structures, thereby offering valuable insights into the practices that shape householders’ cooling preferences. This research enriched the understanding of the dynamics of energy consumption in the pursuit of thermal comfort and contributes to the broader discourse on sustainable development and energy policy in the context of climate change. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ₄₀ and Aβ₄₂, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ₄₀, indicating why trimming of this substrate is so infrequent. Full article

Systemic chronic inflammation (SCI) due to intrinsic immune over-activation is an important factor in the development of many noninfectious chronic diseases, such as neurodegenerative diseases and diabetes mellitus. Among these immune responses, macrophages are extensively involved in the regulation of inflammatory responses by virtue of their polarization plasticity; thus, dysregulation of macrophage polarization direction is one of the potential causes of the generation and maintenance of SCI. High-temperature demand protein A2 (HtrA2/Omi) is an important regulator of mitochondrial quality control, not only participating in the degradation of mis-accumulated proteins in the mitochondrial unfolded protein response (UPRmt) to maintain normal mitochondrial function through its enzymatic activity, but also participating in the regulation of mitochondrial dynamics-related protein interactions to maintain mitochondrial morphology. Recent studies have also reported the involvement of HtrA2/Omi as a novel inflammatory mediator in the regulation of the inflammatory response. HtrA2/Omi regulates the inflammatory response in BMDM by controlling TRAF2 stabilization in a collagen-induced arthritis mouse model; the lack of HtrA2 ameliorates pro-inflammatory cytokine expression in macrophages. In this review, we summarize the mechanisms by which HtrA2/Omi proteins are involved in macrophage polarization remodeling by influencing macrophage energy metabolism reprogramming through the regulation of inflammatory signaling pathways and mitochondrial quality control, elucidating the roles played by HtrA2/Omi proteins in inflammatory responses. In conclusion, interfering with HtrA2/Omi may become an important entry point for regulating macrophage polarization, providing new research space for developing HtrA2/Omi-based therapies for SCI. Full article

Calciprotein particles (CPPs) are indispensable scavengers of excessive Ca²⁺ and PO₄³⁻ ions in blood, being internalised and recycled by liver and spleen macrophages, monocytes, and endothelial cells (ECs). Here, we performed a pathway enrichment analysis of cellular compartment-specific proteomes in primary human coronary artery ECs (HCAEC) and human internal thoracic artery ECs (HITAEC) treated with primary (amorphous) or secondary (crystalline) CPPs (CPP-P and CPPs, respectively). Exposure to CPP-P and CPP-S induced notable upregulation of: (1) cytokine- and chemokine-mediated signaling, Ca²⁺-dependent events, and apoptosis in cytosolic and nuclear proteomes; (2) H⁺ and Ca²⁺ transmembrane transport, generation of reactive oxygen species, mitochondrial outer membrane permeabilisation, and intrinsic apoptosis in the mitochondrial proteome; (3) oxidative, calcium, and endoplasmic reticulum (ER) stress, unfolded protein binding, and apoptosis in the ER proteome. In contrast, transcription, post-transcriptional regulation, translation, cell cycle, and cell–cell adhesion pathways were underrepresented in cytosol and nuclear compartments, whilst biosynthesis of amino acids, mitochondrial translation, fatty acid oxidation, pyruvate dehydrogenase activity, and energy generation were downregulated in the mitochondrial proteome of CPP-treated ECs. Differentially expressed organelle-specific pathways were coherent in HCAEC and HITAEC and between ECs treated with CPP-P or CPP-S. Proteomic analysis of mitochondrial and nuclear lysates from CPP-treated ECs confirmed bioinformatic filtration findings. Full article