Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of thiophene group as mitochondrial carrier for drugs and fluorescent markers, based on a new concept of nonprotonable, noncharged transporters. We implemented this concept in a medicinal chemistry application by developing an anti-tumoral, metabolic chimeric drug, based on PDHK inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-aimed drugs.

The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in the maintenance and regulation of neuronal network dynamics. Research on microglia, the resident innate immune cells of the CNS, has advanced considerably in recent years, and our understanding of their diverse functions continues to grow. Microglia play critical roles in the formation and regulation of neuronal synapses, myelination, responses to injury, neurogenesis, inflammation and many other physiological processes. In parallel with advances in microglial biology, cutting-edge techniques for the characterization of microglial properties have emerged with increasing depth and precision. Labeling tools and reporter models are important for the study of microglial morphology, ultrastructure and dynamics, but also for microglial isolation, which is required to glean key phenotypic information through single-cell transcriptomics and other emerging approaches. Strategies for selective microglial depletion and modulation can provide novel insights into microglia-targeted treatment strategies in models of neuropsychiatric and neurodegenerative conditions, cancer and autoimmunity. Finally, fate mapping has emerged as an important tool to answer fundamental questions about microglial biology, including their origin, migration and proliferation throughout the lifetime of an organism. This review aims to provide a comprehensive discussion of these emerging techniques, with applications to the study of microglia in development, homeostasis and CNS pathologies.

Automatic and blind parameter estimation based on the inherent features of wireless signals is a major research area due to the fact that these techniques lead to the simplification of receivers, especially in terms of coarse synchronization, more importantly reduce down the signaling load at the control channels. Thus, in the literature many techniques are proposed to estimate a vast set of parameters including modulation types and orders, data and chip rates, phase and frequency offsets and so on. In this paper, a cyclostationary feature detection based method is proposed to estimate the carrier numbers and carrier spacing of carrier-aggregated direct sequence spread spectrum cellular signals blindly. The particular chip rate of the signal is also estimated through the process jointly. In the paper, after the proposed method is formulated, the measurement setup which is developed to collect the data for the validation of the proposed method is introduced. The measurement results are post-processed for performance analysis purposes. To that end, the method is investigated in terms of SNR values, different channel conditions, and measurement durations. Furthermore, the performance of the proposed method is compared with that of energy detection. Measurement results indicate superior performance of the proposed method under significant wireless channel impairments and in low-SNR regions.

This study aimed to identify whether gyrate atrophy of the choroid and retina (GACR) heterozygous individuals have possible clinical manifestations and to explore the potential pathogenic mechanism. In this retrospective study, we surveyed a two-generation pedigree of an individual diagnosed with GACR. Two family members underwent ophthalmological, hematologic, and genetic tests. An arginine-restricted diet with vitamin B6 supplementation was implemented; clinical assessments were repeated every 3 months during follow-up. Relative OAT mRNA expression was determined using real-time quantitative polymerase chain reaction. The 19-year-old compound heterozygous daughter (OAT: c.1186C>T; c.748C>T), had bilateral high myopia, posterior staphyloma, chorioretinal atrophy, macular abnormalities, and elevated hematologic ornithine. The 54-year-old heterozygous mother (OAT: c.1186C>T), presented with bilateral severe myopia, asymmetric posterior staphyloma, retina and choroidal capillary layer atrophy, retinal pigment epithelium abnormalities, and mildly elevated hematologic ornithine. Compared to normal individuals, the daughter and mother had 29% and 46% relative OAT mRNA expression, respectively (P<0.001). We believe that this is the first report of a carrier of one OAT variant allele with mild phenotypes, suggesting that family members should be aware of the possible involvement of autosomal recessive conditions. Additional data suggests nonsense mediated decay-initiated mRNA degradation may cause GACR.

According to many research groups, high glucose induces over production of superoxide anions, and reactive oxygen species (ROS) in general is the link between high glucose levels and the toxicities seen at cellular levels. Respiratory complex anomalies could lead to the production of ROS. Calcium [Ca2+], at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production which could be lethal to the mitochondria through various mechanisms. The F1F0-ATPase (ATP syn-thase or complex V) is the enzyme that is responsible for catalyzing the final step of oxidative phosphorylation. It does so by coupling the translocation of protons in the mitochondrial in-termembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space thereby blocking ATP synthesis leading to Neuropathy, Ataxia and Retinitis Pigmentosa Syndromes (NARP). This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain mediated mitochondrial stress. The NARP cybrids are the in vitro experimental models for the cells with F1FO-ATPase defects, these cells harbor 98% of mtDNA T8993G mutation. Their coun-terparts 143B osteosarcoma cell lines are the parental cell lines used for comparisons. We uncov-ered that, NARP cells mediated and enhanced the death of the cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose respectively as depicted by the MTT assay of cell viability. Furthermore, using the fluorescence probe-coupled laser scanning confocal imag-ing microscopy, NARP cells significantly enabled mitochondrial reactive oxygen species (mROS) formation and enhanced the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar enhanced toxicity on mitochondria would help in the fu-ture to alleviate the symptoms of patients associated with (NARP) syndromes.

Using coherent optical detection and digital signal processing, laser phase noise and equalization enhanced phase noise can be effectively mitigated using the feed-forward and feed-back carrier phase recovery approaches. In this paper, theoretical analyses of feed-back and feed-forward carrier phase recovery methods have been carried out in the long-haul high-speed n-level phase shift keying (n-PSK) optical fiber communication systems, involving a one-tap normalized least-mean-square (LMS) algorithm, a block-wise average algorithm, and a Viterbi-Viterbi algorithm. The analytical expressions for evaluating the estimated carrier phase and for predicting the bit-error-rate (BER) performance (such as the BER floors) have been presented and discussed in the n-PSK coherent optical transmission systems by considering both the laser phase noise and the equalization enhanced phase noise. The results indicate that the Viterbi-Viterbi carrier phase recovery algorithm outperforms the one-tap normalized LMS and the block-wise average algorithms for small phase noise variance (or effective phase noise variance), while the one-tap normalized LMS algorithm shows a better performance than the other two algorithms for large phase noise variance (or effective phase noise variance). In addition, the one-tap normalized LMS algorithm is more sensitive to the level of modulation formats.

Recently, microfluidics deformability cytometry has emerged as a powerful tool for high throughput mechanical phenotyping of large populations of cells. These methods characterize cells by their mechanical fingerprints through exerting hydrodynamic forces and monitoring the resulting deformation. These devices have shown great promise for label free cytometry, yet there is a critical need to improve their accuracy and reconcile any discrepancies with other methods, such as atomic force microscopy. In this study, we employ computational fluid dynamics simulations and uncover how the elasticity of frequently used carrier fluids such as methyl-cellulose dissolved in phosphate-buffered saline is significantly influential to the resulting cellular deformation. We conducted CFD simulations that are conventionally used within the deformability cytometry field, which neglect fluid elasticity. Subsequently, we incorporated a more comprehensive model that simulates the viscoelastic nature of the carrier fluid. A comparison of the predicted stresses between these two approaches underscores the significance of the emerging elastic stresses in addition to the well-recognized viscous stresses along the channel. Furthermore, we utilize a two-phase flow model to predict the deformation of a promyelocyte (i.e. HL-60 cell type) within a hydrodynamic constriction channel. The obtained results highlight a substantial impact of the elasticity of carrier fluid on cellular deformation and raise questions about the accuracy of mechanical property estimates derived by neglecting elastic stresses.

This paper integrates carrier manifolds from control theory and hybrid systems modeling to develop a novel mathematical framework for Artificial General Intelligence (AGI). Carrier manifolds represent the state space of complex AGI systems, while hybrid systems model discrete and continuous dynamics together. The proposed architecture embeds carrier manifold into GPTProX, a hybrid AI solver combining conversational AI, logic programming, and optimization.

The article aims to present the results of research on anaerobic digestion (AD) of waste wafers (WF - control) and co-substrate system - waste wafers and cheese (WFC - control), combined with digested sewage sludge. The aim of the study was to evaluate the physicochemical parameters of the chitosan/perlite (Ch/P; 3:1) carrier material and to verify its effect on the directions of change of the bacterial microbiome, removal kinetics of organic matter and AD process efficiency. The experiment was conducted in a laboratory, in a periodical mode of operation of bioreactors, under mesophilic conditions. The results of analyses of morphological-dispersive, spectroscopic, adsorption, thermal and microbiological properties confirmed that the tested carrier material can be an excellent option to implement in biotechnological processes, especially in anaerobic digestion. The microstructural properties of the carrier were influenced by both components: perlite determined the development of the specific surface area, while chitosan shaped the porosity of the system. The thermal properties were determined by the less heat-resistant component, present in a threefold higher weight proportion, i.e. chitosan. The evaluation of quantitative and qualitative changes in the genetic diversity of bacterial communities, carried out using Next Generation Sequencing (NGS), showed that the material has a modifying effect on the bacterial microbiome. Amount of bacteria from phyla Actinobacteria, Bacteroidetes, Campilobacterota, Chloroflexi, Euryarchaeota, Planctomycetes, and Proteobacteria decreased while Firmicutes, Synergistetes, and Thermotogae increased during the course of the experiment. The shapes of the FT-IR spectra indicated a dependence of the degradation rate on both the presence of the carrier and the cosubstrate system. Monitoring of the course of AD was carried out by measuring key parameters for the stability of the process: pH, VFA and VFA/TA ratio (volatile fatty acids/total alkalinity). As a result, an increase in the volume of biogas/methane produced, under the influence of the carrier, was recorded for WF-control by 12.05% and for WFC-control by 19.16%. The volume of methane for the WF-control increased from 351.72 m3 Mg-1 VS to 411.14 m3 Mg-1 VS, while for the cosubstrate sample it increased from 476.84 m3 Mg-1 VS to 518.08 m3 Mg-1 VS, confirming the validity of combining the respective cosubstrate with microbial carrier in anaerobic bioreactor.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and memory loss. Oxidative stress (OS) has emerged as a central element in the pathophysiology of AD, linking various pathological features including amyloid-β (Aβ) plaque formation, tau hyperphosphorylation, and synaptic dysfunction. This review comprehensively examines the role of OS in AD, focusing on the mechanisms of reactive oxygen species (ROS) production, mitochondrial dysfunction, and their impact on neuronal integrity. Additionally, the review highlights recent advances in antioxidant therapy. Elevated ROS levels in the aging brain exacerbate oxidative damage to lipids, proteins, and DNA, contributing to neuronal atrophy and synaptic loss. Mitochondrial dysfunction further amplifies OS, disrupting cellular energy metabolism and promoting neurodegeneration. Despite the strong association between OS and AD, antioxidant therapies have shown inconsistent clinical outcomes. Emerging strategies targeting offer promising avenues for therapeutic intervention. This review highlights the need for a multifaceted approach in understanding and mitigating OS-related damage in AD, aiming to pave the way for more effective treatments and improved patient outcomes.

Plant activators have emerged as promising alternatives to conventional pesticides for crop disease manage-ment due to their unique mode of action. By priming the plant's innate immune system, these compounds can induce systemic acquired resistance against a broad spectrum of pathogens without directly inhibiting their proliferation. Key advantages of plant activators include prolonged defense activity, lower effective dosages, and negligible risk of developing pathogen resistance. Among the various defensive pathways tar-geted, the salicylic acid (SA) signaling cascade has been extensively explored, leading to the successful devel-opment of commercial activators like benzothiadiazole for widespread application in crop protection. While the action sites of many SA-targeting activators have been preliminarily mapped to different steps along the pathway, a comprehensive understanding of their precise mechanisms remains elusive. This review provides a historical perspective on plant activator development and outlines diverse screening strategies employed across multiple levels, from whole-plant bioassays to molecular and transgenic approaches. We expound on the intricate components, biological relevance, and regulatory circuits governing the SA pathway, while criti-cally examining the structural features, bioactivities, and proposed modes of action of classical activators such as benzothiadiazole derivatives, salicylic acid analogs, and other small molecules. Insights from field trials as-sessing their practical applicability are also discussed. Furthermore, we highlight the current status, challenges, and future prospects in the realm of SA-targeting activator development globally, with a focus on recent en-deavors in China. Collectively, this comprehensive review aims to synthesize existing knowledge and provide a roadmap for future research toward developing more potent and mechanistically understood plant activa-tors that fortify crop immunity against disease.

As one of the representatives of emerging metallic transition metal dichalcogenides, niobium ditelluride (NbTe₂) has attracted intensive interest recently due to its distorted lattice structure and unique physical properties. Here, we report on the ultrafast carrier dynamics in NbTe₂ measured using time-resolved pump-probe transient reflection spectroscopy. A thickness-dependent carrier relaxation time is observed, exhibiting a clear increase in the fast and slow carrier decay rates for thin NbTe₂ flakes. In addition, pump power dependent measurements indicate that the carrier relaxation rates are power-independent, with the peak amplitude of the transient reflectivity increasing linearly with pump power. Isotropic relaxation dynamics in NbTe₂ is also verified by performing polarization-resolved pump-probe measurements. These results provide an insight into the light-matter interactions and charge carrier dynamics in NbTe₂ and will pave the way for its applications to photonic and optoelectronic devices.

Purpose: Expanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date. Methods: Couples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management. Results: Three hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis. Conclusions: ECS results impacted couples’ reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.

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.

The evidential value of an mtDNA match between biological remains and its potential donor is determined by the random match probability of the haplotype. This probability is based on the haplotype’s population frequency estimate. Consequently, implementing a population study representative of the population relevant to the forensic case is vital to correctly evaluating the evidence. The emerging number of poaching cases and the limited availability of such data emphasizes the need for improved fallow deer mtDNA population databank for forensic purposes, including targeting the entire mitochondrial control region. By sequencing the whole mitochondrial control region in 138 animals from five populations in Hungary we found four different haplotypes, including one which has not yet been described. Our results, supplemented with data already available from previous research do not support the possibility of determining the population of origin, although some patterns of geographical separation can be distinguished. Estimates of molecular diversity indicate approximately similarly low mtDNA diversity (Hd=0.565 and π = 0.002), compared with data from other countries. The calculated random match probability of 0.547 shows a high probability of coincidence and, therefore, a limited capacity for exclusion. Consequently, it may be necessary to search for polymorphic sites on other mitochondrial gene sections or to sequence the entire mitogenome of fallow deer.

Long COVID, characterized by persistent symptoms lasting from weeks to several months following initial infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), significantly impacts individuals' quality of life and poses a potential long-term burden on global healthcare systems. Clinical manifestations of Long COVID are diverse, affecting multiple systems including respiratory, cardiovascular, neurological, and gastrointestinal. While the precise mechanisms underlying Long COVID remain unclear, emerging evidence suggests involvement of various bodily pathways. This study employs bioinformatics tools to investigate the mechanisms of Long COVID and identify potential drug targets associated with key pathways, including inflammation, cytokines, immune response, coagulation, mitochondrial function, oxidative stress, and autonomic dysfunction. Tools such as the National Center for Biotechnology Information (NCBI) database, PubChem, UniProt, and iGEMDOCK were utilized for pathway analysis and molecular docking. The analysis aimed to identify drug molecules that may interact with target proteins to regulate or inhibit pathway activity, yielding several potential drug candidates for further investigation.

In France, the regional airport’s demand for services is facing challenges due to the continuous expansion of the high-speed train, high-speed line, and highway networks. This study focuses on the viability of regional airports in France through technical efficiency using data envelopment, principle component analysis, Malmquist productivity index, and regression analysis using bootstrapping. To face the current competitive environment, the regional airports in France adopted strategies, such as the construction of low-cost carrier (LCC) dedicated terminals (LCCTs) with lower expenses to attract more LCCs, increasing non-aeronautical revenue, and hosting regional hubs of LCCs. This is the first study that analyzes all of the French regional airports. The findings indicate that the existence of LCCTs positively affects technical efficiency on the airport’s performance, and share of LCCs at a regional airport leads to neither the efficiency nor the profit level.

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.

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

The Ylistrum japonicum is a commercially valuable scallop known for its long-distance swimming abilities. Despite its economic importance, genetic and genomic research on this species is limited. This study presents the first complete mitochondrial genome of Y. japonicum. The mitochondrial genome is 19,475 bp long and encompasses 13 protein-coding genes, 3 ribosomal RNA genes, and 23 transfer RNA genes. By selecting 15 Pectinidae species and additional outgroup taxa, we have constructed phylogenetic trees to elucidate the evolutionary placement of Ylistrum within the family Pectinidae. Our analysis reveals that Ylistrum is a basal lineage to the Pectininae clade, distinct from its previously assigned tribe, Amusiini. This study offers critical insights into the genetic makeup and evolutionary history of Y. japonicum, enhancing our knowledge of this economically vital species.

Capulus danieli, a distinct member of Capulidae, exhibits a unique ecological behaviour by attaching and drilling onto the pecten, distinguishing itself from other gastropods. Herein, we present the first characterisation of the mitochondrial genome of Capulus danieli. The results showed that the genome spans 15600 base pairs, with an A + T content of 71.12% and a G + C content of 28.88%. Within this genetic makeup, we identified 13 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes. Phylogenetic analysis revealed a close evolutionary relationship between Capulus danieli and members of the Ficoidea superfamily. The divergence time estimation suggested that Capulus danieli diverged approximately 52.29 million years ago. These findings significantly contribute to our understanding of the evolutionary history and genetic architecture of Capulus danieli, shedding light on its unique ecological adaptations to the marine environment.

Solution-based inorganic-organic halide perovskites are of great interest to researchers because of their unique optoelectronic properties and easy processing. However, polycrystalline perovskite films often show inhomogeneity due to residual strain induced during the film’s post-processing phase. In turn, these strains can impact both their stability and performances. An exhaustive study of residual strains can provide a better understanding and control of how they affect the performance and stability of perovskite films. In this work, we explore this complex interrelationship between residual strains and electrical properties for methylammonium \chemform{CH_3NH_3PbI_{3-x}Cl_x} films using grazing incident X-ray diffraction (GIXRD). We correlate with their resistiviy and carrier mobility using Hall effect. The sin^2($\psi$) technique is used to optimize the annealing parameters for the perovskite films. We also establish that temperature-induced relaxation can yield significant enhancement of the charge carrier transports in perovskite films. Finally, we also use Raman micro-spectroscopy to assess the degradation of perovskite films as a function of their residual strains.

A superparamagnetic graphene oxide based drug carrier Fe3O4@SiO2/N–rGO was prepared through surface modification, material doping, and composite methods. This carrier has a large number of active sites, suitable for loading anticancer drugs, It can increase the drug load. Currently, the widely used drug in clinical use is epirubicin hydrochloride (EPI). The graphene based complex has a pH sensitive property and exhibits a pH sensitive property at pH=4.3. The release efficiency (RE) is 77.4%, making it suitable for drug release in cancerous acidic liquids. The physicochemical properties of drug carriers were studied using X–ray diffraction, Raman spectroscopy, and Fourier transform infrared spectroscopy. Electrochemical signals confirm that the anticancer drug EPI acts on the graphene plane through hydrogen bond interactions and π – π stacking.

Transmembrane carriers of the Slc11 family catalyze proton (H+)-dependent uptake of divalent metal-ions (Me2+) such as manganese and iron - vital elements coveted during infection. Slc11 mechanism of high affinity Me2+ cell import is selective and conserved between prokaryotic (MntH) and eukaryotic (Nramp) homologs, though processes coupling the use of the proton motive force to Me2+ uptake evolved repeatedly. Adding bacterial piracy of Nramp genes spread in distinct environmental niches suggests selective gain of function that may benefit opportunistic pathogens. To better understand Slc11 evolution Alphafold (AF2)/Colabfold (CF) 3D predictions for bacterial sequences from sister clades of eukaryotic descent (MCb and MCg) were compared using both native and mutant templates. AF2/CF model an array of native MCb intermediates spanning the transition from outward open (OO) to inward open (IO) carrier. In silico mutagenesis targeting i) a set of (evolutionary coupled) sites that may define Slc11 function (putative synapomorphy), and ii) residues from networked communities evolving during MCb transition, indicate Slc11 synapomorphy primarily instructs Me2+-selective conformation switch which unlocks carrier inner gate, and contributes to Me2+ binding site occlusion and outer gate locking. Inner gate opening apparently proceeds from interaction between transmembrane helix (h) h5, h8 and h1a. MCg1 xenologs revealed marked differences in carrier shape and plasticity, owing partly to altered intramolecular H+-network. Yet, targeting Slc11 synapomorphy also converted MCg1 IO models to OO state, apparently mobilizing the same residues to control gates. But MCg1 response to mutagenesis differed, extensive divergence within this clade correlating with MCb-like modeling properties. Notably, MCg1 divergent epistasis marks emergence of the genus Bordetella-Achromobacter. Slc11 synapomorphy localizes to the 3D areas that deviate least among MCb and MCg1 models (either IO or OO) implying it constitutes a 3D network of residues articulating Me2+-selective carrier conformation switch which is maintained in fast evolving clades at the cost of divergent epistatic interactions impacting carrier shape and dynamics.

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 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.

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.

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.

For semiconducting two-dimensional transition metal dichalcogenides, carrier transport proper-ties of the material are affected by strain engineering. In this work, we investigate the carrier mo-bility of monolayer hafnium disulphide (HfS2) under different biaxial strains by first-principles calculations combined with Kubo-Greenwood mobility approach and compact band model. The decrease/increase in effective mass of conduction band of monolayer HfS2 caused by biaxial ten-sile/compressive strain is the major reason for the enhancement/degradation of its electron mobil-ity. Lower hole effective mass of valence bands in the monolayer HfS2 under biaxial compressive strain results in the better hole transport performance of monolayer HfS2 than the one with biaxial tensile strain. In summary, biaxial compressive strain decreases both effective mass and phonon scattering rate of monolayer HfS2, resulting in an increase in carrier mobility. When the biaxial compressive strain reaches 4%, for the conduction band of monolayer HfS2, electron mobility en-hancement ratio is ~90%. For the valence band of monolayer HfS2, the maximum hole mobility enhancement ratio appears ~13% at biaxial compressive strain of 4%. Our results indicate that the carrier transport performance of monolayer HfS2 can be greatly improved by the strain engineer-ing.

According to the development needs of marine seismic station networking, it is necessary to develop a marine seismometer with a networking function to realize quasi-real-time and large-scale long-term observation of undersea seismic signals. This can lay a solid foundation for marine seismic research and research on earth tectonics, activities, and processes. Based on the advantages and disadvantages of the existing observation equipment, this study proposed to develop a new type of the Autonomous Glide Marine Seismometer(AGMS) that can be applied to the global sea area, focusing on the design and study of the main structure of the carrier of the AGMS. The ultimate strength of the ellipsoidal pressure-resistant spherical shell is investigated by using the finite element analysis method. A reasonable finite element analysis model is proposed through comparing the finite element parameter results with the theoretical formulas and relevant specifications. Finally, the design process and strength checking of the pressure-resistant shell of the AGMS are established. These relevant results can also provide a reference for the design of other deep-sea pressure-resistant chambers.

Nanomedicine holds great potential to devise better drug delivery systems (DDSs). However, many reported nanomedicines still fall short of commercial requirements including specific targetability, scale-up manufacturing and safety. Cell/tissue based carriers, including cell membrane vehicle and exosome, are biocompatible and targeting platforms but usually suffered from low yields and unstable reproducibility. Here in this study, we proposed the concept and preparation of reconstituted lipid nanoparticles (rLNPs) to develop highly reproducible cell/tissue based lipid nanoparticles (LNPs) for drug delivery, which holds the potential as a versatile drug delivery platform. The whole lipids of cell or tissue were firstly extracted and then prepared into rLNPs using solvent diffusion method. In this way, the preparation of ultra-small (~20 nm) rLNPs can be easily applied to both cell (mouse breast cancer cell line, 4T1) and tissue (mouse liver tissue). Our results demonstrated that mouse liver tissue derived rLNPs can be further labeled/modified with imaging, targeting or other functional moieties. Furthermore, rLNPs were highly biocompatible and capable of loading different drugs including doxorubicin hydrochloride (Dox) and curcumin (Cur). Most importantly, Dox loaded rLNPs (rLNPs/Dox) showed preferable in vitro and in vivo anticancer performance. Therefore, rLNPs might be a versatile drug delivery platform for future application in the treatment of a variety of diseases.

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

Landing is one of the most dangerous tasks in all the operations on the aircraft carrier, and the landing safety is very important to the pilot and the flight deck operation. The problem of landing path selection is studied in this paper as there several candidates corresponding to different situations. A fuzzy path selection strategy is proposed to solve the problem considering the fuzziness of environmental information and human judgment, and the goal is to provide the pilot with more reasonable decision. The strategy is based on Fuzzy Multi-attribute Group Decision Making (FMAGDM), which has been widely used in industry. Firstly, the background of the path selection problem is given. Then the essential elements of the problem are abstracted to build the conceptual model. A group decision-making method is applied to denote the preference of each decision maker for each alternative route, and the optimal landing path under the current environment is determined taking into account the knowledge and the weight of both decision makers. Experimental studies under different setups, i.e., different environments, are carried out. The results demonstrate that the proposed path selection strategy is validated in different environments, and the optimal landing paths corresponding to different environments can be determined.

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.

Cell aging is associated with the increased production of mitochondrial reactive oxygen species (mtROS) due to mitochondrial dysfunction, and various phytonutrients and estrogens have been shown to improve skin health. Thus, the aim of the current study was to examine damage to dermal fibroblasts by chemically-induced mitochondrial dysfunction and to study the mechanism of the protective effects of carotenoids, polyphenols, and estradiol. Rotenone, a Complex I inhibitor, caused mitochondrial dysfunction in human dermal fibroblasts, substantially reducing respiration and ATP levels, followed by increased mitochondrial and cytosolic ROS, which resulted in apoptotic cell death, increased matrix metalloproteinase-1 (MMP1) secretion, and decreased collagen secretion. Pre-treatment with carotenoid-rich tomato extracts, rosemary extract, and estradiol reversed these effects. These protective effects can be partially explained by a cooperative activation of antioxidant response element (ARE/Nrf2) transcriptional activity by the protective compounds and rotenone, which led to upregulation of antioxidant proteins such as NQO1. To determine if ARE/Nrf2 activity is crucial for cell protection, we inhibited it using the Nrf2 inhibitors ML385 and ochratoxin A. This inhibition markedly reduced the protective effects of the test compounds by diminishing their effect to reduce cytosolic ROS. Our study results indicate that phytonutrients and estradiol protect skin cells from damage caused by mitochondria-generated ROS and, thus, may delay skin aging and improve skin health.

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.

The perovskite solar cells (PSCs) have been significantly improved by utilizing inorganic hole transporting layer (HTL), such as nickel oxide. Despite the promising properties, there are still limitations due to defects. Recently, research on self-assembled monolayers (SAM) is being actively conducted, which show promise in reducing defects and enhancing device performance. In this study, we successfully engineered a p-i-n perovskite solar cell structure utilizing HC-A1 and HC-A4 molecules. These SAM molecules were found to enhance the grain morphology and uniformity of the perovskite film, which are critical factors in determining optical properties and device performance. Notably, HC-A4 demonstrated superior performance due to its distinct hydrophilic properties with a contact angle of 50.3°, attributable to its unique functional groups. Overall, the HC-A4 applied film exhibited efficient carrier extraction properties, attaining a carrier lifetime of 117.33 ns. Furthermore, HC-A4 contributed the superior device performance with its favorable band alignment, achieving the highest device efficiency of 20%.

The influence of various energetic particles and electron injection on transport of minority carriers and non-equilibrium carrier recombination in Ga₂O₃ is summarized in this review. In Ga₂O₃ semiconductor, if robust p-type material and bipolar structures become available, diffusion length of minority carriers will be of critical significance. Diffusion length of minority carriers dictates functionality of such electronic devices as diodes, transistors, and detectors. One of the problems in ultra-wide band gap materials technology, is the short carrier diffusion length, due to scattering on extended defects. Electron injection in n- and p-type Gallium Oxide results in a significant increase of the diffusion length, even after its deterioration due to exposure to alpha- and proton-irradiation. Furthermore, post electron injection diffusion length in irradiated material exceeds that in Ga₂O₃ prior to irradiation and injection. The root cause of the electron injection-induced effect is attributed to the increase of minority carrier lifetime in the material due to trapping of non-equilibrium electrons on native point defects. It is, therefore, concluded that the electron injection is capable of “healing” the adverse impact of radiation in Ga₂O₃ and can be used for control of minority carrier transport and, therefore, device performance.

This work describes the preparation of mesoporous silica by the green reaction of rice husk ash (RHA) with glycerol, followed by the modification and the potential use as a drug carrier. The reaction was carried out at 215 °C for 2 h. The solution was further hydrolyzed with deionized water and aged for various times (24, 48, 120, 360, 528 and 672 h) before calcinations at 500 oC for 24 h. Further treatment of prepared mesoporous silica was performed using trimethylmethoxysilane (TMMS) to obtain hydrophobic Mesoporous silica. For all synthesized silica, silica contents were as high as 95%wt, whereas organic residues were less than 3%wt. RHA-glycerol showed the highest specific surface area with smallest pore diameter (205.70 m2/g, 7.46 nm) when aged for 48 h. The optimal hydrolysis-ageing period of 120 h resulted in 500.7 m2/g BET surface area, 0.655 cm3/g pore volume and 5.23 nm pore diameter. The surface modification of RHA-glycerol was succeeded through the reaction with TMMS as confirmed by FTIR. Ibuprofen was selected as a model drug for the adsorption experiments. The adsorption under supercritical CO2 was carried out at isothermal temperature of 40 ˚C and 100 bar, % ibuprofen loading of TMMS modified mesoporous silica (TMMS-g-MS) was 6 times less than mesoporous silica aged for 24 h (MS-24h) due to the hydrophobic nature of modified mesoporous silica, not surface and pore characteristics. The release kinetics of ibuprofen-loaded mesoporous silicas were also investigated in vitro. The release rate of ibuprofen-loaded MS-24h was much faster than that of ibuprofen-loaded TMMS-g-MS, but comparable to the crystalline ibuprofen. The slower release rate was attributed to the diffusion control and the stability of hydrophobic nature of modified silica. This would allow the design for the controlled release drug delivery system.

InGaN/GaN samples grown on c-plane sapphire substrate with different In concentrations by metal organic chemical vapor deposition are demonstrated. The subsequent capping GaN layer growth opens a possibility for dislocation reduction due to the lateral strain relaxation in growth geometry. We present the further growth optimization and innovative characterization of InGaN layers overgrown on different structures with varying In concentrations. The photoelectrical and optical properties of the InGaN layers with or without capping GaN layer were investigated by time-resolved picosecond transient grating and temperature dependence photoluminescence. We note a 10-fold increase in carrier lifetime in the InGaN layers when the sample structure changes from PIN to single InGaN layer.

The medical care and welfare of domestic dogs are now respected worldwide at the same level as that of humans. We previously established a test method to determine whole mitochondrial DNA (mtDNA) using oral mucosal DNA that may be useful for the medical care and welfare of dogs. However, the sample types tested in dogs are not limited to those obtained from the oral mucosa. Therefore, in the present study, we attempted to establish a test method to determine whole mtDNA sequences using feces, which represents the least invasive specimen. Two Japanese domestic dogs were used in the present study. DNA was extracted from approximately 100 mg of fresh feces from each dog, and PCRs were performed using four primer-pairs that can amplify whole mtDNA. Following PCR, amplicons were pooled to create a DNA library using an experimental robot with an original program. Data were then acquired via NGS and data analysis was performed. The results showed that the whole mtDNA sequence of the two dogs was determined with high accuracy. Our results suggest that feces can be adapted for mitochondrial disease and individual identification testing and could serve as a useful testing method for the future medical care and welfare of domestic dogs.

Antibiotic beads were used to treat surgical infections. In this study, polylactide–polyglycolide (PLGA) was mixed with vancomycin, osteogenic enhancer lithium chloride (LiCl), and hot com-pressing to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was employed to characterize the in vitro release characteristics of the vancomycin and the Li over a 42-day period. The released profiles lasted for more than 42 days for vancomycin and 28 days for Li. The concentration of vancomycin in each sample was well above the breakpoint sensitivity. Lithium co-treatment enhanced the bactericidal effect of vancomycin. Released Li and vancomycin increased mRNA or protein expressions of osteogenic markers of mesenchymal stem cells (MSCs). In vivo, the PLGA delivery systems were implanted into the rabbit distal femoral cavities and the cavity fluid content was aspirated and analyzed at each time point. The released Li and vancomycin lasted more than 6 weeks, and vancomycin concentrations were much above the breakpoint sensitivity. Four rabbits in each group were killed at 8 weeks for histologic observation. More mature bone tissue was shown in the Li treatment group. This study provides a PLGA drug delivery system to meet the requirements of patients with bone infections.

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.

Astaxanthin (ATX) is a carotenoid nutraceutical with a poor bioavailability due to its high lipophilicity. We tested a new tailored nano-droplet capable of solubilizing ATX in an oil-in-water micro-environment (LDS-ATX, manufactured by Lyotropic Delivery Systems (LDS)), for its capacity to improve ATX pharmacokinetic profile and anti-oxidant efficacy. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to compare the pharmacokinetic profile of ATX and LDS-ATX and protein carbonylation and lipid peroxidation assays to compare their basal and lipopolysaccharide (LPS)-induced oxidative damage. Our results show that only LPS-induced oxidative damage was corrected by ATX and LDS-ATX. While in the liver and muscle LDS-ATX was more efficacious than ATX in attenuating oxidative damage to both proteins and lipids, only oxidative damage to lipids was preferably corrected by LDS-ATX in the brain. These results strongly suggest improvement of ATX bioavailability and efficacy by the LDS-ATX nano-formulation.

In this review, we provide an overview of the most common majority and minority charge carrier traps in n-type 4H-SiC material. We focus on the results obtained by different applications of junction spectroscopy techniques. The basic principles behind the most common junction spectroscopy techniques are given. These techniques, namely, deep level transient spectroscopy (DLTS), Laplace DLTS (L-DLTS) and minority carrier transient spectroscopy (MCTS) have led to recent progress in identifying and better understanding of the charge carrier traps in n-type 4H-SiC material.

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.

The development of novel ionic liquid crystals for energy storage applications has gained significant attention in recent years due to their potential to develop the field of energy storage. Ionic liquid crystals represent a unique class of materials with high ionic conductivity and thermal stability, making them ideal candidates for use in advanced energy storage devices. This research aims to explore the fundamental properties, structure and liquid crystals performance of these novel materials, with the goal of advancing their practical application in next-generation energy storage technologies. By understanding the structure-function relationship of ionic liquid crystals, researchers can tailor their properties to meet specific energy storage requirements, such as high energy density, fast charging capabilities, and long cycle life. This study seeks to contribute to the growing body of knowledge in the field of energy storage by investigating the potential of novel ionic liquid crystals as efficient and sustainable energy storage solutions. The two ionic liquid crystals show mesomorphic behavior and typical zwitterion characteristics that revealed by the cyclic voltammetry techniques. These materials uploaded with lithium ions for more stability and higher ionic conductivity.

Preconception or prenatal carrier screening for hereditary deafness is an effective early intervention strategy to reduce the incidence of newborn deafness, but current research is limited. This study aimed to investigate the carrier frequencies of common deafness genes in the Chinese population and to follow up on pregnancy outcomes in high-risk couples. Carrier screening for common deafness genes in the Chinese population, including the GJB2 and SLC26A4 genes, was performed using next-generation sequencing technology. Of the 9,993 subjects screened, the carrier rate was 2.86% for the GJB2 gene and 2.63% for the SLC26A4 gene. Of the six high-risk couples, four made alternative reproductive decisions (three with prenatal diagnosis and one with preimplantation genetic testing), with consequent successful termination of the birth of two affected fetuses. The frequencies of preconception or prenatal carrier screening for the deafness genes GJB2 and SLC26A4 in 9,993 subjects from China in this study were 2.86% and 2.63%, respectively. In addition, four out of six high-risk couples made alternative reproductive decisions, followed by the successful prevention of the birth of two affected fetuses. These findings confirmed the clinical utility of preconception or prenatal carrier screening for hereditary deafness.

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.

Background and Purpose: Oxidative stress is an important factor in the pathogenesis of neurological problems. One of the compounds causing oxidative stress is diazinon. In the present project, the protective role of gallic acid compound in reducing oxidative stress in brain tissue of mice exposed to diazinon was investigated. Method: In this study, eight groups of six series of mice including the first group (control) of normal saline, the second group of diazinon (40 kg/mg) as IP, three groups of diazinon with gallic acid (50, 100, 200 kg/mg), was prescribed as a single dose and for 24 hours. The atropine + pralidoxime group was also evaluated as a standard treatment group. At 24 hours after the last dose, the animals were sacrificed and brain tissue was examined to assess oxidative stress parameters, including glutathione content, protein carbonyl content, lipid peroxidation, reactive oxygen species (ROS) and mitochondrial function in mitochondria isolated from brain tissue. Results: The results of this research showed that oxidative stress biomarkers increased significantly (P<0.001) in the diazinon group compared to the control group. Oxidative stress was significantly reduced in the groups receiving gallic acid at a dose of 200 and 100 kg/mg of diazinon compared to the diazinon group. Conclusion: The results of the present study show that diazinon causes damage to brain tissue by inducing oxidative stress. Therefore, according to the reduction of oxidative stress by gallic acid compound, it can be concluded that this compound can protect against brain toxicity caused by diazinon in animal model by stimulating antioxidant and radical scavenging pathways.

Nanostructured lipid carriers (NLC) are typically composed of liquid lipids, solid lipids, and surfactants, enabling the encapsulation of lipophilic drugs. Butamben is a Class II anesthetic drug according to the Biopharmaceutical Classification System (BCS), it has a log P 2.87 and is considered a 'brick dust' (poorly water-soluble and poorly lipid-soluble) drug. This characteristic poses a challenge for the development of NLCs, as they are not soluble in the liquid lipid present in the NLC core. In a previous study [1] we have developed a NLC core consisting of solid lipid (CrodamolTM CP), liquid lipid of medium polarity (SRTM Lauryl lactate), and a hydrophilic excipient (SRTM DMI) that allowed the solubilization of 'brick dust' type of drugs including butamben. In this study, starting from the NLC core formulation previously developed we carried out the optimization of the surfactant system and evaluated their performance in aqueous medium. Three different surfactants (CrodasolTM HS HP, SynperonicTM PE/F68, and CroduretTM 40) were studied and, for each of them, a 2³ factorial design was stablished, with total lipids, % surfactant, and sonication time (min) as the input variables and particle size (nm), polydispersity index (PDI) and zeta potential (mV) as the response variables. Stable NLCs were obtained using CrodasolTM HS HP and SynperonicTM PE/F68 as surfactants. Through a comparison between NLCs developed with and without SRTM DMI, it was observed that besides helping the solubilization of butamben in the NLC core, this excipient helped stabilizing the system and decreasing particle size NLCs containing CrodasolTM HS HP and SynperonicTM PE/F68 presented particle size values in the nanometric scale, PDI lower than 0.3 and zeta potential above |10|mV. Concerning NLCs stability, SBTB-NLC with SynperonicTM PE/F68 and butamben demonstrated stability over a 3-month period in aqueous medium. The remaining NLCs showed phase separation or precipitation during the 3-month analysis. Nevertheless, these formulations could be freeze-dried after preparation, which would avoid precipitation in aqueous medium.

Exposure to cadmium sulfate (CdSO4) can lead to neurotoxicity. Nevertheless, the precise molec-ular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO4 exposure-induced neurotoxicity in HT22 cells. Additionally, the inves-tigation sought to elucidate the molecular mechanisms underlying this phenomenon. Our findings demonstrated that exposure of HT22 cells to CdSO4 resulted in apoptosis, which was effectively reversed by EA supplementation. EA supplementation also decreased reactive oxygen species (ROS) and mitochondrial ROS productions, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5–20 μM significantly counteracted Cd-induced mitochondrial membrane potential and ATP losses and reduced the ratio of Bax/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation upregulated Nrf2 and HO-1 protein expression while downregulating the phosphorylation of JNK and p38 proteins. Pharmacological inhibition of JNK partially inhibited CdSO4-induced Nrf2/HO-1 activation and exacerbated its cytotoxicity. In conclusion, our results indicate that EA supplementation provides protection against CdSO4-induced cell apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 pathway. Activation of the JNK pathway plays a protective role in CdSO4-induced cell apoptosis in HT22 cells.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

Numerous study reports on chitosan hydrogels in different forms such as films, porous structures, nanoparticles, and microspheres for biomedical applications, however, this study concentrates on their modifications with different crosslinking agents and observing their effects on drug loading and releasing capacities. Linear chitosan along with crosslinked by two major cross-linkers, i.e., genipin and disulfide have been used to formulate three different hydrogel systems. The cross-linking process is heavily impacted by the temperature and the pH conditions. Three different drugs, i.e., thymoquinone, gefitinib, and erlotinib are loaded in phosphate buffer solutions and infused with three different hydrogel systems, thus, a total of nine combinations are studied and analyzed for drug loading and releasing capabilities with Ultraviolet–visible (UV-Vis) spectroscopy. This study finds thymoquinone shows the lowest loading efficacy compared to two other drugs in all three systems. Gefitinib shows stable loading and releasing regardless of crosslinking systems and genipin crosslinked system shows stable loading and releasing with all three drug molecules. These experimental results agree well with the findings of our previously published results conducted with molecular dynamics simulations.

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.

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.

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.

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 high interest in N-heterocyclic platinum carbene complexes in cancer research stems from their high cytotoxicity to human cancer cells, their stability, as well as their ease of functionalization. However, the development of these new molecules as anticancer agents still faces multiple challenges, in particular solubility in aqueous media. Here, we synthesized platinum-NHC bioconjugates that combine water-solubility and cytotoxicity by using polyethyleneimine as polymer carrier. We showed that the activity of these conjugates is modulated by the size of the polymer and the overall density of metal ions onto polymer chains. They displayed an effective activity after only 45 minutes of exposure in vitro correlated with a quick uptake by the cells as shown by the use of various fluorescent-tagged derivatives.

Transplanted organs experience several episodes of ischemia and Ischemia-reperfusion. The graft injury resulting from ischemia-reperfusion (IRI) remains a significant obstacle to the successful survival of transplanted grafts. Temperature plays an important role in cellular metabolic rates since biochemical reactions are highly temperature dependent. Therefore, ischemia-triggered degradative reactions could be mitigated by lowering temperature. Whether a local hypothermia on liver before blockage of blood flow protects liver grafts against IRI has not been investigated. In this study, we applied local hypothermia to mouse donor livers for a specific duration before stopping blood flow to liver lobes, a procedure called "liver precooling." Mouse donor liver temperature in control groups was controlled at 37ºC. Subsequently, the liver donors were preserved in cold University of Wisconsin solution for various durations followed by orthotopic liver transplantation. Liver graft injury, function and inflammation were assessed at 1- and 2-days post-transplantation. Liver precooling exhibited a significant improvement in graft function, revealing more than a 47% decrease in plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, coupled with a remarkable reduction of approximately 50% in liver graft histological damage compared to the control group. The protective effects of liver precooling were associated with the preservation of mitochondrial function, substantial reduction in hepatocyte cell death, and a significantly attenuated inflammatory response. A retrospective analysis of patient data revealed a close correlation between hypothermia and enhanced liver graft function. Taken together, reduction of the cellular metabolism and enzymatic activity to a minimum level before ischemia protects against IRI during transplantation.

Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSD

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 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&lt;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.

Fire blight, caused by Erwinia amylovora, is a devastating bacterial disease that threatens world-wide production of apples and pears. In Canada and the US, streptomycin and kasugamycin are commonly used for the control of this pathogen. There is an urgent need for development of biocontrol agents (BCAs) that can be easily incorporated into integrated pest management pro-grams with high efficacy against streptomycin sensitive and resistant strains of E. amylovora. In addition, excessive use of antibiotics in agriculture has increased awareness of the possibility of antibiotic resistance gene transfer to human, animal and environmental microbes. To address this issue, a phage-carrier system (PCS) that combines Pantoea agglomerans as an antagonistic bacterial carrier of Erwinia phages as a double-pronged treatment for fire blight have been de-veloped. The low viability of P. agglomerans cells following spray drying challenged the industrial scale production of this PCS. In the present research, a spray drying protocol was developed for P. agglomerans by modifying the growth medium and the bacterial cell formulation using D(+)-trehalose and maltodextrin. The developed protocol is amenable to industrial scale pro-duction of the BCA/PCS. The P. agglomerans viability was greater than 90% after spray drying, had a prolonged shelf life of 4 months at 4 C, and the reconstituted cells showed an approximate 3 log reduction in E. amylovora counts with a green pear disc challenge assay.

DC-connected parallel inverter systems are gaining popularity in industrial applications. However, such parallel systems generate excess current ripple (harmonics) at the DC-link due to harmonic interactions between the inverters in addition to the harmonics from the PWM switching. These DC-link harmonics cause the failure of fragile components such as DC-link capacitors. This paper proposes an interleaving scheme to minimize the current harmonics induced in the DC-link of such a system. The results show that when the carrier waves of the two inverters are phase-shifted by 90° angle, the maximum high-frequency harmonic ripple cancellation occurs, which reduces the overall RMS value of the DC-capacitor current.The outcome of this proposed solution is a cost-effective DC-harmonics mitigating strategy for the industrial designers to practically configuring multi-inverter systems, even when most of the drives are not operating at rated power levels. Experimental and simulation results presented in this paper verify the effectiveness of the proposed carrier-based phase-shifting scheme for two different configurations of common DC connected multi-converter systems.

Due to their short range (2–500 nm), Auger electrons (Auger e-) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Au-ger e-, it remains challenging to maximize the interaction between Auger e- and DNA. To assess the DNA-damaging effect of Auger e- released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by im-munofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incuba-tion), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by release of Auger e- very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e-.

The drug delivery systems receive more and more attention for the control and treatment of many diseases due to their increased number in recent years. The main aims of this study were to develop and to characterize a polyurethane drug delivery system that it is intended to be used for the transmembrane transport of nucleosides. Three different samples have been synthesized based on aliphatic diisocyanates (hexamethylene diisocyanate, isophorone diisocyanate and lysine diisocyanate) as organic phase, respectively a mixture of polyethylene glycol, polycaprolactone diol and low molecular weight diols as aqueous phase. The samples were characterized by pH, refractivity index and solubility measurements, drug loading efficacy and release investigations, thermal behavior, Zetasizer, cells viability and irritation tests on mice skin. The results indicate the obtaining of different populations of neutral acido-basic particles with size between 132 and 190 nm; the Zeta potential values and SEM images show a medium tendency to form clusters, while UV-Vis evaluations indicate an almost 70% encapsulation efficacy, a prolonged release (45% of encapsulated substance is released in the first 5 days) and around 70% of particles have penetrated an artificial membrane in the first 24h. The synthesized products can be tested in further clinical trials, the currently tests on cells culture and mice skin revealing no side effects.

The part transportation efficiency is a main factor of aircraft sortie generation rate. Part transportation is used to transport spare part from base to carrier. Transportation strategy depends on both demand on carrier and inventory in transportation base. The transportation time and stochastic demand will induce fluctuations of cost and inventory. Thus, a Takagi-Sugeno fuzzy system of dynamic part transportation is established considering transportation time and stochastic demand. And a novel Takagi-Sugeno fuzzy robust control is designed for dynamic part transportation, which will keep transportation cost and part inventory stable. First of all, a fuzzy model with stochastic demand and transportation time is proposed. Then, a novel robust control with cross rule groups is conducted according to production and transportation strategy, which will reduce fluctuations induced by strategies switch. Moreover, robust stability is guaranteed and part can be supplied in time under a low cost. Finally, simulation illustrates usefulness and quickness of the novel Takagi-Sugeno fuzzy robust control. Besides, the proposed method will be useful in other transportation electrification systems with delay time and uncertainty.

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.

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.

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.

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.

Abstract: Chitosan spherical scaffolds, derived from the deacetylation of chitin, are natural polymers with significant potential, though challenges remain in optimizing their properties. The use of chitosan as a carrier for the controlled release of iron chloride is not yet fully established, despite iron’s critical role in various essential biological processes, including as a component of metalloenzymes and in the maintenance of life. Methods: This study aimed to develop a novel protocol for synthesing chitosan scaffolds and to characterize their properties using analytical techniques. Additionally, the release profile of iron was modeled using two primary controlled-release mathematical models. Results: The results demonstrated successful synthesis and physicochemical characterization of the chitosan sphere scaffolds. These scaffolds exhibited appropriate topography for iron loading and cellular interaction, as confirmed by SEM analysis, and contained functional groups as identified by FTIR. The scaffolds were also semi-crystalline (XRD), showed controlled degradation, and were confirmed to be non-toxic biomaterials. Furthermore, the modeling of the controlled release of iron chloride adsorbed on the scaffold surface, as well as the modeling of iron chloride specimens using the MEDUZA software, was successfully conducted. A theoretical curve was generated from the experimental dose-response data collected over time, considering variations in pH and medium concentration. Conclusions: In conclusion, a novel protocol for chitosan-based carriers was successfully developed, enabling thorough physicochemical characterization and modeling of both absorption and controlled release.

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 term deviation frequency denotes the boundary between the variable part of the amplitude and phase scintillation spectrum and the part of uninformative noises. We suggested the concept of the “characteristic deviation frequency” during the observation period which is defined as the most probable value of the deviation frequency under current local conditions. This work is a case study of the characteristic deviation frequency (fd) registered for GPS, GLONASS, Galileo and SBAS signals under quiet and weakly disturbed geomagnetic conditions in April 2021 at the mid-latitude GNSS station. Our results demonstrated that the fd value for all signal components of GPS, GLONASS and GALILEO signals varied within 15-22 Hz. The characteristic deviation frequency was 20 Hz for the mentioned GNSS signals. In difference, the deviation frequency was limited within 13-20 Hz for SBAS with the lower characteristic deviation frequency at 18 Hz. We assume that the concept of the characteristic deviation frequency can be used to determine the optimal sampling rate of the GNSS carrier phase data for the ionospheric studies. The characteristic deviation frequency can also characterize the state of the regular trans-ionospheric radio channel.

Legacy IPv4 networks are strenuous to manage and operate. Network operators are in need to minimize the capital and operational expenditure of running network infrastructure. The implementation of Software-defined networking (SDN) addresses those issues by minimizing the expenditures in the long run. Legacy networks need to integrate with the SDN networks for the smooth migration towards the fully functional SDN environment. In this paper, we compare the network performance of the legacy network with the SDN network for IP routing in order to determine the feasibility of the SDN deployment in the Internet Service provider (ISP) network. The simulation of the network is performed in the Mininet test-bed and the network traffic is generated using distributed Internet traffic generator. Open network operating system is used as a controller for the SDN network in which SDN-IP application is used for IP routing. Round trip time, bandwidth, and packet transmission rate from both SDN and legacy networks are first collected and then the comparison is done. We found that SDN-IP performs better in terms of bandwidth and latency as compared to legacy routing. The experimental analysis of interoperability between SDN and legacy networks shows that SDN implementation in production level carrier-grade ISP network is viable and progressive.

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.

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.