Curcumin, found in the rhizome of turmeric, has extensive therapeutic promises via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown curcumin to be an effective treatment for multiple cancers. These effects are drived by curcumin's ability to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptotic pathways, disruption of molecular signaling, inhibition of invasion and metastasis, and by increasing the efficacy of existing chemotherapeutics. Here we focused on the hormetic behaviour of curcumin. Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress whereas high dose activates acute responses like autophagy and cell death. This phenomenon is referred to as hormesis. Many molecules that cause cell death elicite an initial autophagic step that is a cytoprotective mechanism relying on elimination of dysfunctional structures intracellular, notably by mitophagy. This phenomenon is considered as a primarily protective mechanism against stressors. At higher doses, cells undergo mitochondrial outer membrane permeabilization due to calcium release from the endoplasmic reticulum and die. Herein, we address the complex crosstalk between the induced mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy and cell death that can also be at play.

It has been proposed that procedures which up-regulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones, may prevent the development of several heart diseases. A member of serine and threonine kinases, AMPK, could play essential roles in the autophagy and/or mitophagy. AMPK is widely distributed in various cells, which might play diverse regulatory roles in different tissues and/or organs. In fact, changes in the kinase function of AMPK due to alteration of activity have been linked with diverse pathologies including cardiac disorders. AMPK can regulate mitochondrial biogenesis via PGC1α signaling and also improve oxidative mitochondrial metabolism through inhibition of mTOR pathway, which may also modulate the autophagy/mitophagy through ULK1 and/or TGF-β signaling. Therefore, the modulation of AMPK in autophagy/mitophagy pathway might be considered as a therapeutic tactic for several cardiac disorders. As kinases are amongst the most controllable proteins, in general, the design of small molecules targeting kinases might be an eye-catching avenue to modulate the cardiac function. Some analyses of the molecular biology underlying mitophagy suggests that nutraceuticals and/or drugs including specific AMPK modulator as well as physical exercise and/or dietary restriction that could modulate AMPK may be useful against several heart diseases. In particular, some nutraceutical regimens may have encouraging potential for controlling some of cardiac disorders.

Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked with defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of altered mitochondrial dynamics in pancreatic β cells using ge-netic/pharmacologic approaches, and how these affect insulin secretion.

As the most active plateau on the Earth, the Qinghai-Tibet Plateau has a complex crust-mantle structure. Knowledge of the distribution of such a structure provides information for understanding the underlying geodynamic processes. We obtains a three-dimensional density model of crustal and upper mantle beneath Qinghai-Tibet plateau and its surrounding areas from the residual geoid anomalies using the Earth Gravitational Model (EGM) 2008. We estimate a refined density model by iterations, using an initial density contrast model. We confirm that the EGM2008 mission products can be used to constrain the crust-mantle density structures. Our major findings are: (1). At 300-400 km depth, high-D anomalies terminate around Jinsha River Suture (JRS) in the central TP, suggesting that the Indian plate has been reached over the Bangong Nujiang Suture (BNS) and almost reach to the JRS. (2). On the eastern TP, low-D anomalies at the depth of 0-300 km together with high-D anomalies at 400-670 km further verified the current eastward subduction of Indian plate. The ongoing subduction provides forces to the occurrences of frequent earthquakes and volcano. (3). At 600 km depth, low-D anomalies inside the TP illustrate the existence of hot weak material beneath there, contributing to the external material inward-thrusting.

Biohydrogen is a versatile energy carrier for the generation of electric energy from renewable sources. Hydrogenases can be used in enzymatic fuel cells to oxidize dihydrogen. The rate of electron transfer (ET) at the anodic side between the [NiFe]-hydrogenase enzyme distal iron-sulfur cluster and the electrode surface can be described by the Marcus equation. All parameters for the Marcus equation are accessible from DFT calculations. The distal cubane FeS-cluster has a three cysteine and one histidine coordination [Fe₄S₄](His)(Cys)₃ first ligation sphere. The reorganization energy (inner- and outer-sphere) is almost unchanged upon a histidine-to-cysteine substitution. Differences in rates of electron transfer between the wild-type enzyme and the all-cysteine mutant can be rationalized by a diminished electronic coupling between the donor and acceptor molecules in the [Fe₄S₄](Cys)₄ case. The fast and efficient electron transfer from the distal iron-sulfur cluster is realized by a fine-tuned protein environment which facilitates the flow of electrons. This study enables the design and control of electron transfer rates and pathways by protein engineering.

Mitochondria are highly dynamic organelles that continuously change their shape. Their main function is ATP production; however, they are additionally involved in a variety of cellular phenomena, such as apoptosis, cell cycle, proliferation, differentiation, reprogramming, and aging. The change in mitochondrial morphology is closely related to the functionality of mitochondria. Normal mitochondrial dynamics are critical for cellular function, embryonic development, and tissue formation. Thus, defect in proteins involved in mitochondrial dynamics that control mitochondrial fusion and fission can affect cellular differentiation, proliferation, cellular reprogramming, and aging. Here we review the processes and proteins involved in mitochondrial dynamics and its various associated cellular phenomena.

Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Recent studies have implicated mitophagy in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here, we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.

Salmonella is the intracellular pathogen and etiological known for the cause of asymptomatic carriage, gastroenteritis, systemic disease (typhoid fever), in severe cases death may also occur. Altered function of mitochondria due to Salmonella infection impacts the immune response. Mitochondria which are recognized as the “powerhouse” of the cells are also know to play central role in the immune metabolism. Mitochondrial dynamics such as fusion, fission, signaling, transport and mitophagy influences the immune system and also maintains the cellular integrity. Mitochondrial DNA and Reactive oxygen species formation also elicits the inflammatory responses. This review discusses the immune metabolism and effect of altered mitochondrial dynamics in case of Salmonella infection.

The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization.

The information of seismic damage of buildings in SAR images of different time phase, especially in SAR images after earthquake, is easily disturbed by other factors, which affects the accuracy of information discrimination. In order to identify and evaluate the distribution information of the seismic damage accurately and make full use of the abundant texture features in the SAR image. The conventional method of change detection based on texture features usually takes the pixel as the calculating unit. In this paper, a method of texture feature change detection of SAR images based on watershed segmentation algorithm is proposed. Based on the optimization of texture feature parameters, the feature parameters are segmented by the watershed segmentation algorithm, and the feature object image is obtained. This method introduces the idea of object oriented, and carries out the calculation of the difference map at the object level, Finally, the classification threshold value of different types of seismic damage types is selected, and the recognition of building damage is achieved. Taking the ALOS data before and after the earthquake in Yushu as an example to verify the effectiveness of the method, the overall accuracy of the building extraction is 88.9%, Compared with pixel-based methods, it is proved that the proposed method is effective.

Food systems will need to undergo considerable transformation. To be better prepared for and resilient to uncertainty and disturbances in the future, resource users and managers need to further develop knowledge about the food and farming system, with its dominating feedback structures and complexities, and to test robust and integrated system-based solutions. This paper investigates how participatory system dynamics modeling can be adapted to groups at the community level with low or no formal educational background. The paper also analyzes the refinement of workshop participants’ mental models as a consequence of a participatory system dynamics intervention. For this purpose, we ran two workshops with small-scale farmers in Zambia. Analysis of workshop data and post-workshop interviews shows that participatory system dynamics is well adaptable to support an audience-specific learning-by-doing approach. The use of pictures, objects and water glasses in combination with the basic aspects of causal loop diagramming makes for a well-balanced toolbox. Participants acquire understanding that is also relevant beyond systems thinking in that is offers a range of practical insights such as a critical evaluation of common food security strategies.

Glioblastoma is a central nervous system cancer type with a poor prognosis. One of its main features is the constant change of metabolism phenotype to support its development and progression. Mitochondria play a critical role in cellular metabolism. Acetylation on lysine residues of mitochondrial enzymes is a mechanism for regulating protein function. This modification negatively affects the mitochondrial proteome function and is counteracted by the enzyme sirtuin 3 (SIRT3). To better understand how SIRT3 regulates mitochondrial metabolism, we inhibited SIRT3 and examined by high-resolution mass spectrometry analysis the proteome and acetylome of two glioblastoma cell lines with different metabolic preferences. Our results indicate that protein synthesis machinery is regulated by lysine acetylation and plays a role in the metabolic phenotype. We also identified new SIRT3 targets not previously associated with specific functions, highlighting their potential as future targets for further study. This study shed light on the role of SIRT3 in mitochondria and its implication for cellular metabolism. We have generated knowledge at the proteome and acetylome levels on the dynamics between two glioblastoma cell lines with opposing metabolic phenotypes. Our results might guide in searching for biomarkers at both proteome and acetylome levels in glioblastoma.

Ischemia/reperfusion (I/R) injury results in cell death by inducing apoptosis. During I/R, early generation of mitochondrial reactive oxygen species (mtROS) can induce neighboring mitochondria to release additional ROS, a toxic cycle resulting in significant mitochondrial and cellular injury. Oxidative damage in the mitochondria contributes to various pathologies, including I/R injury. Accordingly, preventing mitochondrial oxidative damage should be therapeutically relevant for many disorders, including cardiovascular diseases. We recently discovered an Indole-Peptide-Tempo Conjugate (IPTC) that served as a novel bifunctional agent with both antioxidant and autophagy-modulating capacity. Here, we demonstrate that IPTC can protect H9C2 cardiomyocytes from hypoxia/reoxygenation (H/R) injury that results from mtROS overproduction due to impaired mitophagy and resultant mitochondrial dysfunction. We hypothesize that the mechanism of action of IPTC involves the capacity to decrease mtROS combined with induction of mitophagy.

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo Rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the Rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with Rapamycin (10 ng/ml) for 1 hour before LPS. In contrast, Rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo Rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of Rapamycin treated DCs to WT recipients 24 hrs before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/ml) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

Equine metabolic syndrome (EMS) is a major health threat in veterinary endocrinology medicine worldwide, and there is growing interest in utilizing molecular agents for modulation of hepatocyte function for potential clinical applications with recent studies showing promising results in the inhibition of PTP1B on adipose-derived stromal cells. In this study, we investigated the effects of MSI-1436 on equine hepatic progenitor cells (HPCs) in terms of their proliferative activity, glucose uptake, and mitochondrial morphogenesis under lipotoxic condition. Our study found that MSI-1436 promotes the entry of HPCs in the cell cycle and rescues them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the morphological architecture of the cells. Additionally, our findings suggest that MSI-1436 enhances the 2-NBDG internalization by increasing the expression of SIRT1, which is associated with liver insulin sensitivity, and promotes mitochondrial dynamics by modulating their number and morphotype through PINK1, MFN1, and MFN2 increased expression. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in the treatment of EMS and insulin dysregulation.

Lifespan extension was recently achieved in Caenorhabditis elegans nematodes by mitochondrial stress and mitophagy, triggered via iron depletion. Conversely in man, deficient mitophagy due to Pink1/Parkin mutations triggers iron accumulation in patient brain and limits survival. We now aimed to identify murine fibroblast factors, which adapt their mRNA expression to acute iron manipulation, relate to mitochondrial dysfunction and may influence survival. After iron depletion, expression of the plasma membrane receptor Tfrc with its activator Ireb2, the mitochondrial membrane transporter Abcb10, the heme-release factor Pgrmc1, the heme-degradation enzyme Hmox1, the heme-binding cholesterol metabolizer Cyp46a1, as well as the mitophagy regulators Pink1 and Parkin showed a negative correlation to iron levels. After iron overload, these factors did not change expression. Conversely, a positive correlation of mRNA levels with both conditions of iron availability was observed for the endosomal factors Slc11a2 and Steap2, as well as for the iron-sulfur-cluster (ISC)-containing factors Ppat, Bdh2 and Nthl1. Positive correlation only after iron depletion was observed for the iron export factor Slc40a1, mitochondrial iron transporters Slc25a28, Abcb7 and Abcb8, mitochondrial ISC-containing factors Glrx5, Nfu1, Bola1 and Abce1, cytosolic Aco1 and Tyw5, as well as nuclear Dna2, Elp3, Pold1 and Prim2. The latter are regulators of nucleotide synthesis and DNA quality control, which have known importance for growth and lifespan. The only Pink1-/- triggered transcript modulation was the reduced expression of the ISC-containing ribosomal factor Abce1. These mammalian findings support previous fly data that Pink1 influences co-translational quality control via Abce1, as well as mitophagy. Our findings provide the first systematic survey how iron dosage triggers homeostatic transcriptional regulations and elucidate how iron deprivation results in mitophagy.

ND1 subunit possesses the majority of the inhibitor binding domain of the human MRC-I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-THF acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate the molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, QM optimizations, MD simulations and MM/PBSA analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger BFE compared to the rotenone complex. Detailed analysis of the BFE shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of MRC-I.

Stueckelberg-Horwitz-Piron (SHP) electrodynamics formalizes the distinction between coordinate time (measured by laboratory clocks) and chronology (temporal ordering) by defining 4D spacetime events x^μ as functions of an external evolution parameter τ. Classical spacetime events x^μ (τ) evolve as τ grows monotonically, tracing out particle worldlines dynamically and inducing the five U(1) gauge potentials through which events interact. Since Lorentz invariance imposes time reversal symmetry on x⁰ but not τ, the formalism resolves grandfather paradoxes and related problems of irreversibility. The action involves standard first order field derivatives but includes a higher order τ derivative that while preserving gauge and Lorentz invariance removes certain singularities and makes the related QFT super-renormalizable. The resulting field equations are Maxwell-like but τ-dependent and sourced by a current that represents a statistical ensemble of instantaneous events distributed along the worldline. The width λ of this distribution defines a correlation time for the interactions and a mass spectrum for the photons that carry the interaction. As λ becomes very large, the photon mass goes to zero and the field equations become τ-independent Maxwell’s equations. Maxwell theory thus emerges as an equilibrium limit of SHP, in which λ is larger than any other relevant time scale. Particles and fields are not constrained to mass shells in SHP theory, and by exchanging mass may produce pair creation/annihilation processes at the classical level. On-shell evolution with fixed particle masses is restored through a self-interaction associated with the 5D wave equation.

In patients with heart failure, the evaluation of left ventricular (LV) diastolic function is vital, offering crucial insights into hemodynamic impact and prognostic accuracy. Echocardiography stands as the primary imaging modality for diastolic function assessment, and using it effectively requires a profound understanding of the underlying pathology. This review covers four main topics: first, the fundamental driving forces behind each phase of normal diastolic dynamics, along with the physiological basis of two widely used echocardiographic assessment parameters, E/e' and mitral annulus early diastolic velocity (e'); second, the intricate functional relationship between the left atrium and LV in patients with varying degrees of LV diastolic dysfunction (LVDD); third, the role of stress echocardiography in diagnosing LVDD and the significance of parameter changes in this context; and fourth, the clinical utility of evaluating diastolic function from echocardiography images across diverse cardiovascular care areas.

Cancer cells show an increased glutamine consumption. The glutaminase (GLS) enzyme controls a limiting step in the glutamine catabolism. Breast tumors, especially the triple negative subtype, have a high expression of GLS. Our recent study demonstrated that GLS activity and ammonia production are inhibited by Sirtuin 5 (SIRT5). We have developed MC3138, a selective SIRT5 activator. Treatment with MC3138 mimicked the deacetylation effect mediated by SIRT5 overexpression. Moreover, GLS activity is regulated by inorganic phosphate (Pi). Considering the interconnected role of GLS, SIRT5 and Pi for cancer growth, our hypothesis is that activation of SIRT5 and reduction of Pi could represent a valid anti-tumoral strategy. Treating cells with MC3138 and lanthanum acetate, a Pi chelator, decreased cell viability and clonogenicity. We also observed a modulation of LC3 and ULK1 with MC3138 and lanthanum acetate. Interestingly, inhibition of mitophagy marker BNIP3 was observed only in the presence of MC3138. Such autophagy and mitophagy modulation was accompanied by an increase of cytosolic and mitochondrial reactive oxygen species (ROS). In conclusion, our results show how SIRT5 activation and/or Pi binding can represent a valid strategy to inhibit cell proliferation by reducing glutamine metabolism and mitophagy leading to a deleterious accumulation of ROS.

In this paper we introduce a computational model for the simulation of hypervelocity impact (HVI) phenomena which is based on the Discrete Element Method (DEM). Our paper constitutes the first application of DEM to the modeling and simulating of impact events for velocities beyond 5 kms⁻¹. We present here the results of a systematic numerical study on HVI of solids. For modeling the solids, we use discrete spherical particles that interact with each other via potentials. In our numerical investigations we are particularly interested in the dynamics of material fragmentation upon impact. We model a typical HVI experiment configuration where a sphere strikes a thin plate and investigate the properties of the resulting debris cloud. We provide a quantitative computational analysis of the resulting debris cloud caused by impact and a comprehensive parameter study by varying key parameters of our model. We compare our findings from the simulations with recent HVI experiments performed at our institute. Our findings are that the DEM method leads to very stable, energy–conserving simulations of HVI scenarios that map the experimental setup where a sphere strikes a thin plate at hypervelocity speed. Our chosen interaction model works particularly well in the velocity range where the local stresses caused by impact shock waves markedly exceed the ultimate material strength.

Obtaining a genetic diagnosis of a primary mitochondrial disease (PMD) is often framed as a diagnostic odyssey. Yet, even after receiving a diagnosis, parents of affected children experience ongoing therapeutic and prognostic uncertainty, and considerable psychosocial challenges. Semi-structured interviews (N= 24) were conducted with parents of 13 children (aged 2-19 years) with a genetically confirmed PMD. Paternal (N=11) and maternal (N=13) perspectives were obtained, and thematic analysis performed on all interviews. A genetic diagnosis was valuable and empowering for parents, despite eliciting varied emotional responses. While the diagnosis helped focus management decisions, families often felt overwhelmed and unsupported in navigating the healthcare system. Most parents reported a serious impact on their romantic relationship. The sources of social support varied with a preference for established friendship and family support networks over disease-specific community support groups. Most parents favored prenatal genetic testing in the event of a future pregnancy. This study provides insight into the lived experiences of parents after a genetic diagnosis of PMD in their children. The findings draw awareness to supportive care needs and highlight important gaps that should be addressed to ensure that parents feel supported within a holistic framework of management for PMDs.

This work presents a novel approach for the study of the movement of droplets on inclined surfaces under the influence of gravity and chemical heterogeneities. The developed numerical methodology uses data-driven modeling to extend the applicability limits of an analytically derived reduced-order model for the contact line velocity. More specifically, while the reduced-order model is able to capture the effects of the chemical heterogeneities to a satisfactory degree, it does not account for gravity. To alleviate this shortcoming, datasets generated from direct numerical simulations are used to train a data-driven model for the contact line velocity, which is based on the Fourier neural operator and corrects the reduced-order model predictions to match the reference solutions. This hybrid surrogate model, which comprises of both analytical and data-driven components, is then integrated in time to simulate the droplet movement, offering a speedup of five orders of magnitude compared to direct numerical simulations. The performance of this hybrid model is quantified and assessed in different wetting scenarios, by considering various inclination angles and values for the Bond number, demonstrating the accuracy of the predictions as long as the adopted parameters lie within the ranges considered in the training dataset.

Interactions between receptors and ligands of the tumor necrosis factor superfamily (TNFSF) provide costimulatory signals that control the survival, proliferation, differentiation, and effector function of immune cells. All components of the TNF superfamily are associated with NF-kB functions that are not limited to cell death and may promote survival in the face of adipose tissue inflammation in obesity. Inflammation and pro-inflammatory dysfunction of mitochondria are key factors associated with insulin resistance in obesity. The aim of the study was to analyze the relationship of soluble forms of receptors and ligands of the TNF superfam-ily in blood plasma with mitochondrial dynamics in adipose tissue (greater omentum (GO) and subcutaneous adipose tissue (Sat)) of obese patients with and without type 2 diabetes mellitus (T2DM). Increased plasma sTNF-R1, sTNF-R2, sTNFRSF8 receptors and ligands TNFSF12, TNFSF13, TNFSF13B are characteristic of obese patients without T2DM. Increases in TNFSF12, TNFSF13B, and sTNF-R1 levels are associated with decreased glucose concentration and decreased BMI in obese patients. The gene expression levels responsible for regulating mitochondrial dynamics were increased in obese patients without T2DM and were unbalanced in patients with obesity and T2DM.

Sodium butyrate (NaB) is one of the short-chain fatty acids and is notably produced in large amounts from dietary fiber in the gut. Recent evidence suggests that NaB induces cell proliferation and apoptosis. The skeletal muscle is rich in plenty of mitochondrial. However, it is unclear how NaB acts on host muscle cells and whether it is involved in mitochondria-related functions in myocytes. The present study aimed to investigate the role of NaB treatment on the proliferation, apoptosis, and mitophagy of bovine skeletal muscle satellite cells (BSCs). The results showed that NaB inhibited the proliferation and promoted apoptosis of BSCs, and promoted mitophagy in a time and dose-dependent manner in BSCs. In addition, 1mM NaB increased the mitochondrial ROS level, decreased the mitochondrial membrane potential (MMP), increased the number of autophagic vesicles in mitochondria, and increased the mitochondrial DNA(mtDNA) and ATP level. The effects of the mTOR pathway on BSCs were investigated, and the results showed that 1mM NaB inhibited the mRNA and protein expression of mTOR and genes AKT1, FOXO1, and EIF4EBP1 in the mTOR signaling pathway, while the addition of PP242, an inhibitor of the mTOR signaling pathway, also inhibited mRNA and protein expression levels of mTOR, AKT1, FOXO1, and EIF4EBP1, and promoted mitophagy and apoptosis, which were consistent with the effect of NaB treatment. In conclusion, NaB might promote mitophagy and apoptosis in BSCs by inhibiting the mTOR signaling pathway. Our results would expand the knowledge of sodium butyrate on bovine skeletal muscle cell state and mitochondrial function.

Fibroin-chitosan composites, especially those containing nanohydroxyapatite, show potential for bone tissue regeneration. The physicochemical properties of these biocomposites depend on the compatibility between their components. In this study, the intermolecular interactions of fibroin and chitosan were analyzed using a molecular dynamics approach. Two types of systems were investigated: one containing acetic acid and the other containing calcium (Ca²⁺) and hydrogen phosphate (HPO₄²⁻) ions mimicking hydroxyapatite conditions. After obtaining the optimal equilibrium structures, the distributions of several types of interactions including hydrogen bonds, ionic contacts, and hydrophobic contacts along with the structural and energetical features were examined. The calculated binding energy values for the fibroin-chitosan complexes confirm their remarkable stability. The high affinity of fibroin for chitosan can be explained by the formation of a dense network of interactions between considered biopolymers. These interactions were found to be primarily hydrogen bonds and ionic contacts involving ALA, ARG, ASN, ASP, GLN, GLU, GLY, LEU, PRO, SER, THR, TYR, and VAL residues. As it was established, the complexation of fibroin with chitosan maintains the β-sheet conformation of the peptide. β-Sheet fragments in fibroin are involved in the formation of significant amount of hydrogen bonds and ionic contacts with chitosan.

The work proposes a backtesting analysis in comparison between the Lee-Carter and the Cairns-Blake-Dowd mortality models, employing Italian data. The mortality data come from the Italian National Statistics Institute (ISTAT) database and span the period 1975-2014, over which we computed back-projections evaluating the performances of the models in comparisons with real data. We propose three different backtest approaches, evaluating the goodness of short-run forecast versus medium-length ones. We find that both models were not able to capture the improving shock on the mortality observed for the male population on the analyzed period. Moreover, the results suggest that CBD forecast are reliable prevalently for ages above 75, and that LC forecast are basically more accurate for this data.

In mesoscale eddies, chemical properties and biological composition are different from those in surrounding water, due to their unique physical processes. It is unclear how physical-biological coupling occurs in warm-core eddies, particularly since no study has examined the relationship between bacteria and viruses. The purpose of the present study was to examine the influence of anticyclonic warm eddy on the relationship between bacterial and viral abundances as well as viral activity (viral production) in different depths. In the core of warm eddy, bacterial abundance (0.48 to 2.82 ×105 cells mL−1) fluctuated less than that of the outside eddy (1.12 to 7.03×105 cells mL−1). In particular, there was four-folds higher of viral-bacterial abundance ratio (VBR) estimated within the eddy below DCM than the outside eddy. We suggest that prevailing physical forces with downwelling at the center of the anticyclonic warm eddy, viruses can also be transmitted into the deep ocean directly through adsorption on particulate organic matter during sinking. Overall, our findings provide valuable insights into the interaction between bacterial and viral communities and their ecological mechanism within the warm eddy.

Objective: To investigate the effects and mechanisms of different concentrations of CCCP on mitophagy in human peripheral blood regulatory T cells. Methods: Tregs were isolated, identified and then grouped, treating with CCCP at a concentration of 2.5 μM, 5 μM, 10 μM, 20 μM and 40 μM for 24h in an incubator. Flow cytometry detected the reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial quality, and fluorescence microscopy observed the co-localization of mitochondria and lysosomes in each group. Results: The purity of CD4⁺CD25⁺Tregs was (93.36 ± 1.87) %. With the increase of CCCP concentration, the level of ROS gradually increased, while the MMP decreased gradually. About the mitochondria and lysosome fusion, the fluorescence intensity of orange (yellow) was the highest when the concentration of CCCP was in the range of 5-10 μM while decreased with the CCCP concentration continually increasing. The mitochondrial quality decreased with the increase of CCCP concentration. However, there was no significant difference between groups C, D and E. The mitochondrial quality of groups F and G were significantly lower than that of group E. Conclusions: With the concentration of CCCP gradually increased, the level of ROS in Treg cells increased, and MMP decreased, which promoted the mitophagy, mitochondrial quality maintains homeostasis; When ROS accumulated, and MMP decreased significantly, the mitophagy was inhibited, and the mitochondrial quality was significantly decreased.

In this paper, the boiling flow inside a nanochannel with 700000 argon particle has been simulated by molecular dynamics (MD) simulation. This approach has been employed to analysis the superheated flow and its heat transfer pattern as well. For all simulations an external thrust force varying from 1 PN to 12 PN is exerted on inlet nanoparticles along the channel to have the forced annular boiling flow. Computations reveal that saturation condition and superheat degree have significant impacts on the liquid-vapor interface. Furthermore, because of the major influence of surface tension throughout a nanochannel, the x-velocity of liquid film and vapor core has not considerable fluctuations and stay smooth. All provided results show the behaviors completely similar to the available outcomes in the literature.

This research investigates the complex transformation of the Baltic Clean and Dirty Tankers markets from 1998 to 2023. Our study quantifies the market multifractality in two distinct periods, from 1998 to 2010 and 2010 to 2023. We compare multifractal measures of the original, surrogated, and shuffled data, which indicate high multifractality and a complex market structure influenced by temporal organization and inherent volatility. Shuffled data analysis emphasizes the critical role of temporal sequences within market behaviour. Additionally, the study delves into external factors such as regulatory changes, economic disturbances, technological innovation, and environmental concerns contributing to market complexity. A distinct shift in multifractal values between the two periods suggests an evolution from crisis-induced complexities to a market influenced by diversified and modern dynamics. Our findings offer a concise understanding of the multifractal nature of the tanker markets and how global crises can impact the markets, emphasizing the importance of considering systemic risks in freight market analysis.

The study delves into the multifaceted landscape of human-macaque conflict within temple ecosystems, with a specific focus on Bonnet Macaques. In the context of intertwined religious, cultural, and social values, understanding public attitudes towards these commensal species becomes pivotal. The research aims to decipher the socio-economic factors that shape perceptions of human-monkey conflict within temples and to explore public attitudes within sacred groves. To achieve these objectives, a comprehensive questionnaire was administered through household interviews to 100 residents living within both a 1 sq. km and a 2 sq. km radius of the study area, ensuring direct participant interaction. The survey, taking approximately 40 minutes per participant, examined six variables, including occupation, religion, and annual income. The data collected was analysed using SPSS ver. 24 software, employing the chi-square test of independence to explore associations between categorical variables. The findings revealed that occupation and religion emerged as influential factors in shaping perceptions of Bonnet Macaques as problematic. While annual income hinted at significance, age, education, and knowledge of Kysannur Forest Disease (KFD) did not significantly impact Bonnet Macaque perception. Interestingly, age emerged as a significant factor influencing the perception of the monkeys' religious significance, whereas only education and religious affiliation impacted feeding practices towards the monkeys. Surprisingly, other demographic variables such as age, gender, occupation, and income showed no significant influence on monkey feeding practices. These results underscore the intricate interplay of socioeconomic, cultural, and religious factors in shaping public attitudes and behaviours towards Bonnet Macaques. The study further sheds light on the impact of education and religious affiliation on feeding practices, emphasizing the need for nuanced conservation strategies. Recognizing these complexities is crucial for developing culturally sensitive conservation efforts. By acknowledging the influential factors identified in this research, conservation strategies can be tailored to specific communities, fostering harmonious coexistence between humans and Bonnet Macaques in temple ecosystems. This nuanced approach ensures that conservation efforts are not only effective but also respectful of the diverse socio-cultural contexts within which they are implemented.

It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 minutes, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with reverse transcriptase (RT) real-time -PCR. At the time points of 15, 30, 45, and 60 minutes, as well as 3 and 24 hours of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 hours of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

This study examined the impact of differences in fruit load of olive trees on the rate of stem refilling. The experiment was conducted in a commercial olive orchard over the consecutive years of 2021 and 2022, during which the biennial bearing cycle of olive trees resulted in minimal fruit production in 2021 and maximal production in 2022. The rate of stem refilling was determined by quantifying the differences in water volume traversing the apex and base of the principal branches of experimental trees using sap flow sensors. Concurrent measurements of tree water status were also conducted using psychrometers, while soil moisture content dynamics were continuously recorded. Results indicate that alternate bearing significantly influences the stem refilling process, while soil moisture availability also plays a pivotal role. Water reserves were more intensively utilized during the year of full production (“ON” year) primarily to fulfill the water demands of developing fruits. This replenishment occurred in various periods during the day, including early morning, afternoon, and night, when stomatal conductance measurements indicated stomatal closure. The study suggests a more intense replenishment of reserves during the night in "ON" year trees, irrespective of soil moisture, water vapor pressure deficit, or phenological fruit development stage.

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently growing number of preclinical studies has revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among other. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to development of pathological conditions including neurological and psychiatric disorders. This narrative review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

The study of the concentrations and effects of fine particulate matter in urban areas have been of great interest to researchers in recent times. This is due to the acknowledgment of the far-reaching impacts of fine particulate matter on public health. Remote sensing data have been used to monitor the trend of concentrations of particulate matter by deriving aerosol optical depth (AOD) from satellite images. The Center for International Earth Science Information Network (CIESIN) has released the second version of its global PM_2.5 data with improvement in spatial resolution. This paper revisits the study of spatial and temporal variations in particulate matter in Saudi Arabia by exploring the cluster analysis of the new data. Cluster analysis of the PM_2.5 values of Saudi cities is performed by using Anselin local Moran’s I statistic. Also, the analysis is carried out at the regional level by using self-organizing map (SOM). The results show an increasing trend in the concentrations of particulate matter in Saudi Arabia, especially in some selected urban areas. The eastern and south-western parts of the Kingdom have significantly clustering high values. Some of the PM2.5 values have passed the threshold indicated by the World Health Organization (WHO) standard and targets posing health risks to Saudi urban population.

This research investigates the intricate dynamics between intellectual Capital (VAIC) and the stability of banks in the evolving context of Saudi Arabia's banking sector. Against the backdrop of rapid economic reforms under Vision 2030 and the challenges imposed by the COVID-19 pan-demic, the research provides a nuanced analysis of how intellectual capital and intellectual capital's components—Human Capital Efficiency (HCE), Structural Capital Efficiency (SCE), and Capital Employed Efficiency (CEE)—affect the financial stability of Saudi banks. The research analyses a decade-long panel dataset from 2012 to 2022, utilizing both fixed effects and cross-section random effects models to discern the impact of intellectual capital on bank stability. The findings reveal a positive overall influence of intellectual capital on bank stability; however, individual compo-nents present a complex relationship, with CEE showing a positive association and HCE and SCE demonstrating unexpected negative correlations with bank stability. The research identifies lev-erage (LEV) as a significant factor negatively impacting stability. Operational efficiency (OPEF) and size (SIZE) also negatively affect stability. Surprisingly, macroeconomic indicators and bank size exhibit non-significant effects on bank stability. Similarly, the direct impact of the COVID-19 pandemic was found to be non-significant, suggesting a resilient banking environment or the presence of effective mitigating strategies. As Saudi Arabia continues its ambitious economic transformation, this research underscores the critical role of effectively managed intellectual capital in ensuring the banking sector's stability. It provides a foundation for ongoing research in this vital area.

The three-pronged sliding universal coupling is a new kind of three-pronged coupling. To study its kinematic and dynamic characteristics, directional cosine matrices are utilized as tools to analyze the coordinate systems by establishing simplified geometric models and corresponding motions. Through the analysis of the motions of the input and output shafts and employing the method of single-force element, a set of equilibrium equations for the forces acting on the output shaft and the input shaft are formulated for solution analysis. The research indicates that during the rotation process, there exists a small angular difference between the input shaft and the intermediate shaft, demonstrating the quasi-constant angular velocity characteristics of the new tripod sliding universal coupling. The curves of the forces and torques acting on each component of the coupling approximate sinusoidal curves. The optimal operating angle range for the new tripod universal coupling is at angle , during which the system exhibits good transmission and mechanical performance.

Progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into risk factors and the time course of biomarker abnormalities point to a role for mitochondrial dysfunction and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD.

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible phenotypic and genetic diversity of mtD can be attributed at least in part to the RC dual genetic control (nuclear DNA [nDNA] and mitochondrial DNA [mtDNA]) and the complex interaction between the two genomes. Despite the increasing use of next-generation-sequencing (NGS) and various -omics platforms in unraveling novel mtD genes and pathomechanisms, current clinical practice for investigating mtD essentially involves a multipronged approach including clinical assessment, metabolic screening, imaging, pathological, biochemical and functional testing to guide molecular genetic analysis. This review addresses the broad muscle pathology landscape including genotype-phenotype correlations in adult and paediatric mtD, the role of immunodiagnostics in understanding some of the pathomechanisms underpinning the canonical features of mtD, and recent diagnostic advances in the field.

This study concerns the transport and retention of polydisperse micron-sized (16 ± 6 µm) of microplastics (MPls) in porous media under varying flow rate conditions. Sorption kinetics were modeled using first-order reversible and irreversible kinetic sorption models, with sensitivity analyses providing insights into each sorption parameter's effect. Both numerical modeling and experimental measurements were employed to assess sand filter retention rates. The impact of flow rate on sorption reveals variations in distribution coefficient (Kd), mass transfer coefficient (β), and irreversible sorption rate (K1). Lower flow rates are correlated with higher Kd and β values, indicating an increase in sorption and diminished mass transfer rates. The findings revealed that an increase in Kd resulted in a more gradual sorption process with a decrease in peak concentration, whereas changes in β influenced the rate of sorption and peak concentration to a lesser extent compared to Kd. Lower K1 values are associated with higher peak concentrations and decreased retention efficiency. Retention rates were evaluated by a numerical model and found as 28 ± 1% at a flow rate of 31 ml min⁻¹ and 17 ± 1% at 65 ml min⁻¹. The introduction of MPls into soil environments has been noted to modify transport dynamics into soil. As a result, these alterations effects hydrological characteristics of soil, thereby impacting quality of groundwater and agricultural output. The mean absolute error (MAE) of 6% between modeled and observed retention rates suggests minor discrepancies. This study highlights the importance of examining retention efficiency and the accuracy of numerical models in porous media during MPl transport.

Glaucomatous optic neuropathy, a major cause of blindness, is characterized by the loss of retinal gan-glion cells (RGCs) and degeneration of their axons. Mitochondria are deeply involved in maintaining RGCs and their axons. Therefore, lots of attempts have been made to develop diagnostic tools and therapies tar-geting mitochondria. Recently, we reported that mitochondria are uniformly distributed in unmyelinated axons of RGCs, possibly owing to the ATP gradient. Thus, using transgenic mice expressing yellow fluo-rescent protein targeting mitochondria exclusively in RGCs within the retina, we assessed the alteration of mitochondrial distributions induced by optic nerve crush (ONC) via in vitro flat-mount retinal sections and in vivo fundus images captured through the cornea with a confocal scanning ophthalmoscope. We observed that the mitochondrial distribution in unmyelinated axons of RGCs that survived the ONC remained uni-form, although their density increased. Furthermore, via in vitro analysis, we discovered that the mitochon-drial size is attenuated following ONC. These results suggest that ONC induces mitochondrial fission without disrupting the uniform mitochondrial distribution. This mechanism may help to prevent axonal degeneration and apoptosis. The in vivo visualization system of axonal mitochondria in RGCs may be ap-plicable in the diagnosis of progression of optic neuropathy.

Computational simulations of three-dimensional flow around a NACA 0018 wing with an aspect ratio of AR=5 are carried out using the Unsteady Reynolds-Averaged Navier-Stokes (URANS) equations with the Shear-Stress Transport turbulence model closure. Simulations were performed to capture the aerodynamic stall hysteresis using a developed Pseudo-Transient Continuation (PTC) method based on a dual time step approach in the CFD code OpenFOAM. The flow was characterized by an incompressible Mach number of M=0.12 and a moderate Reynolds number Re=0.67×10^6. The results obtained indicate the presence of a noticeable aerodynamic hysteresis in the static dependencies of the force and moment coefficients, as well as the manifestation of bi-stable flow separation patterns, accompanied by the development of asymmetry in the stall zone. The URANS simulation results are in good agreement with the experimental data obtained for the NACA 0018 finite aspect ratio wing from the low-speed wind tunnel under the same test conditions. A new phenomenological bifurcation model of aerodynamic stall hysteresis under static and dynamic conditions is formulated, which is proven to be able to closely match the experimental data.

Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Mitochondria are classically termed as powerhouse of a mammalian cell. Most of the cellular chemical energy in the form of adenosine tri phosphate (ATP) is generated by mitochondria and dysregulation of mitochondrial functions thus can be potentially fatal of cellular homeostasis and health. Acute respiratory distress has been earlier linked to mitochondrial dysfunction. SARS-CoV-2 infection severity leads to acute respiratory distress syndrome (ARDS) and can be fatal. We tried to investigate possible connection between SARS-CoV-2, ARDS and mitochondria. Here, we report identification of SARS-CoV-2 non-structural proteins (particularly Nsp12 and 13) that have recognition sequence with respect to mitochondrial entry. We also report that these proteins can potentially shuttle between cytoplasm and mitochondria based on the localization signals and help in downstream maintenance of the virus. Their properties to use ATP for enzymatic activities may cause ATP scavenging allowing viral RNA functions in lieu of host cell health.

Understanding the dynamics of Organic Carbon mineralization is fundamental in forecasting biosphere to atmosphere Net Carbon Ecosystem Exchange (NEE). With this perspective, we developed 3D-CMCC-PSM, a new version of the hybrid Process Based Model 3D‐CMCC FEM where also heterotrophic respiration (R_h) is explicitly simulated. The aim was to quantify NEE as a forward problem, by subtracting Ecosystem Respiration (R_eco) to Gross Primary Productivity (GPP). To do so, we developed a simplification of the Soil Carbon dynamics routine proposed in DNDC [1]. The method calculates decomposition as a function of soil moisture, temperature, state of the organic compartments, and relative abundance of microbial pools. Given the pulse dynamics of soil respiration, we introduced modifications in some of the principal constitutive relations involved in phenology and littering sub-routines. We quantified the model structure related uncertainty in NEE, by running our training simulations over 1000 random parameter-sets extracted from parameters distributions expected from literature. 3D-CMCC-PSM predictability was tested on independent time series for 6 Fluxnet sites. The model resulted in daily and monthly estimations highly consistent with the observed time series. It showed lower predictability in Mediterranean ecosystems, suggesting that it may need further improvements in addressing evapotranspiration and water dynamics.

The transition to sustainable energy systems in the Middle East and North Africa (MENA) region addresses critical challenges of environmental protection, energy security, and socio-economic resilience. Using neo-institutional theory, this paper examines the intricate relationship between formal and informal institutions and their significant impact on the region’s energy transition. Despite the MENA region’s abundant renewable energy resources, numerous institutional barriers, such as governance inefficiencies, regulatory inconsistencies, and entrenched socio-cultural norms, significantly hinder this transition. Through a review of existing literature, this study presents a comprehensive analytical framework designed to overcome these barriers, with a focus on the Just and Sustainable Energy Transition model. This strategic model emphasizes equity, sustainability, and inclusive governance as pillars for reform. The study offers detailed recommendations for institutional change and underscores the importance of collaborative efforts among governments, industry stakeholders, and international partners to unlock the MENA region’s renewable energy potential, advance global sustainability goals, and ensure a more secure and resilient energy future.

Background: Capsaicinoid are a group of compounds and widely used in the food, medical, and pharmaceutical industries. Capsaicinoid are unique synthesized and accumulated in the pepper fruits. MeJA can enhance the capsaicinoid production. Temporal and spatial expression of capsaicinoid biosynthetic genes are helpful to understand the molecular mechnism of capsaicinoid biosynthesis in the fruits of pepper. Although some of the capsaicinoid biosynthetic genes in pepper have been identified, the expression of these genes at different developing stages of fruit has not been systemically investigated, and little is known about the molecular basis of MeJA inducing capsaicinoid biosynthesis. Results: HPLC study revealed that the capsaicinoid accumulation in the developing fruit of pepper initially appeared at 24 DAP (day after pollination), was actively development at 36 DAP and peaked at 48 DAP. 11 genes that encoded enzymes involved in capsaicinoid biosynthesis were isolated and characterized. Gene expression with quantitative reverse-transcription polymerase chain reaction analysis demonstrated that the CaCS was unique expressed in placenta and the other 10 genes were expressed in all selected tissues and 9 of 11 genes (except CaCa4H and CaCa3H) were strongly expressed in placenta tissue. Spatial expression analysis demostrated that the 11 gene could be collectively grouped into four categories based on the patterns of relative expression of the genes during fruit development. Category I has 2 and they displayed a bell-shaped expression pattern with the peak expression at 24 DAP, Category II contains 5 genes and expression of the 5 genes was constantly increased from 0 to 36 DAP and peaked at 36 DAP. Category III comprises of 2 genes and both genes reached the peak at 48 DAP. Category IV consists of 2 genes and they showed a high expression at 36 and 48 DAF, but unexpressed from 0 to 12 DAP. The gene expressions of the 11 genes were up-regulated by MeJA. 3 genes showed a high expression at 24 h; 4 genes reached the peak at 12 h; the top expression were observed at 18 h; The last one, CaACYase, achieved the highest level at 8 h. Conclusion: The biosynthesis of capsaicinoid in pepper fruit is developmentally regulated. The expression of the majority of capsaicinoid biosynthetic genes is highly consistent with the development accumulation of capsaicinoid in pepper fruit. These results not only provide the initial information on spatial and temporal expression of capsaicinoid biosynthetic genes in pepper developing fruit, but are also valuable to identify the MeJA-induced genes for capsaicinoid biosynthesis and accumulation during pepper fruit development.

In today's context of rising sea levels and subsiding land topography, coastal flooding is a major concern for coastal areas, both nationally, regionally, and internationally. A detailed understanding of these two phenomena is a prerequisite for effective coastal flood management. The main objective of the present study is to contribute to the understanding of the impact of subsidence and sea-level rise on coastal flooding in Saint-Louis, and in particular the Langue de Barbarie, by producing a vulnerability map of submerged surfaces. To this end, the Synthetic Aperture Radar (SAR) interferometry technique is used to process a time series of Sentinel-1 images and estimate land subsidence in the Saint-Louis and Langue de Barbarie area. Interferometric SAR (InSAR) measurements are merged with RCP 2.6 sea-level rise scenarios to identify predicted flooded areas and provide a flood vulnerability map. At the Langue de Barbarie, topographic subsidence is estimated at between -6.4 and -0.4mm/year. In this study, we show that local land subsidence may increase vulnerability to flooding caused by sea-level rise based on 2100 projections. This may represent an increase in the flood zone in the study area. Based on the RCP 2.6 scenario and the subsidence rates obtained, a significant part of the St. Louis coastline and city would be subject to coastal and fluvial flooding for the years 2040 and 2100. For these dates, 29 to and 36 Km2 of the studied area would be occupied by water. Given this situation, research in Saint-Louis needs to focus on adaptation scenarios to coastal risks, to protect coastal communities and safeguard the city's historical heritage.

Retention of placenta (RP) in crossbred cattle poses health, reproductive, and economic challenges linked to oxidative stress, hormonal imbalances, and complex causative factors. Emphasizing the key role of mitochondria in oxidative phosphorylation (OXPHOS) and hormone synthesis, our study is the first to explore differences in OXPHOS activity, mitochondrial content, and mtDNA-encoded gene expression between normal and RP. In addition, gross morphological examination of placental tissues from both groups revealed noticeable disparities in cotyledons of RP as compared to normal placenta. Moreover, OXPHOS complex I specific activity was decreased in RP, and RT-qPCR analysis unveiled a significant reduction in transcript levels of 10 mtDNA-encoded protein genes. While COX3 and ATP8 genes showed no significant changes, ND6 increased in RP. Whereas, mtDNA copy number varied between animals but showed no statistically significant differences among groups. Retained placenta manifests alterations in the transcript levels of various mitochondrial genes, complex activity, and mtDNA content, potentially linked to heightened energy demands or mitochondrial insufficiency, posing an elevated risk. Overall, our study suggests a link between mitochondrial abnormalities, gene expression, and RP. This connection could influence the removal of fetal membranes by affecting energy supply, hormonal balance, and oxidative stress. This study also offers novel insights and serves as a valuable animal model for studying placental insufficiency in humans. Moving forward, comprehensive investigations are imperative to unravel underlying mechanisms and intricate roles of mitochondria in the context of RP, paving the way for targeted interventions to mitigate health, reproductive, and economic challenges in crossbred cattle.

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the OXPHOS system for ATP production. It requires, in addition, the import of thousands of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPR^mt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial PHB (prohibitin) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Nanoporous membranes promise energy-efficient water desalination. Hexagonal boron nitride (h-BN), like graphene, exhibits outstanding physical and chemical properties, making it a promising candidate for water treatment. We employed Car–Parrinello molecular dynamics simulations to establish accurate modeling of Na+ and Cl- permeation through hydrogen passivated nanopores in graphene and h-BN membranes. In these complex systems the classical potentials cannot properly account for the physics at play. We demonstrate that ion separation works well for the h-BN by imposing a barrier of 0.13 eV and 0.24 eV for Na+ and Cl- permeation respectively, compared to the graphene where the Cl- ion faces a negative barrier of 0.68 eV and is prone toward blockade and Na+ permeation is associated with a slightly negative barrier of 0.03 eV. From the change in the solvation shell, we get the following trend: Na/h-BN > Na/G > Cl/G > Cl/h-BN. We argue that the trend in the permeation barrier changes to Cl-h-BN > Na-h-BN > Na-G > Cl-G due to a combination of several interactions, including the distortion of the water network induced by the ions, the ion-water interaction, and the ion-nanopore interaction. Overall, the desalination performance of h-BN surpasses that of their graphene counterparts.

Climate warming is expected to have pronounced effects on Arctic and Subarctic ecosystems, especially regions underlain by discontinuous and relatively warm permafrost. The main goal of this research is to evaluate the vulnerability and dynamics of permafrost under climate warming across the various ecotypes in respect of ecosystem stability, socioeconomic impact, and for better understanding possible future environmental changes. We suggested the new version of the spatially distributed permafrost dynamics model (GIPL2-MPI), which is developed in the Geophysical Institute, University of Alaska Fairbanks. This model is based on the ecosystem approach to simulate the permafrost dynamics, which we are discussing in this paper. We combined ground-based observations and numerical freeze/thaw modeling using climate-ecosystem-permafrost interactions to understand the physical processes and mechanisms controlling permafrost physical state. We predict the changes in permafrost conditions using output from two GCMs (NCAR-CCSM4 and GFDL-CM3) and Five-Model Average Ensemble for the RCP-4.5 and RCP-8.5 scaled down to 1 by 1 km spatial resolution (https://uaf-snap.org/) across entire Alaska. Our result shows that by the end of the current century widespread near-surface permafrost degradation could begin everywhere in Alaska southward of the Brooks Range as well as across some spots at the North Slope Alaska.

Yerba maté, an herbal tea derived from Ilex paraguariensis, has previously been reported to be protective against obesity-related and other cardiometabolic disorders. Using high-resolution respirometry and reverse-phase high-performance liquid chromatography, the effects of four weeks of yerba maté consumption on mitochondrial efficiency and cellular redox status in skeletal muscle, adipose, and liver, tissues highly relevant to whole body metabolism, were explored in healthy adult mice. Yerba maté treatment increased mitochondrial oxygen consumption in adipose, but not in other tissues examined. Yerba maté increased ATP concentration in skeletal muscle and decreased ATP concentration in adipose. Combined with observed changes in oxygen consumption, these data yielded a significantly higher ATP:O2, a measure of mitochondrial efficiency, in muscle and a significantly lower ATP:O2 in adipose, which were consistent with yerba maté-induced weight loss. Yerba maté treatment also altered the hepatic glutathione (GSH)/glutathione disulfide (GSSG) redox potential to a more reduced redox state, suggesting potential protective effects against oxidative stress and preservation of cellular function. Together, these data indicate beneficial, tissue-specific effects of yerba maté supplementation on mitochondrial bioenergetics and redox states in healthy mice that are protective against obesity.

Small scale carp polyculture plays a key role for food supply in Bangladesh, however, factors including water pollution, limited infrastructure and inadequate disease management hinder its sustainability. This paper reports on a survey of 231 farmers across the 6 major carp producing regions in Bangladesh, analyzing factors including, farmers’ social aspects, farm characteristics, information on disease and approaches adopted to combat them, and biosecurity practices. Almost half (46.8%) of the farms surveyed experienced disease in carp species, with clear regional variations. Eighty four percent of farms reported carp mortalities during disease outbreak, with an average mortality level 10.23±11.81%. Clinical signs during outbreaks lasted between a week and a month, and there was a peak in disease outbreaks in two seasonal periods between June to July and October to December. Disease incidence was related to a range of factors including the farmer experience, ponds/farm type, stocked species, and biosecurity practice. A combination of disinfecting measures during pond preparation and measures during stocking, including discarding fingerling transport water off-farm, fingerling disinfection and check the health of fingerlings before stocking significantly reduced disease occurrence. Treatments involving the antibiotics, ciprofloxacin, erythromycin, and azithromycin were reported as ineffective, raising concerns about non-prudent use, inadequate dosing (perhaps without appropriate veterinary guidance) and the potential for further driving antimicrobial resistance in the environment. The research unveils a concerning pattern of disease high disease incidence across small-scale carp farms in Bangladesh and the significant potential for disease spread highlights the need for responsible disposal practices. The study emphasizes the need for improving training and awareness programs are vital for addressing biosecurity and disease management challenges, ensuring sustainable aquaculture and community well-being.

(1) Background: In this work, a series of benzimidazole derivatives containing colchicine-like and cathechol-like moieties with methyl group substitution in the benzimidazole ring were evaluated for their in vitro antiproliferative, pro-apoptotic and antioxidative activity against highly invasive breast cancer cell line MDA-MB-231 and related impairment of tubulin dynamics; (2) Methods: MTT assay was used to evaluate the antiproliferative activity. In vitro tubulin polymerization assay as well as docking analysis was applied to prove the alterations in tubulin polymerization. Immunofluorescent and DAPI staining reveal the pro-apoptotic potential of benzimidazole derivatives and the effect on tubulin’s dynamics in living cells. The antioxidant activity was evaluated by scavenging of H2O2 and hypochlorite ion and ortho-phenanthroline tests; (3) Results: The compounds containing colchicine-like moiety displayed significant growth inhibitory effect against cancer cell line as was highlighted the role of methyl functional group on the tubulin aggregation and blockage of mitosis. All compounds showed an ability to scavenge H2O2, while the compounds with cathecol-like moiety were more effective against hypochlorite ion and chelation of iron; (4) Conclusions: The benzimidazole derivative containing colchicine-like moiety and methyl group substitution in benzimidazole ring is a potential antiproliferative and microtubule destabilizing agent.

Cardiovascular disease (CVD), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disa-bility. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central, South America. Thirty percent of the cases evolve into chronic cardiomyopathy (CCC) with worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate and severe CCC patients. MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with Brazilian healthy individuals. The European lineage is associated to protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. By mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of Chronic Chagas disease Cardiomyopathy.

Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing more effective treatments. Current literature suggests toxins present in cigarette smoke and aerosolized e-vapor trigger abnormal intercellular responses, damage mitochondrial function, and consequently disrupt the homeostasis of the organelle’s biochemical processes by increasing reactive oxidative species. Increased oxidative stress sets off a cascade of molecular events, disrupting optimal mitochondrial morphology and homeostasis. Furthermore, smoking-induced oxidative stress may also amalgamate with other health factors to contribute to various pathophysiological processes. An increasing number of studies show that toxins may affect mitochondria even though exposure to secondhand or thirdhand smoke. This review assesses the impact of toxins present in tobacco smoke and e-vapor on mitochondrial health, networking, and critical structural processes including mitochondria fission, fusion, hyperfusion, fragmentation, and mitophagy. The efforts are focused on discussing current evidence linking toxins present in first, second, and thirdhand smoke to mitochondrial dysfunction

The activity of the mitochondrial Permeability Transition Pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging Reactive Oxygen Species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either, inhibit, or accelerate aging, retards, or enhance the progression of aging-driven degenerative diseases, and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Diseases. The Increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

Gelephu, located in the Himalayan region, has experienced one of the strongest development activities due to the suitable topography and geographic location, which has led to rapid urbanization. The main objective of the study is to perform land use land cover (LULC) mapping for Gelephu for 2016 and 2023 by a Random Forest (RF) classifier, using the Semi-automatic Classification Plugin (SCP) in QGIS and identify LULC changes. Furthermore, the study assessed the vegetation change dynamics within the study area by analysing the Normalized Difference Vegetation Index (NDVI) for 2016 and 2023. Additionally, the study characterized the resulting LULC change for Gelephu Thromde, a sub-administrative municipal entity, as a result of the notable intensity of the infrastructure development activities. The current study used a framework to collect Sentiniel-2 satellite data, which was then used for pre- and post-processing to create LULC and NDVI maps. The classification model achieved high accuracy, with an area under the curve (AUC) of up to 0.89. The corresponding LULC and NDVI statistics were analysed to determine the current status of the LULC and vegetation indices, respectively. The LULC change analysis reveals urban growth of 5.65% and 15.05% for Gelephu and Gelephu Thromde, respectively. The NDVI assessment shows significant deterioration in vegetation health with a 75.11% loss of healthy vegetation in Gelephu between 2016 and 2023. This research provides the first version of LULC and NDVI maps of Gelephu. The analysis results indicate possible future implications on sustainable development management in Gelephu Bhutan.

The hyper-arid environment is characterized by high inter-annual climatic fluctuations. The yearly average rainfall can change substantially for several years, forming wet or dry sub-periods. Observing rainfall trends over a sub-period can lead to a false perception of a change in the trend but may in fact represent a periodic cycle when examined on a larger time scale. We aimed to better characterize the rainfall regime prevailing in the hyper-arid Arava Valley (Israel/Jordan), and to examine the response of vegetation to annual rainfall. We hypothesized that annual and perennial vegetation would respond differently to wet and dry sub-periods, and that grazing activities will impact vegetation growth. We used a time series of monthly rainfall, from which we calculated Standard Precipitation Index (SPI), and calculated proxies of perennial and annual vegetation over the last four decades using Landsat-derived Normalized Difference Vegetation Index (NDVI). We found no clear trend in rainfall amounts during this period, however we did identify wet and dry sub-periods which were statistically distinct in rain and in vegetation patterns from each other. The highest levels of correlation between rainfall and the NDVI derived proxies were found when examining average rainfall over a period of two- three years for the annual vegetation and over four years for perennial vegetation. Using the Mann-Kendall test, we identified a time lag of two to four years, with the proxies of annual vegetation responding faster than the proxies of perennial vegetation, to shifts between wet and dry sub-period. In addition, we found a consistent difference between natural vegetation cover in Jordan (grazed) and Israel (non-grazed), favoring the development of natural vegetation on the Israeli side. We conclude that integrating between long-term remote sensing satellite imagery and climatic records revealed the greater resilience of perennial vegetation in the hyper-arid region to climatic fluctuation, and enabled us to identify the vegetation’s sensitivity to anthropogenic impact.

Mitochondrial introgression raises questions of biogeography, and extent of reproductive isolation and natural selection. Previous phylogenetic work on the Sorex araneus complex revealed apparent mitonuclear discordance in Iberian shrews indicating past hybridization of S. granarius and the Carlit chromosomal race of S. araneus, enabling introgression of the S. araneus mitochondrial genome into S. granarius. To further study this, we genetically typed 61 S. araneus/coronatus/granarius from localities in Portugal, Spain, France and Andorra at mitochondrial, autosomal and sex-linked loci, and combined our data with the previously published sequences. Our data are consistent with the earlier data that S. coronatus and S. granarius are the most closely related of the three species and confirm that S. granarius from the Central System mountain range in Spain captured the mitochondrial genome from a population of S. araneus. The mitochondrial capture event can be explained by invoking a biogeographical scenario whereby S. araneus was in contact with S. granarius during the Younger Dryas in central Iberia despite the two species currently having disjunct distributions. We discuss whether selection favoured S. granarius with an introgressed mitochondrial genome. Our data also suggest recent hybridization and introgression between S. coronatus and S. granarius and between S. araneus and S. coronatus.

Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical mitochondrial carrier family SLC25, the past decade led to the discovery of additional protein families that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins and mitochondrial cation/H+ exchangers that have been linked to vital physiological functions and disease. Their structures and transport mechanisms are still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combined sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanism and structure of these novel mitochondrial carriers.

Mitochondrial dysfunction is relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the heart of aged rats. The protein expression of selected mediators (i.e., mitochondrial antioxidant enzymes, energy metabolism, mitochondrial biogenesis, dynamics, and autophagy) was measured in old rats randomly assigned to receive enalapril (n=8) or placebo (n=8) from 24 to 27 months of age. We also assessed mitochondrial DNA (mtDNA) content, citrate synthase activity, oxidative lesions to protein and mtDNA (i.e., carbonyls and abundance of mtDNA4834 deletion), and mitochondrial transcription factor A (TFAM) binding to specific mtDNA regions. Enalapril attenuated cardiac hypertrophy and oxidative stress-derived damage (mtDNA oxidation, mtDNA4834 deletion, and protein carbonylation), while increasing mitochondrial antioxidant defenses. TFAM binding to mtDNA regions involved in replication and deletion generation was increased following enalapril administration. Increased mitochondrial mass as well as mitochondriogenesis and autophagy signaling was found in enalapril-treated rats. Late-life enalapril administration mitigates age-dependent cardiac hypertrophy and oxidative damage, while increasing mitochondrial mass and modulating MQC signaling. Further analyses are needed to conclusively establish whether enalapril may offer cardioprotection during aging.

This work is a top-level summary of several contributions published in the last three decades. It makes the case that complex dynamics of nonlinear systems lies at the heart of foundational physics.

This review investigates links between post-acute sequelae of SARS-CoV-2 infection (PASC), post-infection viral persistence, mitochondrial involvement and aberrant innate immune response and cellular metabolism during SARS-CoV-2 infection. Advancement of proteomic and metabolomic studies now allows deeper investigation of alterations to cellular metabolism, autophagic processes and mitochondrial dysfunction caused by SARS-CoV-2 infection while computational biology and machine learning have advanced methodologies of predicting virus-host gene and protein interactions. Particular focus is given to interaction between viral genes and proteins with mitochondrial function and that of the innate immune system. Finally, the authors hypothesise that viral persistence may be a function of mitochondrial involvement in sequestration of viral genetic material. While further work is necessary to understand the mechanisms definitively, a number of studies now point to resolution of questions regarding the pathogenesis of PASC.

‘Inner mitochondrial membrane peptidase 2 like’ (IMMP2L) is a nuclear encoded mitochondrial peptidase that has been conserved through evolutionary history as has its target enzyme ‘mitochondrial glycerol phosphate dehydrogenase 2’ (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear encoded mitochondrial respiratory related protein cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD-/- KO mouse and in this study EchoMRI analysis found that many organs of the Immp2lKD-/- KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p<0.05). Moreover, all of the organs analysed from the Immp2lKD-/- KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD-/- KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lower in the kidney of the Immp2lKD-/- KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to wildtype when glutamate was used as substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2 we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD-/- KO mice over time. Together these findings suggest that the respiratory related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues in the Immp2lKD-/- KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial encoded cytochrome b (Cyb) in Complex III had been altered as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD-/- KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS) which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD-/- KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD-/- KO mouse displayed a ~27% decrease in total respiration comprised of a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration where the latter was consistent with the decreases in substrate specific mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.

Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1 or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene results in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, Bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, ATP production, oxygen consumption and s improved mitochondrial morphology in patient’s fibroblasts, albeit concomitantly causing a mild increase ROS production. Further studies would be needed to show the consistency of the response to Bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that Bezafibrate could be a possible treatment option for patients with certain DNM1L mutations.

Mitochondrial dysfunction and oxidative stress are thought to be relevant to the pathogenesis of age-related macular degeneration (AMD). Glutathione (GSH) homeostasis fulfills a number of important roles in mitochondria, such as maintenance of mitochondrial DNA and respiratory competency of cells. Although the transport of mitochondrial GSH (mGSH) is not fully understood, increasing evidence from non-ocular tissues suggests that OGC (2-oxoglutarate carrier, SLC25A11) and DIC (dicarboxylate carrier, SLC25A10) are involved in mGSH transport. However, whether OGC and DIC mediate the transfer of GSH into the mitochondria of retinal pigment epithelial cells (RPE) remains unknown. Thus, we investigated the expression, localization, and function of OGC and DIC in human RPE (hRPE) in relation to oxidative stress and GSH. Both OGC and DIC are expressed in hRPE and are localized in mitochondria. We also found a dose and time-dependent decrease of OGC and DIC expression under oxidative stress and increased expression in polarized RPE. Our data show that the downregulation of OGC and DIC resulted in increased apoptosis and mGSH depletion which can be overcome by co-treatment with GSH-MEE. These findings suggest that overexpression of OGC and DIC may be an effective strategy to decrease susceptibility to mitochondrial toxicants by elevation of mGSH.

The main sources of intrinsic noise in excitable cells at the microcircuit and network levels are the stochastic characteristics of ion channel gating and activation of the synaptic conductance. Studies using in vivo, in vitro, and in silico methods to examine the effects of synaptic background activity were not adequately investigated in non-neuronal excitatory cells, where neurotransmitter-based innervation also occurs. We created a mathematical model to replicate the background synaptic noise dynamics in a non-neuronal cell. We utilized the stochastic Ornstein-Uhlenbeck process to represent excitatory synaptic conductance, which was incorporated into a whole-cell model to produce spontaneous and evoked cellular electrical activities. The single-cell model includes many biophysically detailed ion channels represented by a set of ordinary differential equations in Hodgkin-Huxley and Markov formalisms. This paradigm effectively induced irregular spontaneous depolarizations (SDs) and spontaneous action potential (sAP) resembling in vitro-like electrical activity in the cells. The input resistance decreased by multiple factors, and the spontaneous action potential firing rate elevated. The potential to reach the action potential threshold is altered. Background synaptic activity can alter the input/output characteristics of non-neuronal excitatory cells. Suppressing these baseline activities would facilitate the discovery of new pharmaceutical targets for different clinical diseases.

The APOE locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects, partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either up- or down-regulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes, possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.

Breast cancer has an important incidence in the worldwide female population. Although alterations in the mitochondrial genome probably play an important role in carcinogenesis, the actual evidence is ambiguous and inconclusive. The purpose of the present work was to explore mitochondrial sequences of clinical cases with breast cancer from different origins and determine the polymorphisms associated. The search for complete and partial mtDNA sequences obtained from breast cancer patients and controls was performed in NCBI Genbank database. We identified 124 mtDNA sequences associated to breast cancer cases of which 86 were complete and 38 partial sequences. Of these 86 complete sequences, 52 belong to patients with a confirmed diagnosis of breast cancer and 34 sequences were obtained from healthy mammary tissue of the same patients used as controls. From mtDNA analysis, two polymorphisms with significative statistical differences were found in D130 in sequences analyzed: m.310del (rs869289246) in 34.6% (27/78) breast cancer cases and 61.7% (21/34) of controls; and m.315dup (rs369786048) in 60.2% (47/78) of breast cancer cases and 38.2% (13/34) of controls. Also, the variant m.16519T>C (rs3937033) was found in 59% of control sequences and 52% of breast cancer sequences with a significant statistical difference. Polymorphic changes are evolutionarily related to haplogroup H of Indo-European and Euro Asiatic origins, however, were found in all non-European sequences with breast cancer.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the ‘dependence’ on the normal cells. This article illustrates the benefits of new, functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in cancer stem cells’ metabolism. This theory highlights the mitochondria in cancer biology and explains how targeted anti-mitochondrial treatments can improve oncological outcomes.

Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurological disorder, defined by progressive deterioration of the peripheral nerves. Clinical manifestations of CMT mutations are typically limited to peripheral neurons, the longest cells in the body. Currently, mutations in at least 80 different genes are associated with CMT and new mutations are regularly being discovered. A large portion of the proteins mutated in axonal CMT have documented roles in mitochondrial mobility. This suggests that trafficking defects may be a common underlying mechanism in CMT. This review will focus on the potential role of altered mitochondrial mobility in the pathogenesis of axonal CMT, highlighting the challenges and opportunities to this “impaired mobility” model of the disease.

Oligodendrocytes are myelinating cells of the central nervous system, which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, isolating them and facilitating nerve conduction through saltatory propagation. The myelination process requires the consumption of a lot of energy and a high metabolic turnover. Mitochondria are essential organelles which regulate many cellular functions including the energy production through oxidative phosphorylation. Any mitochondrial dysfunction impacts cellular metabolism and negatively affects the health of the organism. If the functioning of the mitochondria is unbalanced the myelination process is impaired. At the end of myelination, oligodendrocytes synthesize about 40% of the total lipids present in the brain. Since lipid synthesis occurs in the cellular endoplasmic reticulum, the alteration of this organelle can lead to partial or deficient myelination, triggering numerous neurodegenerative diseases. In this review the main dysfunctions of oligodendrocytes caused by exogenous or endogenous stimuli will be investigated. Furthermore, the oligodendrocyte reactions to excessive mitochondrial oxidative stress and an altered regulation of the functioning of the endoplasmic reticulum will be discussed.

Autism has been described as a gastrointestinal and neurological condition that is represented by impairments in language and social situations. Recently reported increases in the occurrence of Autism Spectrum Disorder (ASD) have resulted in increased research into the environmental differences between areas with a high occurrence, as in the “Western” diet populations, and a more locally derived diet population, wherein the rate appears to be significantly less. Thirty autistic children (USA) ages 6 to 21, were sampled at three different intervals: prior to any intervention, post-xylitol intervention, and post-probiotic intervention. The sampling consisted of buccal swabs for MITOSWAB testing, and saliva for metatranscriptomics to determine the entire range of microorganisms and the metabolome. In addition, a “Blue Zone” subject component that included 30 Colombian children, ages 6-16, and who were healthy and within normal behavior standards, also had buccal swabbing and salivary sampling performed for comparison along with 30 healthy (no history medications, illnesses, or behavior issues) USA children matched for age and gender. Saliva samples were analyzed metatranscriptomically and artificial intelligence was utilized to discern important differences in the microbiome that included bacteria, archaea, fungi, and viruses, and microbial functions. Significant differences were noted, and seen in the temporal data, demonstrating shifts that may have been precipitated by the interventions, with both the probiotics and the polyols. Particular bacterial strains were significantly more prevalent in the autism subject group including a strain that reduces neurotransmitters by enzymatic degradation. This provided supporting evidence to the hypothesis that the occurrence of autism may also be influenced by low Gamma Amino Butyric Acid (GABA) levels during development. Also, of interest was the un-expected finding that verbal skills dramatically increased in 6 of the 30 ASD subjects following xylitol supplementation.

Calcium (Ca2+) ions act as second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. Many evidences demonstrate that dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been showed.

Neurodegenerative diseases like Alzheimer’s disease (AD) are poised to become a global health crisis, and therefore understanding the mechanisms underlying the pathogenesis is critical for the development of therapeutic strategies. Mutations in genes encoding presenilin occur in most familial Alzheimer’s disease but the role of PSEN in AD is not fully understood. In this review, the potential modes of pathogenesis of AD are discussed, focusing on calcium homeostasis and mitochondrial function. Moreover, research using Caenorhabditis elegans to explore the effects of calcium dysregulation due to presenilin mutations on mitochondrial function, oxidative stress and neurodegeneration is explored.

Biological membranes are fascinating. Santiago Ramón y Cajal, who received the Nobel prize in 1906 together with Camillo Golgi for their work on the nervous system, wrote “[..]in the study of this membrane[..] I felt more profoundly than in any other subject of study the shuddering sensation of the unfathomable mystery of life”[1]. The visualization and conceptualization of these biological objects have profoundly shaped many aspects of modern biology, drawing inspiration from experiments, computer simulations, as well as from the imagination of scientists and artists. The aim of this review is to provide a fresh look on current ideas of biological membrane organization and dynamics by discussing selected examples across fields [1] The full quotation is “I must not conceal the fact that in the study of this membrane I for the first time felt my faith in Darwinism (hypothesis of natural selection) weakened, being amazed and confounded by the supreme constructive ingenuity revealed not only in the retina and in the dioptric apparatus of the vertebrates but even in the meanest insect eye. There, in fine, I felt more profoundly than in any other subject of study the shuddering sensation of the unfathomable mystery of life.” from the autobiography Recollections of My Life.

The COVID-19 pandemic crisis has brought about unprecedented economic and social consequences worldwide. The implementation of isolation measures, including national and international travel restrictions, significantly affected contact-intensive sectors such as tourism. During this lockdown period, Information and Communication Technology (ICT) was crucial in maintaining connectivity and enabling remote activities. Governments across the world implemented discretionary measures to mitigate the crisis's adverse effects on economic activity. This paper aims to analyze whether the level of ICT adoption and the importance of tourism influence the fiscal policy efforts pursued by governments. Based on the results of a linear regression analysis for 154 countries, the findings suggest that in countries with higher international tourism receipts, the governments had to promote higher fiscal stimulus. At the same time, ICT development diminished the efforts of the fiscal policy response to the crisis since it facilitated economic resilience. The findings of this study can contribute to understanding how governments responded to the pandemic crisis and the factors that influenced their fiscal policy decisions.

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries [1]. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease [1], all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.

Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells’ biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironment, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The patients' reactions to radiation are varied, ranging from a complete response to even cancer progression during treatment. This concept illustrates how different levels of mitochondrial metabolism might contribute to this heterogeneity. Considering this notion can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.

Zinc is a highly abundant cation in the brain, where it is essential for cellular function, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc, can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential, leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

The mitochondrial network (MN) is a dynamic structure undergoing constant remodeling in the cell. It is assumed that the violation of MN may be associated with various pathologies, including Parkinson’s disease (PD). Using automatic image analysis and super-resolution microscopy, we have assessed the MN parameters in fibroblasts from patients with established hereditary PD mutations (associated with PINK1, LLRK2, α-synuclein, PINK1 and Parkin simultaneously proteins) under normal conditions and after hydrogen peroxide-induced stress. Fibroblasts with Pink1/Parkin mutation are the most different in morphology from fibroblasts obtained from conditionally healthy donors: MN is larger, contains longer mitochondria and accumulated individual mitochondria. In addition to MN, we evaluated other cellular parameters, such as: cytosolic and mitochondrial ROS production and mitochondrial membrane potential. It has been shown that mitochondria of fibroblasts with mutations in genes encoding PINK1, α-synuclein and Pink/Parkin tends to hyperpolarization and cytosolic ROS overproduction, while mitochondrial ROS production was higher only in fibroblasts with PINK1 and α-synuclein mutation.

Breast cancer is a serious disease and the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are urgently needed. Repurposing FDA-approved drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on breast cancer cell lines including patient derived cell lines. Proguanil caused apoptosis through increased production of ROS and consequent decrease of mitochondrial membrane potential, mitochondrial respiration, and ATP production rates. ROS generation by proguanil was up to 3-fold higher when compared to the control. Proguanil treatment increased the expression of Bax, p-H2AX, cleaved-caspase 9, cleaved PARP, and down-regulated bcl-2 and survivin in breast cancer cell lines. The enlargement of 4T1 breast tumors in female Balb/c mice was suppressed by 55% through daily oral administration of 20mg/kg of proguanil. Western blot analyses of proguanil- treated tumors showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Proguanil proved to be an efficient in vitro and in-vivo inhibitor of breast cancer cells, hence should be considered further for clinical investigation against breast cancer.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID. To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

One of the most frequent brain diseases, Alzheimer's is defined by poor cognitive function brought on by the build-up of Beta Amyloid plaques and the gradual death of neurons. Glucose metabolism and the development of amyloid plaques are being studied together. Under physiologically normal circumstances, glucose is the primary substrate for the adult human brain. The prodromal phases of AD are significantly influenced by glucose hypometabolism. Hypometabolism of glucose in the brain is a clear sign of mitochondrial dysfunction and bioenergetic system impairment. By regulating energy synthesis and cell death, mitochondria play a crucial role in the functioning of cells. Increased formation of reactive oxygen species (ROS) and oxidative stress are a result of mitochondrial dysfunction, which also accelerates the development of Alzheimer's disease. For the maintenance of balance, autophagy is crucial because it selectively destroys damaged mitochondria. AD affects this route for mitochondrial breakdown. Targeting specific mitochondrial ligands by interventions along this pathway might be a useful therapeutic approach. Due to a number of biological obstacles, this method has significant limitations. As a result, many nanocarriers have been created to improve drug delivery effectiveness. All potential nanotechnology-based treatments for AD have been examined in this study, with a particular emphasis on medication delivery to the mitochondria

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from the oxidative damage and the coexistence of different sources of energy production, such as mitochondrial and glycolytic ATP, allows faster adaptative mechanisms to situations of high energy demand and may help in the maintenance of neuronal function in stress situations. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of Multiple Sclerosis. This work has been performed in a model of oxidative damage on neuronal cell cultures exposed to menadione, in presence or absence of fingolimod phosphate. We have studied the mitochondrial function and several pathways related with glucose metabolism, including oxidative, glycolytic and pentose phosphate in neuronal cells cultures. Our results showed a beneficial effect on neuronal survival probably based in the recovery of all, oxidative balance, glycolysis and pentose phosphate, promoted by fingolimod phosphate. These effects are mediated, at least in part by the interaction with its specific receptor. These actions would make this drug a potential tool to the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data show that Aldh2+/- mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in CoQ biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.

Landscape changes based on spectral responses allow showing plant cover changes through diversity, composition, and ecological connectivity. The spatial and temporal vegetation dynamics of the Bijagual Massif from 1986 to 2021 were analyzed as a measure of ecological integrity, conservation, and territory. The covers identified were high open forest (Hof), dense grassland of non-wooded mainland (Dgnm), a mosaic of pastures and crops (Mpc), lagoons (Lag), and bare and degraded lands (Bdl). The Bijagual Massif has 8,574.1 ha. In 1986, Dgnm occupied 42.6% of the total area, followed by Mpc (32.8%) and Hof (24.5%); by 2000, Mpc and Hof increased (43.7 and 28.1%, respectively), while Dgnm decreased (28%); by 2021, Dgnm was restricted to the northeastern zone and continued to decrease (25.2%), Mpc occupied 52.9%, Hof 21.7% and Bdl 0.1%. Of the three fractions of the connectivity probability index, only dPCintra and dPCflux contribute to ecological connectivity. Hof and Dgnm show patches with biota habitat quality and availability. Between 1986 and 2021, Dgnm lost 1,489 ha (41%) and Hof 239.5 ha (11%). Mpc replaced various covers (1,722.2 ha; 38%) in 2021. Bijagual has a valuable biodiversity potential limited by Mpc. Territorial planning and sustainable agroecological and ecotourism proposals are required due to the context of the ecosystems.

Why are pieces of spaghetti generally broken into three to ten segments instead of two as one thinks? How can one obtain the desired number of fracture segments? For these problems, in this paper a strand of spaghetti is considered an elastic rod, and the finite-element software ABAQUS is used to simulate the detailed fracture dynamics of the elastic rod. By changing the size (length and diameter) of the rod, the relevant data on the fracture limit curvature and the number of fractured segments of the elastic rod are obtained. The ABAQUS simulation results confirm the scientific judgment of B. Audoly and S. Neukirch (Fragmentation of rods by cascading cracks: Why spaghetti does not break in half. Phys Rev Lett 95: 095505). Using dimensional analysis to fit the finite-element data, two relations of the elastic rod fracture dynamics are obtained: (1) the relationship between the fracture limit curvature and the diameter, and (2) the relationship between the number of fracture segments and the diameter-length ratio. Results reveal that when the length is constant, the larger the diameter (the smaller the diameter-length ratio D/L), the smaller the limit curvature; and the larger the diameter-length ratio D/L, the fewer the number of fractured segments. The relevant formulations can be used to obtain the desired number of broken segments of spaghetti by changing the diameter-to-length ratio.

This study delves into the intricate dynamics of classical mechanics, exploring the interplay between force, mass, and energy. Through fundamental principles and mathematical formulations, it elucidates key relationships governing physical systems. Beginning with an overview of classical mechanics, the study establishes the foundational principles laid down by Newton, emphasizing concepts such as inertia, acceleration, and the relationship between force and motion. Central to the investigation is Newton's second law of motion, highlighting the direct proportionality between force and acceleration, and the inverse relationship between acceleration and mass when acted upon by a force. The study extends to the concept of effective mass, elucidating how the application of force influences the inertial mass of an object and contributes to its effective mass through the acquisition of kinetic energy. Furthermore, the study examines the total energy composition of systems, emphasizing the holistic nature of energy as a combination of potential and kinetic forms. Through the work-energy theorem, a direct link between force and kinetic energy is established, revealing how mechanical work done on an object results in changes in its kinetic energy and effective mass. Mathematical formulations and conceptual analyses provide deeper insights into the intricate relationships between force, mass, and energy, shedding light on the underlying mechanisms governing classical mechanical systems. Through validation against empirical observations and experimental data, the study ensures the accuracy and reliability of derived equations, contributing to a richer understanding of classical mechanics and paving the way for further exploration in the field of physics.

RNA transcripts play a crucial role as witnesses of gene expression health. Identifying disruptive short sequences in RNA transcription and regulation is essential for potentially treating diseases. Let’s delve into the mathematical intricacies of these sequences. We’ve previously devised a mathematical approach for defining a “healthy” sequence (10.14218/GE.2023.00079). This sequence is characterized by having at most four distinct nucleotides (denoted as nt≤4). It serves as the generator of a group denoted as fp. The desired properties of this sequence are as follows: fp should be close to a free group of rank nt−1, it must be aperiodic, fp should not have isolated singularities within its SL2(C) character variety (specifically within the corresponding Groebner basis). Now, let’s explore the concept of singularities. There are cubic surfaces associated with the character variety of a four-punctured sphere denoted as S24. When we encounter these singularities, we find ourselves dealing with some algebraic solutions of a dynamical second-order differential (and transcendental) equation known as the Painlevé VI equation (10.3390/dynamics4010001). In certain cases, S24 degenerates, in the sense that two punctures collapse, resulting in a “wild” dynamics governed by the Painlevé equations of an index lower than VI. In our paper, we provide examples of these fascinating mathematical structures within the context of miRNAs. Specifically, we find a clear relationship between decorated character varieties of Painlevé equations and the character variety calculated from the seed of oncomirs. These findings should find applications in cancer research.

The treasury of a DAO is purported to uphold the value of the DAO-issued token, and this study represents a pioneering effort to delve into these realms. We explore the relationship between the treasury and market capitalization in two DAO projects, namely Olympus DAO and KlimaDAO. Employing Granger Causality tests, we scrutinize the relationship between market capitalization and the treasuries of these DAOs. Furthermore, we use an EGARCH model to investigate the in-fluence of carbon offset tokens on KlimaDAO’s market capitalization, incorporating this variable into the model's conditional mean equation. The findings reveal a significant relationship between market capitalization and the treasuries of the DAOs, indicating a potential impact of market capitalization on treasuries. Additionally, the well-specified EGARCH model highlights the sig-nificance of carbon offset tokens, suggesting their potential to influence the overall market capi-talization of a DAO project and support its value.

Mitochondria are essential to cell homeostasis, and alterations in mitochondrial distribution, segregation or turnover have been linked to complex pathologies such as neurodegenerative diseases or cancer. Understanding how these functions are coordinated in specific cell types is a major challenge to discover how mitochondria globally shape cell functionality. In this review, we will first describe how mitochondrial transport and dynamics are regulated throughout the cell cycle in yeast and in mammals. Second, we will explore the functional consequences of mitochondrial transport and partitioning on cell proliferation, fate acquisition, stemness, and on the way cells adapt their metabolism. Last, we will focus on how mitochondrial clearance programs represent a further layer of complexity for cell differentiation, or in the maintenance of stemness. Defining how mitochondrial transport, dynamics and clearance are mutually orchestrated in specific cell types may help our understanding of how cells can transition from a physiological to a pathological state.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic dis-orders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β -propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects and secondary pathological con-sequences in cellular models derived from two patient harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibro-blasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. Transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron ac-cumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochon-drial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the ex-pression levels of WDR45 neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidant partially improved cell physiopathology, however autophagy and cell bioenergetics remained affected.

Ethoxyquin (EQ) is used as a synthetic antioxidant mainly in animal food, but it has also been reported to have neuroprotective properties by diminishing the peripheral neuropa-thy resulting from anti-cancer chemotherapy in animal models. However, EQ has not been thoroughly evaluated in humans and its use is under debate. The objective of this work was to examine the effect of EQ on primary fibroblasts derived from controls and patients with confirmed mitochondrial dysfunction. To this end, we incubated primary fibroblasts from patients with mitochondrial respiratory chain complex 1 (C1) deficiency, cyto-chrome-c-oxidase (COX) deficiency and genetic form of Parkinson’s disease (PD). Alt-hough EQ did not alter ATP production it significantly increased oxygen consumption and improved energy status in C1 and COX cells while decreasing ROS production in COX, PD and control cells and maintaining mitochondrial content. These effects could possibly be attributed to the antioxidant and chaperone-modulating properties of EQ and to induced SOD2 expression in some cells. Our results indicate that EQ has the potential to improve some mitochondrial functions. Still, caution should be exerted since overdose of this com-pound affected cell growth.