We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations include severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband’s low levels of citrulline and lactic acidosis provoked by administration of depakoke are evocative of a mitochondrial etiology. However, the genotype-phenotype correlation remains undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provide evidence of a deficient oxidative phosphorylation pathway responsible for ATP synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis reveals metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirms the suspected mitochondrial etiology, as the proband’s mitochondria exhibit an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that sub-optimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward OXPHOS leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of fetal and postnatal brain.

In our work, using the analysis of DNA barcodes and morphology (wing color, male genitalia, sphragis shape in females), we show that the group of species close to P. mnemosyne is represented by two phylogenetic lineages, the western and eastern ones. The eastern lineage includes P. stubbendorfii, P. glacialis and P. hoenei. The western lineage includes three morphologically similar species, P. mnemosyne (Western Eurasia), P. turatii (southwestern Europe) and P. nubilosus stat. nov. (Turkmenistan and NE Iran), as well as P. ariadne (Altai). The latter species differs from the rest of the group in the presence of red spots on the wings. Parnassius mnemosyne s.s. is represented by four differentiated mitochondrial clusters that show clear association with specific geographic regions. We propose to interpret them as subspecies: P. mnemosyne mnemosyne (Central and Eastern Europe, N Caucasus, N Turkey), P. mnemosyne adolphi (the Middle East), P. mnemosyne orientalis (Tian Shan) and P. mnemosyne gigantea (Gissar-Alai in Central Asia). We demonstrate that in P. ariadne the red spots on the wing evolved as a reversion to the ancestral wing pattern. This reversion is observed in Altai, where the distribution areas of the western lineage, represented by P. ariadne, and the eastern lineage, represented by P. stubbendorfii, overlap. These two species hybridize in Altai, and we hypothesize that the color change in P. ariadne is the result of reinforcement of prezygotic isolation in the contact zone. Lectotype of Parnassius mnemosyne var. nubilosus Christoph, 1873 is designated.

Recently, we isolated and characterized a new pool of mesenchymal stem cells- HPC (Hoof Progenitor Cells), which reside in the coronary corium of equine hooves. We hypothesize, that due to their location, HPC may be involved in the pathogenesis of laminitis, and could possibly be utilized in its treatment. The aim of this study was to compare the newly described HPC to a well-established cell pool-ASC (Adipose Stem Cells). The two cell populations were maintained either in standard culture conditions or under a hyperinsulinemic milieu as hyperinsulinemia is often observed alongside laminitis. Cell cycle dynamics, mitochondrial membrane potential and oxidative stress were analyzed with microcapillary cytometry. Furthermore, the expression of key markers of mitochondrial metabolism, oxidative stress, apoptosis, immunomodulation and insulin signalling were analyzed with the RT-qPCR method. Additionally, a selected panel of miRNA was analyzed with the RT-qPCR method. In standard culture conditions, ASC exhibit higher proliferation than HPC while in hyperinsulinemia a shift towards S phase was observed in both populations. As for the mitochondrial membrane potential, in standard culture conditions, HPC was characterized by a higher percent of live cells. Hyperinsulinemia did not strongly affect the mitochondrial membrane potential of the analyzed populations. Our findings indicate that HPC are characterized by higher activity in terms of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under standard culture conditions. Yet in both populations, a diminished mitochondrial dynamic and metabolism was observed in hyperinsulinemia. The analysis of oxidative stress revealed, that HPC might possess somewhat higher resistance towards oxidative stress than ASC. Minimal change was observed in the expression of key markers of apoptosis in ASC and HPC under hyperinsulinemia. The analysis of key immunomodulatory markers indicated that HPC may help the cytokine storm for a more effective phenotype change to an immunosuppressing pool of cells with better migratory and healing abilities under hyperinsulinemia than ASC. As for insulin signalling, the obtained data suggests that HPC might be more resistant to hyperinsulinemia and may have greater therapeutic potential in reducing laminitis. Obtained results demonstrated that HPC possesses better potential to modulate the PTEN-AKT pathway by miR-21 and reverse high glucose and high insulin-induced insulin resistance. Taken together, the obtained results indicate that HPC may be a very promising cell pool with therapeutic potential in laminitis treatment, and could be more effective than ASC.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease's immunopathological complexity and explore new therapeutic targets. Since an altered redox state contributes to immune system dysregulation, this document briefly addresses the role of oxidative stress (OS), oxidative DNA damage, antioxidant enzymes, mitochondrial function, and mitophagy in SLE and LN. Although adaptive immunity's participation in the development of autoimmunity is undeniable, increasing data emphasize the importance of innate immunity elements, particularly the Toll-like receptors (TLRs) that recognize nucleic acid ligands, in inflammatory and autoimmune diseases. Here, we discuss the intriguing role of TLR7 and TLR9 in developing SLE and LN. Also included are the essential characteristics of conventional treatments and some other novel and little-explored alternatives that offer options to improve renal function in LN.

Molecular autism research is evolving towards a biopsychosocial framework that is more informed by autistic experiences. In this context, research aims are moving away from correcting external autistic behaviors and towards alleviating internal distress. Autism Spectrum Conditions (ASCs) are associated with high rates of depression, suicidality and other comorbid psychopathologies, but this relationship is poorly understood. Here, we integrate emerging characterizations of internal autistic experiences within a molecular framework to yield insight into the prevalence of psychopathology in ASC. We demonstrate that descriptions of social camouflaging and autistic burnout resonate closely with the accepted definitions for early life stress (ELS) and chronic adolescent stress (CAS). We propose that social camouflaging could be considered a distinct form of CAS that contributes to allostatic overload, culminating in a pathophysiological state that is experienced as autistic burnout. Autistic burnout is thought to contribute to psychopathology via psychological and physiological mechanisms, but these remain largely unexplored by molecular researchers. Building on converging fields in molecular neuroscience, we discuss the substantial evidence implicating mitochondrial dysfunction in ASC to propose a novel role for mitochondrial allostatic load in the relationship between autism and psychopathology. An interplay between mitochondrial, neuroimmune and neuroendocrine signaling is increasingly implicated in stress-related psychopathologies, and these molecular players are also associated with neurodevelopmental, neurophysiological and neurochemical aspects of ASC etiology. Together, this suggests an increased exposure and underlying molecular susceptibility to ELS that increases the risk of psychopathology in ASC. This article describes an integrative framework shaped by autistic experiences that highlights novel avenues for molecular research into mechanisms that directly affect the quality of life and well-being of autistic individuals. Moreover, this framework emphasizes the need for increased access to diagnoses, accommodations, and resources to improve mental health outcomes in autism.

Cytosine (C) to uracil (U) RNA editing is one of the most important post-transcriptional processes, however exploring C-to-U editing events efficiently within the crop mitochondrial genome remains a challenge. An improving predictive RNA editor for crop mitochondrial genomes, iPReditor-CMG, was proposed, which was based on SVM, three common crop mitochondrial genomes and self-sequenced tobacco mitochondrial ATPase. After multi-combination feature extracting, high-dimension feature screening and multi-test independent predicting, the results showed that the average accuracy of intraspecific prediction was 0.85, and the highest value even up to 0.91, which outperformed the previous reference models. While the prediction accuracies were 0.78 between dicotyledons and no more than 0.56 between dicotyledons and monocotyledons, implying a possible similarity in C-to-U editing mechanisms among close relatives. The best model was finally identified with an independent test accuracy of 0.91 and an area under the curve of 0.88, and further suggested that five unreported feature sequences TGACA, ACAAC, GTAGA, CCGTT and TAACA were closely associated with the editing phenomenon. Multiple evaluation findings supported that the iPReditor-CMG could be effectively applied to predict crop mitochondrial editing sites, which may contribute to insight into their recognition mechanisms and even other post-transcriptional events in crop mitochondria.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles which may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlighted that mitochondrial dysfunction due to loss of mitochondrial flexibility, may arise before overt NAFLD and since the early stages of liver injury. Mitochondrial failure not only promotes hepatocellular damage, but also release signals (mito-DAMPs) which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by remodeling of glucidic-lipidic metabolism combined to reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research purposes and for development of potential preventive or curative strategies.

Phospholipase Dα1 (PLDα1) belongs to phospholipases, a large phospholipid hydrolyzing protein family. PLDα1 has a substrate preference for phosphatidylcholine leading to enzymatic production of phosphatidic acid, a lipid second messenger with multiple cellular functions. PLDα1 itself is implicated in biotic and abiotic stress responses. We present here a shot-gun differential proteomic analysis on roots of two pldα1 mutants compared to the Col-0 wild type. Our data suggest new roles of PLDα1 in endomembrane transport, mitochondrial protein import and protein quality control and glucosinolate biosynthesis. Thus, we identified proteins involved in endocytosis, endoplasmic reticulum-Golgi transport and attachment sites of endoplasmic reticulum and plasma membrane (V-type proton ATPases, protein transport protein SEC13 homolog A, vesicle-associated protein 1-2, vacuolar protein sorting-associated protein 29, syntaxin-32, all upregulated in the mutants), mitochondrial import and electron transport chain (mitochondrial import inner membrane translocase subunits TIM23-2 and TIM13, mitochondrial NADH dehydrogenases, ATP synthases, cytochrome c oxidase subunit 6b-1, ADP,ATP carrier protein 2, downregulated in the mutants) and glucosinolate biosynthesis (3-isopropylmalate dehydrogenases 1, 2 and 3, methylthioalkylmalate synthase 1, cytochrome P450 83B1, Glutathione S-transferase F9, indole glucosinolate O-methyltransferase 1, adenylyl-sulfate kinase 1, all upregulated in mutants). Our results suggest broader biological roles of PLDα1 as anticipated so far.

The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese Yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and the extract was analyzed by HPLC. The expression of C2C12 myotubes differentiation and mitochondrial biogenesis regulators were determined by reverse transcriptase (RT)-PCR or Western blot. The glucose levels and total ATP contents were determined by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased of MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of mitochondrial biogenesis regulating proteins, PGC1?, Sirt-1, NRF-1, and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased the glucose uptake levels and the ATP contents. Finally, HPLC analysis revealed that the yam extract contained 1.53% of allantoin. Yam extract and allantoin, stimulated myoblast differentiation into myotubes and increased energy production through upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent the skeletal muscle dysfunction through stimulation of energy metabolism.

A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. Examination of tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some of the neuronal ceroid lipofuscinosis (NCL) diseases. The also dog exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband’s DNA revealed a homozygous C to T substitution that altered the intron 3 – exon 4 splice site of CLN6. Other mutations in CLN6 cause NCL diseases in humans and animals including dogs. CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog is classified as an NCL resulting from the absence of CLN6 protein. Screening the dog’s genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the CLN6 disease variant is likely to be present in other mixed breed dogs and at least some of the ancestral breeds.

High incidence of epithelial malignancies in HIV-1 infection is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), most often HPV16. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells exposed to both viruses have long been anticipated. Here, we delineated the effects on in vitro and in vivo properties of HPV16-infected cervical cancer cells of HIV-1 reverse transcriptase. Epidermoid carcinoma Ca Ski cells were made to express RT of HIV-1 clade A (RT_A) or Green Fluorescence Protein (GFP) by lentiviral transduction, subclones with one or six copies of RT_A and six copies of GFP DNA were generated. Expression by subclones of GFP was assessed by flow cytometry, and of RT_A, by Western blotting. Cells were assessed for the levels of mRNA of the RT_A, E6 and its isoforms, and cellular factors characterizing oxidative stress, and EMT by the real-time PCR. Parameters of glycolysis and mitochondrial respiration were assessed by Seahorse technology. Subclones were surveyed for the changes in cell cycle, doubling time, migration capacity, clonogenic activity and for the capacity to form tumors in nude mice. Ca Ski RT_A produced 20-55 fg of RT_A per cell. Expression of RT_A caused a proportional increase in the expression of E6*I isoform. In Ca Ski, RT_A suppressed mitochondrial respiration and oxygen consumption, and increased glycolysis. Compared to parental cells and GFP control, transcription in Ca Ski RT_A of epithelial (E-CADHERIN) state marker was increased, and of mesenchymal (VIMENTIN) decreased, indicating acquisition by cells of the hybrid epithelial/mesenchymal (E/M) phenotype. While Ca Ski GFP and Ca Ski RT_A with one gene insert had reduced migration rate, decreased clonogenic activity in vitro, and diminished capacity to form tumors in nude mice, increase in RT_A copicity/expression mitigated these effects. Altogether, expression of HIV-1 RT_A gave Ca Ski cells the plasticity required to overcome negative effects of lentiviral transduction and potentially increased their tumorigenicity.

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.

Classic mitochondrial DNA phylogenetic and phylogeographic studies on the aboriginal, historical, and extant human populations of the Canary Islands have contributed to reconstructing the origin and settlement on the islands of the pre-European colonizers. The recent use of new ancient DNA targeted enrichment and next-generation sequencing techniques on new Canary Islands samples has greatly improved these molecular results, but it has also revealed significant contamination in the islands' previous aboriginal genetic pool. Following a thorough review of these cases, new phylogeographic analysis revealed the existence of a heterogeneous aboriginal population, asymmetrically distributed across the various islands, and most likely descended from a unique main settlement. These new results and new proposed coalescent ages are compatible with a Roman-mediated arrival driven by the exploitation of the purple on the Canary Islands.

Glutamate excitotoxicity is implicated in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer’s disease, for which central insulin resistance is a comorbid condition. Massive glutamate release primarily through ionotropic N-methyl-D-aspartate receptors (NMDARs) causes a sustained rise in [Ca2+]i, followed by mitochondrial depolarization and an increase in intracellular O2• (superoxide) production. Recently, we found that insulin protected neurons against excitotoxicity by diminishing the delayed calcium deregulation (DCD), However, a role of insulin in superoxide production in excitotoxicity still needs to be clarified. The present study is aimed to investigate the effects of insulin on glutamate-evoked superoxide generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in rats cultured cortical neurons. We found that insulin significantly diminished both the intracellular and mitochondrial superoxide production in neurons exposed to glutamate and there was a strong linear correlation between [Ca2+]i and intracellular superoxide. MK 801, an inhibitor of NMDAR-gated Ca2+ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments on sister cultures, insulin diminishes neuronal death. Thus, collectively, data obtained suggest that insulin diminishes glutamate-induced superoxide production in neurons via fall of [Ca2+]i increased and thereby improves viability of neurons

The rapid increase in metabolic diseases occurred in the last three decades in both industrialized and developing countries has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as consequence of a high dietary sugars intake. Animal models of high sugars consumption, in particular fructose, have reported AGEs accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agent when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidences also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and brain, affecting not only metabolic control, but global health. Indeed, the here reviewed most recent reports on the effects of high sugars consumption and diet-derived AGEs on human health suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

For the treatment of cancer and other diseases, therapeutic targeting of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) is an attractive approach. RNA-based therapeutics have been extensively researched over the past decade, with antisense oligonucleotides and small interfering RNAs being the most commonly used. Some of these have even gained FDA approval. However, the results of trials have been mixed, with some studies reporting strong effects while others have shown limited effectiveness or toxicity. Alternative treatments, such as antimiRNAs, are currently in clinical trials. There is growing interest in the use of lncRNA-based therapies. This Perspective discusses the main challenges of ncRNA therapeutics, including specificity, delivery and tolerability. It also highlights emerging approaches that aim to improve their success.

Apoptosis, necroptosis, and autophagy are cellular mechanisms by which cells are programmed to die under a wide range of physiological and developmental stimuli. A multitude of protein mediators of programmed cell death have been identified and apoptosis, necroptosis, and autophagy signals have been found to utilize common pathways elucidating the proteins involved. This narrative review focuses on caspase-dependent and caspase-independent programmed cell death systems. Included studies of caspase-dependent programmed cell death include extrinsic pathway apoptotic mechanisms including phosphatidylserine (PS), FAS (APO-1/CD95), Tumor Necrosis Factor (TNF) Receptor type 1 (TNF-R1) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) and intrinsic or mitochondrial pathway such as Cytochrome C, the Bcl-2 family of proteins and Smac/Diablo. The Bcl-2 family has apoptotic mediators Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), Bcl-2-Interacting Protein BIM (Bim), Bcl-2 agonist of cell death (Bad), Bid, Bcl-2 adenovirus E1B 19kDa-interacting protein 1 NIP3 (Bnip3), BMF, HRK, Noxa and PUMA and anti-apoptotic proteins such as Bcl-2 itself, Mcl-1, Bcl-w, A1, and Bcl-XL. Moreover, caspase-independent programmed cell death pathways include the mitochondrial pathway with the protein mediators Apoptosis Inducing Factor (AIF), and Endonuclease G, the pathways Necroptosis, and Autophagy. Understanding programmed cell death from those reported in this review could shed substantial light on the processes of biological homeostasis. In addition, identifying specific proteins involved in these processes is mandatory to identify molecular biomarkers as well as therapeutic targets. This knowledge could provide the ability to modulate the programmed cell death response and could lead to new therapeutic interventions in a wide range of diseases.

The Supersymmetry Genetic code (SSyGC) table is based on five physicochemical symmetries: 1) double mirror symmetry on the principle of the horizontal and vertical mirror symmetry axis between all bases (purines [A, G) and pyrimidines (U, C)], and 2) of bases in form of codons 3) direct – complement like codon/anticodon symmetry in the sixteen alternating boxes of the genetic code columns, 4) A+T rich and C+G rich alternate codons in the same row between both columns of the genetic code, 5) the same position between divided and undivided codon boxes in relation to horizontal mirror symmetry axes. The SSyGC table has a unique physicochemical purine – pyrimidine symmetry net which is as the core symmetry common for all, more than thirty different nuclear and mitochondrial genetic codes. This net is present in the SSyGC table of all RNA and DNA living species. None of these symmetries is present in the Standard Genetic Code (SGC) table which is constructed on the alphabetic horizontal and vertical U-C-A-G order of bases. Here we show that the free energy value of each codon incorporated as fundamentally mapping the “energy code” in the SSyGC table is compatible with mirror symmetry. On the other hand, in the SGC table the same free energy values of codons are dispersed and a mirror symmetry between them is not recognizable. At the same time the mirror symmetry of the SSyGC table and the DNA quadruplets together with our classification of codons/trinucleotides are perfectly imbedded in the mirror symmetry energy mapping of codons/trinucleotides and point out in favor of maintaining the integrity of the genetic code and DNA genome. We also argue that physicochemical symmetries of the SSyGC table in the manner of the purine – pyrimidine symmetry net, the quadruplet symmetry of DNA molecule and the free energy of codons have remined unchanged during all of evolution. The unchangeable and universal symmetry properties of the genetic code, DNA molecule and energy code are decreasing disorder between codons/trinucleotides and shed a new light on evolution. Diversity in all living species on Earth is broad, but the symmetries of the Supersymmetry Genetic Code as the code of life and the DNA quadruplets related to the” energy code” are unique, unchangeable and have the power of natural laws.

Age-related declines in vitamin D receptor (VDR) expression have been implicated in the onset of sarcopenia. The increased expression of VDR in muscle is known to increase muscle mass, whereas VDR knockout in the muscle decreases muscle mass in rats. Similar to VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. 1,25VD3 treatment increases the expression of VDR, SIRT1, and SIRT3 in C2C12 myotubes. Additionally, it stimulates the differentiation of C2C12 myoblasts into myotubes. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins (MyHC I and II), MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown in myoblasts induces myotube atrophy by downregulating SIRT1 and SIRT3 expression. Furthermore, 1,25VD3 ameliorated muscle atrophy and apoptosis induced by IFN-γ/TNF-α co-treatment to C2C12 myotube. Moreover, 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results indirectly suggest that 1,25VD3 has the potential to develop as a therapeutic or preventive agent for age-mediated muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis and inhibiting the FoxO3-mediated atrophy pathway.

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.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus, and in SH-SY5Y cells, after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with most pronounced effects in latently infected-HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the “powerhouse of the cell” turns into the “factory of death” is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction to its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer’s Disease and Parkinson’s Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.

High resolution melting (HRM) analysis is a powerful detection method for fast, high-throughput post-PCR analysis. A two-step HRM marker system was developed for identification of the N-, S-, R- and T-cytoplasms of onion. In the first step for identification of N-, S-, and R-cytoplasms, one forward primer was designed to the identical sequences of both cox1 and orf725 genes and two reverse primers specific to the polymorphic sequences of cox1 and orf725 genes were used. For the second step breeding lines with N-cytoplasm were evaluated with primers developed from the orfA501 sequence to distinguish between N- and T-cytoplasms. An amplicon with primers to the mitocondrial atp9 gene was used as an internal control. The two-step HRM marker system was tested using 246 onion plants. HRM analysis showed that the most common source of CMS, often used by Russian breeders, is S-cytoplasm, the rarest type of CMS is R-cytoplasm, and the proportion of T-cytoplasm among the analyzed breeding lines was 20.5%.

Mitochondrial dysregulation is implicated in numerous neurological disorders. Mitochondrial dynamics, including biogenesis, fusion and fission, are essential components of mitostasis which is modulated by complex regulatory mechanisms. Although expression studies are often used to investigate mitochondrial dynamics, these studies may be limited by the interdependent and temporal nature of mitostasis. Transmission electron microscopy (TEM) and cryogenic preparation methods provide a direct approach to examine mitochondrial ultrastructure in neurons. We investigated the utility of TEM to visualize mitochondrial morphological changes in SH-SY5Y cells treated with propionic acid (PPA). We examined whether morphological alterations were associated with differences in membrane potential or expression of biogenesis, fusion and fission genes. PPA induced a significant decrease in mitochondrial area (p<0.01 5mM), Feret's diameter and perimeter (p<0.05 5mM), and in area2 (p<0.05 3mM, p<0.01 5mM) – consistent with a shift towards fission. Morphological changes were not associated with significant differences in mitochondrial membrane potential. However, we observed decreased gene expression of NRF1 (p<0.01), TFAM (p<0.05), and STOML2 (p<0.0001). These data support a disruption of the balance in dynamics to preserve function under stress. This demonstrates the utility of TEM to provide insight into mitochondrial dynamics and function which can inform targeted mechanistic investigations into neuropathology.

Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protect neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce Hsps. Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.

Short chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1-16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

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

Non-compliant (NC) structures are often encountered in building construction in developing countries. This is a condition whereby erected buildings do not follow regulatory standards, especially in the provision of reinforcements. Therefore, under an earthquake load, the structures do not have sufficient resistance against such load. The structural elements of the building, which often have NC conditions, are the beam-column joints because they do not contain adequate shear reinforcements due to installation difficulty. This study aims to determine the structural performance of the reinforced concrete (RC) frame, which has a reinforcement deficiency in the beam-column joints. Numerical simulation was conducted on the Kakaletsis structure model by modifying the reinforcement details at the joints to represent the NC conditions. The non-linear modeling and analysis of the structural model were carried out using ATENA software. The analysis showed that the reduction in shear reinforcements in the NC model joint caused a decrease in load-carrying capacity by about 26.04%. A shift was also observed in the collapse pattern, i.e., from the beam to the end of the column, causing global failure and reducing the undamaged but increasing more severely damaged condition. This showed that the NC structure, due to the non-conformance of reinforcement, significantly reduced the structure's performance.

An exhaustive list of thirteen instances of reports confirming experimentally the relativistic Doppler relation, are examined. For those involving longitudinal Doppler, the non-relativistic relation is seen to be confirmed, within the reported experimental accuracies, to the same degree as the standard relativistic relation. Higher values of the speed of the emitter would be required to examine further the claimed confirmations. For those reports involving saturation spectroscopy, there is much confusion over the appropriate Doppler relation to be used, together with some serious analytical flaws. For the two cases that involve transverse Doppler, there are seen to be either serious faults in the theoretical part, or intrusion from the first order effect. Therefore, the reported conclusions - that the results for the experiments confirm the relativistic SR relation - cannot be justified by any of the experimental works.

We introduce a novel key exchange protocol based on non-commutative matrix multiplication defined in $\mathbb{F}_p^{n \times n}$. The security of our method does not rely on computational problems as integer factorization or discrete logarithm whose difficulty is conjectured. We show that the public, secret and channel keys become indistinguishable to the eavesdropper under matrix multiplication. Remarkably, for achieving a 512-bit security level, the public key is 1024 bits and the private key is 768 bits, making them the smallest keys among post-quantum key exchange algorithms. Also, we discuss how to achieve key authentication, interdomain certification and Perfect Forward Secrecy (PFS). Therefore, Lizama's algorithm becomes a promising candidate to establish shared keys and secret communication between (IoT) devices in the quantum era.

We introduce a novel key exchange protocol based on non-commutative matrix multiplication defined in $\mathbb{Z}_p^{n \times n}$. The security of our method does not rely on computational problems as integer factorization or discrete logarithm whose difficulty is conjectured. We claim that the unique eavesdropper's opportunity to get the secret/private key is by means of an exhaustive search which is equivalent to the unsorted database search problem. Furthermore, we show that the secret/private keys become indistinguishable to the eavesdropper. Remarkably, to achieve a 512-bit security level, the keys (public/private) are of the same size when matrix multiplication is done over a reduced 8-bit size modulo. Also, we discuss how to achieve key certification and Perfect Forward Secrecy (PFS). Therefore, Lizama's algorithm becomes a promising candidate to establish shared keys and secret communication between (IoT) devices in the quantum era.

This article develops duality principles and numerical results for a large class of non-convex variational models. The main results are based on fundamental tools of convex analysis, duality theory and calculus of variations. More specifically the approach is established for a class of non-convex functionals similar as those found in some models in phase transition. Finally, in the last section we present a concerning numerical example and the respective software.

Let $\mathbb{K}$ be a non-Archimedean (complete) valued field satisfying \begin{align*} \left|\sum_{j=1}^{n}\lambda_j^2\right|=\max_{1\leq j \leq n}|\lambda_j|^2, \quad \forall \lambda_j \in \mathbb{K}, 1\leq j \leq n, \forall n \in \mathbb{N}. \end{align*} For $d\in \mathbb{N}$, let $\mathbb{K}^d$ be the standard $d$-dimensional non-Archimedean Hilbert space. Let $m \in \mathbb{N}$ and $\text{Sym}^m(\mathbb{K}^d)$ be the non-Archimedean Hilbert space of symmetric m-tensors. We prove the following result. If $\{\tau_j\}_{j=1}^n$ is a collection in $\mathbb{K}^d$ satisfying $\langle \tau_j, \tau_j\rangle =1$ for all $1\leq j \leq n$ and the operator $\text{Sym}^m(\mathbb{K}^d)\ni x \mapsto \sum_{j=1}^n\langle x, \tau_j^{\otimes m}\rangle \tau_j^{\otimes m} \in \text{Sym}^m(\mathbb{K}^d)$ is diagonalizable, then \begin{align}\label{WELCHNONABSTRACT} \max_{1\leq j,k \leq n, j \neq k}\{|n|, |\langle \tau_j, \tau_k\rangle|^{2m} \}\geq \frac{|n|^2}{\left|{d+m-1 \choose m}\right| }. \end{align} We call Inequality (\ref{WELCHNONABSTRACT}) as the non-Archimedean version of Welch bounds obtained by Welch [\textit{IEEE Transactions on Information Theory, 1974}]. We formulate non-Archimedean Zauner conjecture.

Nonionizing millimeter-waves (MMW) interact with cells in a variety of ways. Here the inhibited cell division effect was investigated using 85-105 GHz MMW irradiation within the ICNIRP (International Commission on Non-Ionizing Radiation Protection) non-thermal 20 mW/cm2 safety standards. Irradiation using a power density of about 1.0 mW/cm2 , SAR over 5-6 hours on 50 cells/μl samples of Saccharomyces cerevisiae model organism resulted in 62% growth rate reduction compared to the control (sham). The effect was specific for 85-105 GHz range, and was energy and cell density dependent. Irradiation of wild type and Δrad52 (DNA damage repair gene) deleted cells presented no differences of colony growth profiles indicating non-thermal MMW treatment does not cause permanent genetic alterations. Dose versus response relations studied using a standard horn antenna (~1.0 mW/cm2) and compared to that of a compact waveguide (17.17 mW/cm2) for increased power delivery resulted in complete termination of cell division via non-thermal processes supported by temperature rise measurements. We have shown that non-thermal MMW radiation has potential for future use in treatment of yeast related diseases and other targeted biomedical outcomes.

Nonionizing millimeter-waves (MMW) are reported to interact with cells in a variety of ways. Possible mechanisms of the inhibited cell division effect were investigated using 85-105 GHz MMW irradiation within the ICNIRP (International Commission on Non-Ionizing Radiation Protection) non-thermal 20 mW/cm² safety standards. ~1.0 mW/cm² exposure over 5-6 hours treatment on 50 cells/μl samples of Saccharomyces cerevisiae model organism, resulted in 62% growth rate reduction compared to control (sham). The effect was specific for 85-105 GHz range and energy dose and cell density dependent. Irradiation of wild type and Δrad52 (DNA damage repair gene) deletion cells presented no differences of colony growth profiles indicating non-thermal MMW treatment does not cause genetic alterations. Dose versus response relations studied using a standard horn antenna (~1.0 mW/cm²) and compared to that of a compact waveguide (17.17 mW/cm²) for increased power delivery resulted in complete termination of cell division via non-thermal processes supported by temperature rise measurements. Combinations of MMW mediated Structure Resonant Energy Transfer (SRET), membrane modulations eliciting signaling effects, and energetic resonance with biomolecules were indicated to be responsible for the observations reported. Our results provide novel mechanistic insights enabling innovative applications of nonionizing radiation procedures for eliciting targeted biomedical outcomes.

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.

With the rapid increase in diabetes worldwide, the number of patients with diabetic kidney disease (DKD), a complication of diabetes mellitus, is also on the rise. DKD is a major cause of chronic kidney disease progressing to end-stage renal failure; however, current medical treatments for DKD do not achieve satisfactory outcomes. Molecular hydrogen (H2) is an antioxidant that selectively reduces hydroxyl radicals, a reactive oxygen species with a very potent oxidative capacity. H2 was recently shown to exert not only antioxidant, but also anti-inflammatory, cell lethality-regulating, and signal transduction-regulating effects, and is now being applied clinically. Many factors contribute to the onset and progression of DKD, with mitochondrial dysfunction, oxidative stress, and inflammation being strongly implicated. Recent preclinical and clinical trials reported that substances with antioxidant properties may slow the progression of DKD. Therefore, we conducted a literature review on animal models and human clinical trials in which H2 showed efficacy against various renal diseases. This literature review and our previous findings collectively suggest that H2 exerts therapeutic effects in patients with DKD by improving mitochondrial function. Future large-scale clinical studies are needed to confirm these findings.

RNA polymerase III (RNAP III) holoenzyme activity and its products processing have been linked to several metabolic dysfunction in lower and in higher eukaryotes. Alterations in the activity of RNAP III driven synthesis of non-coding RNA, causes extensive changes in the glucose metabo-lism. Increased RNAP III activity in S.cerevisiae maf1Δ strain, manifests with lethality when grown on non-fermentable carbon source. This lethal phenotype is suppressed by reducing tRNA syn-thesis. The cause for the lack of growth neither the underlying molecular mechanism has not been deciphered and has been awaiting a scientific explanation for a decade. Our previous proteomics data suggested mitochondrial dysfunction of the strain. Using model mutant strains maf1Δ (with increased tRNA abundance) and rpc128-1007 (with reduced tRNA abundance) we collected data showing major changes in TCA cycle metabolism of the mutants that explain the phenotypic ob-servations. The present study, based on 13C flux data and analysis of TCA enzymes activities, identifies the flux constraints in the mitochondrial metabolic network. The lack of growth is associated with the de-crease in TCA cycle activity and downregulation of the flux towards glutamate, aspartate and phosphoenolopyruvate (PEP), the metabolic intermediate feeding gluconeogenic pathway. rpc128-1007, the strain that is unable to increase tRNA synthesis due to a mutation in C128 subunit, has increased activity of TCA cycle under non-fermentable conditions. To summarize, cells with non-optimal activity of RNAP III, undergo substantial adaptation to a new metabolic state, that make them vulnerable under specific growth conditions. Our results strongly suggest that balanced, non-coding RNA synthesis that is coupled to glucose signaling is a fundamental requirement to sustain cell’s intracellular homeostasis and flexibility under changing growth conditions. Presented results provide insight into the possible role of RNAP III in mito-chondrial metabolism of other cell types.

Oxidative stress initiates and facilitates the disruption of the structural integrity of hepatic mitochondria, which leads to steatosis, steatohepatitis, fibrosis, and cirrhosis. It is now evident that mitochondrial dysfunction could be responsible for alcoholic liver disease (ALD). The challenge in treating ALD has been the limited availability of hepatoprotective agents and the lack of highly efficient delivery systems. Recent studies have shown that mitochondria-targeted therapies could address mitochondrial dysfunction (MD), which may greatly improve hepatoprotection and ALD treatment. This mini-review discusses the potential role of mitochondria-targeted antioxidants (MTAs) in the maintenance of hepatocellular integrity. This report also considers the mechanism of liver injury induced by alcohol and the progression of ALD from a mitochondrial oxidative damage perspective as well as the possible mechanistic actions of hepatoprotective antioxidants. Preliminary studies suggest the prospect of MTAs as anti-ALD and hepatoprotective agents.

Sideroflexins (SLC56 family) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function but, since their first description, they were thought to be metabolite transporters probably required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 has been recently identified as the previously unknown mitochondrial transporter of serine. Nevertheless, pending questions on the molecular function of sideroflexins remain unsolved, especially their link with iron metabolism. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse - but growing - evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Since an imbalance in iron homeostasis can be detrimental at the cellular and organismal levels, we also investigate the relationship between sideroflexins, iron and physiological disorders. Investigating Sideroflexins’ functions constitutes an emerging research field of great interest and will certainly lead to main discoveries on mitochondrial physiopathology.

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.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders globally, and leads to an excessive loss of dopaminergic neurons in the substantia nigra of the brain. Circulating cell-free DNA (ccf-DNA) are double-stranded DNA fragments of different sizes and origins that are released into the serum and cerebrospinal fluid (CSF) due to cell death (i.e., necrosis and apoptosis) or are actively released by viable cells via exocytosis and NETosis. Methods: Using droplet digital polymerase chain reaction (ddPCR) we comprehensively analyzed and distinguished ccfDNA and ccf mtDNA in the serum and CSF of PD and control patients. Results: The quantitative analysis of serum ccf-DNA in PD patients demonstrated significant increase of ccf mtDNA and ccfDNA compared to healthy control patients and significantly higher copy of ccf mtDNA when compared to ccfDNA. Next, the serum ccf mtDNA levels significantly increased in male PD patients compared to healthy male controls. Furthermore, CSF ccf mtDNA in PD patients increased significantly compared to ccfDNA, and ccf mtDNA decreased in PD patients compared to healthy controls. These decreases were not statistically significant, but were in agreement with previous data. In-terestingly, ccf mtDNA increased in healthy control patients in both serum and CSF as compared to ccfDNA. Limitations: the small sample size of serum and CSF were the main limitations of this study. Conclusion: To the best of our knowledge, this is the first comprehensive study on serum and CSF of PD patients using ddPCR and indicating the distribution of the copy number of ccf mtDNA, as well as ccfDNA. If validated, we suggest that ccf mtDNA has greater than ccfDNA potential to lead the development of novel treatments for PD patients.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical mem-braneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vascula-ture are shown to have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Overproduction of lipids by the tumor is suspected to be due to a combination of two processes: i) dysfunctional oxidative phosphorylation in mitochondria that causes metabolic backup and ac-cumulation of acetyl-CoA, as well as ii) the overproduction of pyruvate due to the tumor cell reli-ance on overactive glycolysis. Tumor cells use lipids for structural components but cannot use them for energy if their oxidative phosphorylation is dysfunctional, which seems to be the case in the tumor cells we examined. This lipid-rich environment, however, offers tumor cells certain advantages: protection from the immune system, non-lipophilic drugs, and oxidative stress. Our research highlights the significant presence of lipid overproduction in both IDH1-wild type glio-blastoma and IDH1-mutant astrocytoma tumors, leading to diverse lipid accumulations in var-ious cellular compartments and structures. This lipid excess stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune re-sponses, non-lipophilic drugs, and free radicals.

Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD) there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an on-line survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood while surgery and the Atkin’s/Modified Atkin’s Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but none-the-less these data provide some insight into novel relationships that may assist in a better understanding of epilepsy in ASD and providing insight into personalizing epilepsy care in ASD.

The fatty acid elongase ELOngation of Very-Long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, do-cosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn6) in-vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondial-dehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with high voltage-dependent anion channel (VDAC) and adenine nucleotide trans-locase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission elec-tron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.

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.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

Non-isocyanate polyurethane synthesis by non-Sn catalysis is an essential challenge toward green polyurethane synthesis. Bismuth compounds are attractive candidates due to their low cost, low toxicity, and availability to urethane chemistry. We applied various Bi catalysts to the self-polycondensation of a bishydroxyurethane monomer and found BiCl3 to be an excellent catalyst through optimization. The catalytic activity and price of BiCl3 are comparable to those of Bu2SnO, while its toxicity is significantly low. BiCl3 is, therefore, a promising alternative to Sn-based catalysts in non-isocyanate polyurethane synthesis.

Wine is a processed beverage that offers high nutritional and health benefits. It is produced from grape must, which undergoes fermentation by yeasts (and sometimes lactic acid bacteria) to create a product that is highly appreciated by consumers worldwide. However, if only one type of yeast, specifically Saccharomyces cerevisiae, were used in the fermentation process, the resulting wine would lack aroma and flavor and may be rejected by consumers. To produce wine with a desirable taste and aroma, non-Saccharomyces yeasts are necessary. These yeasts contribute volatile aromatic compounds that significantly impact the wine’s final taste. They promote the release of primary aromatic compounds through a sequential hydrolysis mechanism involving several glycosidases unique to these yeasts. This review will discuss the unique characteristics of these yeasts (Schizosaccharomyces pombe, Pichia kluyveri, Torulaspora delbrueckii, Wickerhamomyces anomalus, Metschnikowia pulcherrima, Hanseniaspora vineae, Lachancea thermotolerans, Candida stellata, and others) and their impact on wine fermentations and co-fermentations. Their existence and the metabolites they produce enhance the complexity of wine flavor, resulting in a more enjoyable drinking experience.

Post-quantum public cryptosystems introduced so far do not define an scalable public key infrastructure for the quantum era. We demonstrate here a public certification system based in Lizama’s non-invertible Key Exchange Protocol which can be used to implement a public key infrastructure (PKI), secure, scalable, interoperable and efficient. We show functionality of certificates across different certification domains. Finally, we discuss that non-invertible certificates can exhibit Perfect Forward Secrecy (PFS).

It is well established in literature that the public debt and economic growth bear positive and non-linear relationship. However, in recent literature, evidence of no causal relationship is found when accounted for endogeneity in case of advanced economies (Panizza & Presbitero, 2014). Chudik, Mohaddes, Pesaran, & Raissi, (2017) analyse the data on forty countries and find no evidence of universally applicable threshold effect in the relationship between debt and growth. These advancements in the debt-growth literature provides the motivation to re-explore the relationship between public debt and economic growth under non-linearity and endogeneity in context of developing economies of South Asia including Pakistan, India, Bangladesh and Sri-Lanka for the period 1980-2014. There exists a significant, positive but nonlinear relationship between the public debt and economic growth for the selected set of developing countries when accounted for endogeneity and non-linearity. The negative association between the public debt and economic growth for SAARC region is found when the debt level is higher than 61% of GDP which is quite lower than developed economies (90% of GDP). Individual threshold levels for debt-to-GDP ratio divulge that Sri Lanka, Pakistan and India need to control their public borrowings as their current debt levels are higher and/or around the respective threshold levels.

We establish a new Gagliardo-Nirenberg inequality characterized by radial symmetry and involving potentials exhibiting pure power polynomial behaviour. As an application of our result, we investigate the existence of extremals for this inequality, which also correspond to stationary solutions for the nonlinear Schrödinger equation with inhomogeneous nonlinearity, competing with Hs-subcritical nonlinearities, either of local or non-local nature.

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NAFLD-NASH-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progress to NASH, liver cirrhosis, and HCC. However, most of NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet (CDMRHFD) for 60 weeks. Treatment of CDMRHFD for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 36-week treatment. Liver nodule emerged at 12 weeks of the treatment, and diameter >2 mm liver tumors developed in all mice at 24 weeks of the treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemistry for NASH-HCC-targeted therapies or HCC prevention strategies.

Astronauts in space are subject to a continuous bombardment of ionizing radiation. The Earth's magnetic field and the ISS shield some biologically damaging particles traveling through. Still, travel beyond low-Earth orbit and extravehicular activities are exceedingly more dangerous and there is a concern for the acute and late-occurring adverse health effects befalling astronauts. So, it is vital to consider the current tools and models used to describe and study the organic consequences of ionizing radiation exposure. It is equally important to see where these models may improve. This article reviews the historical development and current state of knowledge of radiation effects impacting astronauts in orbit. We explain the space radiation environment, cellular microenvironment, and how these may be incorporated in radiobiological models to aid in our understanding of the influence space travel may have on astronaut health. The topics discussed in this paper include a review of DNA damage and repair mechanisms and the numerical models that aim to explain the biological effects resulting from ionizing radiation damage. Historically, radiobiological models focused on how radiation damages nuclear DNA, built upon the hypotheses of Crowther and Lea in the 1940s and 1960s, and neglected other sub-cellular targets outside of nuclear DNA.

ABSTRACTBackground: Crohn's disease (CD) is a chronic inflammatory bowel disorder with limited treatment options. Mitochondrial dysfunction has been implicated in CD pathogenesis, and mitochondrial-based interventions have emerged as a potential therapeutic avenue. This systematic review aimed to assess the efficacy of mitochondrial-based interventions in the management of CD.Methods: A systematic search of multiple databases was conducted to identify relevant studies in accordance with the PRISMA protocol. Inclusion criteria encompassed studies investigating mitochondrial-targeted interventions in CD patients. Methodological quality and risk of bias assessments were performed. Data synthesis involved both quantitative meta-analysis and qualitative narrative synthesis.Results: A total of 23 studies were included in this review, comprising randomized controlled trials, observational studies, and case reports. Mitochondrial-based interventions encompassed nutraceuticals, probiotics, exercise, and dietary modifications. However, the overall quality of evidence was moderate, primarily due to methodological limitations in some studies.Conclusion: This systematic review suggests that mitochondrial-based interventions hold promise as adjunctive therapies for CD management. They appear to contribute to clinical remission and amelioration of disease activity. Nevertheless, the moderate quality of evidence underscores the need for further well-designed clinical trials to substantiate these findings and delineate optimal intervention strategies.

Mitochondrial dysfunctions, e.g. abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy, activate innate immunity. Recent reports also showed that deletion of mitochondrial matrix peptidase ClpP in mice transcriptionally upregulates inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, immunoblots, and reverse transcriptase polymerase chain reaction. Anomalies in the mitochondrial unfolded protein responses pathway were prominent for the co-chaperone DNAJA3, and for its known interactor STAT1. Their mitochondrial dysregulation affected also their extra-mitochondrial abundance, as possible innate immune modulators. Increased expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). They can be explained by the accumulation of mitoribosomes and mitochondrial nucleoids in ClpP-null cells, which may act as damage-associated molecular patterns. The consistent dysregulation of these factors from early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

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

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.

(1) Background: Although multiple studies have reported on the therapeutic effects of Atezo+Bev for the treatment of NASH-related liver cancer, few studies have focused on its effect on liver reserve. Here, we aimed to compare the changes in hepatic reserve during the Atezo+Bev treatment of NAFLD/NASH-related HCC and of non-NAFLD/non-NASH-related HCC. (2) Methods: We retrospectively compared the changes in ALBI score in 109 patients with NAFLD/NASH or non-NAFLD/non-NASH during 12 weeks of treatment with Atezo+Bev for advanced HCC between September 2019 and January 2022. PSM was performed, and the OS, PFS, and PPS of the two groups were compared. (3)Results: The ALBI after 12 weeks of Atezo+Bev treatment was significantly worse in the NAFLD/NASH group than in the non-NAFLD/non-NASH group. Analysis of the 24 propensity score-matched pairs of cases with NAFLD/NASH or non-NAFLD non-NASH yielded similar results. The prognoses of the two groups were similar with respect to OS and PFS, but the NAFLD/NASH group had a significantly shorter PPS. The 24 matched pairs had similar OS and PFS, but the PPS of the NAFLD/NASH group was shorter. (4)Conclusion: Atezo+Bev treatment may worsen hepatic reserve, and there-fore life expectancy, in patients with NAFLD/NASH-related liver cancer.

This article develops a duality principle and a related convex dual formulation suitable for a large class of models in physics and engineering. The results are based on standard tools of functional analysis, calculus of variations and duality theory. In particular, we develop applications to a model in non-linear elasticity.

The connection of two phenomena - non-conservative friction forces and dissipation-induced instability can lead to many interesting engineering problems. The paper studies general material-dependent damping influence on dynamical instability of disc brake systems leading to brake squeal. The effect of general damping is demonstrated on a minimal and complex model of a disc brake. A complex system including material-dependent damping is defined in the commercial finite element software. The finite element model validated by experimental data on the brake-disc test bench is used to compute the influence of a pad and a disc damping variations on system stability by complex eigenvalue analysis. Analyzes show a significant sensitivity of the experimentally verified unstable mode of the system to the ratio of the damping between the disc and the friction material components.

Near-fault ground motions can cause severe damage to civil structures, including bridges. Safety assessment of these structures for near fault ground motion is usually performed through Non-Linear Dynamic Analyses, while faster methods are often used. IMPAb (Incremental Modal Pushover Analysis for Bridges) permits to investigate the seismic response of a bridge by considering the effects of higher modes, which are often relevant for bridges. In this work, IMPAb is applied to a bridge case study considering near-fault pulse-like ground motion records. The records were analyzed and selected from the European Strong Motion Database and the pulse parameters were evaluated. In the paper results from standard pushover procedures and IMPAb are compared with nonlinear Response-History Analysis (NRHA), considering also the vertical component of the motion, as benchmark solutions and incremental dynamic analysis (IDA). Results from the case study demonstrate that the vertical seismic action has a minor influence on the structural response of the bridge. Therefore IMPAb, which can be applied considering vertical motion, remains very effective conserving the original formulation of the procedure, and can be considered a well performing procedure also for near-fault events.

Abrasive Water Jet Machining (AWJM) is a non-conventional machining process that, unlike other methods, is deemed superior because of its applicability, versatility, and no heat-affected zones in the target material. The main objective of this paper was to develop a cheap, practical model for a low-pressure water jet cutting machine and provide some empirical test data for cutting delicate materials. Proper design calculations were performed and are included for both the water jet machine and the two-axis numerical control. Finite Element Analysis results validate the structural integrity of beams and columns in AWJM. Computational Fluid Dynamic analysis of the nozzle shows good agreement with the theoretical calculations regarding the pressure and velocity of the water-abrasive mixture exiting the nozzle. Modal analysis in ANSYS was done to mitigate potential failure due to resonance induced by vibrations. Limited testing on various thicknesses of polystyrene foam ranging from 1-5 mm thickness and rubber sheet of 1 mm thickness showed that even low pressure of 25-30 bar was sufficient to produce a kerf without any burr. However, extensive testing to report optimized parameters like nozzle transverse speed, standoff distance, abrasive flow rate, etc for working at low-pressure ranges is still a consideration for future investigation.

Postprandial glucose levels between 4 and 7.9 hours (PPG4–7.9h) correlate with mortality from various diseases including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4–7.9h predicted using this model. Receiver operating characteristic curve analysis showed that predicted PPG4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. Simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants.

Turbulent dissipation is a central issue in the star and galaxy formation process. Its fundamental property of space-time intermittency, well characterised in incompressible laboratory experiments, remains elusive in cosmic turbulence. Progress requires the combination of state-of-the-art modelling, numerical simulations and observations. The power of such a combination is illustrated here where the statistical method intended to locate extrema of velocity shears in a turbulent field is applied to numerical simulations of compressible magneto-hydrodynamical (MHD) turbulence dedicated to dissipation scales and to a nearby turbulent diffuse molecular cloud. We demonstrate that short-spacing increments of observables can detect strongly dissipative structures. In our simulations, we compute structure functions of various synthetic observables and show that they verify Extended Self-Similarity. This allows to compute their intermittency exponents and we show how they could help constraining some properties of the underlying three-dimensional turbulence. In observations of a turbulent cloud close to the Sun in our Galaxy, a remarkable coherent structure of velocity shear extremum is disclosed . At the location of the largest velocity shear, this coherent structure is found to foster 10 × more carbon monoxide molecules than standard diffuse molecular gas, an enrichment supported by models of non-equilibrium warm chemistry triggered by turbulent dissipation. The power of the combination between modelling and observations is also illustrated by observations of the CH+ cation that provide unique quantitative informations on the kinetic energy trail in the massive, multi-phase and turbulent circum-galactic medium of a galaxy group at redshift z = 2.8.

In this paper is presented the design and syntheis of a dynamic output feedback neural network controller for a non-holonomic mobile robot. First the dynamic model of a non-holonomic mobile robot is presented, in which these constraints are considered for the mathematical derivation of a feasable representation for this kind of robot. Then two control strategies are provided based on kinematic control for this kind of robot. The first control strategy is based on driftless control, this means, that considering that the velocity vector of the mobile robot is orthogonal to its restriction a dynamic output feedback and neural network controller is designed in order that the control action would be zero only when the velocity of the mobile robot is zero. The Lyapunov stability theorem is implemented in order to find a suitable control law. Then another control strategy is designed for trajectory tracking purposes, which similar to the driftless controller, a kinematic control scheme is provided but suitable to implement in more sophisticated hardware. In both control strategy a dynamic control law is provided along with a feedforward neural network controller, so in this way, by the Lyapunov theory the stability and convergence to the origin of the mobile robot position coordinates is ensured. Finally, two numerical experiment are presented in order to validate the theoretical results synthetized in this research study. Discussions and conclusions are provided in order to analyze the results found in this research study.

Non-vertebrate species represent about ~95% of known metazoan (animal) diversity. They remain to this day relatively unexplored genetically, but understanding their genome structure and function is pivotal for expanding our current knowledge of evolution, ecology and biodiversity. Following the continuous improvements and decreasing costs of sequencing technologies, many genome assembly tools have been released, leading to a significant amount of genome projects being completed in recent years. In this review, we examine the current state of genome projects of non-vertebrate animal species. We present an overview of available sequencing technologies, assembly approaches, as well as pre and post-processing steps, genome assembly evaluation methods, and their application to non-vertebrate animal genomes.

Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Also, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including N=229 African American and N=381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, N = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (N = 27,955) and Hispanic/Latino (N = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1×10^(-4)) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (N=802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

The quality and shelf-life of NCS (Non-centrifugal sugar) mainly depend on the moisture content present in it. NCS formed by the current practice of open sun drying contains moisture substantially greater than the acceptable level of 3%. This paper presents the work taken up to design a tunnel dryer to attain require moisture content in granular NCS for various load conditions. Initially, an experimental investigation had been carried out on a laboratory scale dryer to achieve required moisture content (< 3%) for various load conditions. This experimental data was used for validating two drying models and found that one of the models is best suitable for designing an industrial-scale dryer. For various load conditions on each tray and dryer exit temperature, nine different cases were arrived at. The number of trucks, trays, drying time and energy requirements were computed using the suitable theoretical model. Tunnel dryer with a length of 18 m, a height of 1.2 m, a width of 1 m, number of trucks of 18 and 24 number of trays on each truck was found to be the suitable dryer to dry 1 tone of NCS based on the minimum energy requirement of 176.49 MJ, and a minimum drying time of 68 minutes.

Untranslated regions (UTRs) of flaviviruses contain a large number of RNA structural elements involved in mediating the viral life cycle, including cyclisation, replication, and encapsidation. Here we report on a comparative genomics approach to characterize evolutionarily conserved RNAs in the 3'UTR of tick-borne, insect-specific and no-known-vector flaviviruses in silico. Our data support the wide distribution of previously experimentally characterized exoribonuclease resistant RNAs xrRNAs within tick-borne and no-known-vector flaviviruses and provide evidence for the existence of a cascade of duplicated RNA structures within insect-specific flaviviruses. On a broader scale, our findings indicate that viral 3'UTRs represent a flexible scaffold for evolution to come up with novel xrRNAs

The aim of the study was to identify factors associated with non-adherence to tuberculosis (TB) preventive treatment among contacts with latent TB infection of new cases of pulmonary TB cases reported in Catalonia in 2019-2021. All contacts aged 18 years or older with a latent TB infection who received a TB preventive treatment were included in the study. The Chi square test and the odds ratios (OR) were used to assess the association between non-adherence to TB preventive treatment and the study variables, considering a p < 0.05 as statistically significant. Multiple logistic regression analysis was used to detect the in-dependent factors associated with TB preventive treatment non-adherence, considering a p < 0.05 as statistically significant. The percentage of non-adherence to TB preventive treatment found in this study was 23.7%. A multivariable logistic regression analysis determined that the following factors were significantly associated with TB preventive treatment non-adherence among adult contacts: “exposure at school or workplace” (aOR = 3.34), “exposure to an index case without laboratory confirmation of TB” (aOR = 2.07), “immigrant contact” (aOR = 1.81), “male gender” (aOR = 1.75) and “exposure duration <6 hours per week or sporadic exposure” (aOR = 1.60). By contrast, the factor “short-term TB preventive treatment regimen” (aOR = 0.38) was significantly associated with a lower treatment non-adherence. Adherence to TB preventive treatment should be improved among adult contacts of TB pulmonary cases with latent TB infection by recommending short-term treatment regimens and by developing health education activities, with a greater focus on contacts with factors associated with treatment non-adherence.

Non-alcoholic beer (NAB) or low alcoholic beer (LAB) are taking over the market with a growing sale. Sus-tainable recycling and valorization of exhausted brewer’s spent grains (BSG) coming from craft beer is a relevant issue in brewing process. In this work, recycled BSG and BSG+GJ (supplemented with 10% grape juice) were used as wort-substrate to inoculate already selected non-conventional yeasts to produce NABLAB craft beer. Results showed that wort composed by only recycled BSG produced appreciate NAB beers (ethanol from 0.12% to 0.54 % v/v) while the addition of 10% of grape juice made LAB beers (ethanol from 0.82 to 1.66 % v/v). As expected, volatile compounds production was highest with the addition of grape juice. Lachancea thermotolerans confirmed the lactic acid production and, as Saccharomyces cerevisiae, is characterized by (in both worts) ethyl butyrate and isoamyl acetate, while Torulaspora delbrueckii produced relevant amounts of exanol, phenylethyl acetate and β-phenyl ethanol (wort added with grape juice). Wickeramhomyces anomalus and Pichia kluyvery showed consistent volatile production but only in wort with grape juice addition where a fermentation activity was exhibited. The overall results indicated that reused BSGs, non-conventional yeasts and grape juice is a suitable strategy for specialty NABLAB beer.

With increased vulnerabilities and vast technology landscapes, it is extremely critical to build systems which are highly resistant to cyber-attacks, to break into systems to exploit. It is almost impossible to build 100% secure authentication & authorization mechanisms merely through standard password / PIN (With all combinations of special characters, numbers & upper/lower case alphabets and by using any of the Graphical password mechanisms). The immense computing capacity and several hacking methods used, make almost every authentication method susceptible to cyber-attacks in one or the other way. Only proven / known system which is not vulnerable in spite of highly sophisticated computing power is, human brain. In this paper, we present a new method of authentication using a combination of computer’s computing ability in combination with human intelligence. In fact this human intelligence is personalized making the overall security method more secure. Text based passwords are easy to be cracked ^[6]. There is an increased need for an alternate and more complex authentication and authorization methods. Some of the Methods ^{[7] [8]} in the category of Graphical passwords could be susceptible, when Shoulder surfing/cameras/spy devices are used.

With the increase in life expectancy and consequent aging of the world’s population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of the disease onset, the study and modulation of mitochondrial alterations rise as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplishing this, data on mitochondrial parameters was acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S), a gasotransmitter, promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures and during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS subsequent to acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the corneal kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels in whole brain homogenate and expression of related genes in corneal kindled mice were not altered. However, plasma H2S and MeSH levels were significantly lower during kindling, but not after established kindling. Morever, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, Opa1, Mfn2, Drp1, and Mff during kindling, which did not correlate with gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.

Previous studies demonstrate the critical importance of non-coding RNAs interfacing with chromatin-modifying machinery resulting in promoter-enhancer-based gene regulation and raise the possibility that many other enhancer-like RNAs may operate via similar mechanisms. Critically, more than 80% of the disease-linked variations identified in genome-wide studies are located in the non-coding regions of genomes, especially non-coding RNA, suggesting non-coding RNAs are relevant to disease. Thus, a critical path forward for understanding non-coding RNAs' role, especially long non-coding RNAs, is to understand the genomic regions' transcriptional regulation, especially non-coding regions. Here, we developed a user-friendly R package called SomaGene for studying and identifying enhancer-like non-coding RNAs with enriched somatic mutations in the cancer genome. SomaGene accepts different genomic variants (whole genome/exome somatic point mutations, structural variations, copy number variations) to identify those RNAs that significantly mutated in diseases (e.g., cancer). It then uses multiple publicly available genomics and epigenetics datasets including ENCODE epigenomics annotations, FANTOM5 tissue-specific expression profiles, disease-associated genome-wide association SNPs, and tissue-specific eQTL pairs to identify those RNAs with potentially enhancer function. SomaGene, as a powerful R package, can provide the opportunity to cancer scientists to study the roles of non-coding RNAs in different cancer genomes.

In this article, the usual factorials and binomial coefficients have been generalized and extended to the negative integers. Basing on this generalization and extension, a new kind of polynomials has been proposed, which led directly to the non-classical hypergeometric orthogonal polynomials and the non-classical second-order hypergeometric linear DEs. The resulting polynomials can be used in non-relativistic and relativistic QM, particularly, in the case of the Schrödinger equation, and Dirac equations for an electron in a Coulomb potential field.

Numerical models widely used for hydrocarbon phase behavior and compositional flow simulations are based on assumption of thermodynamic equilibrium. However, it is not uncommon for oil and gas-condensate reservoirs to exhibit essentially non-equilibrium phase behavior, e.g., in the processes of secondary recovery after pressure depletion below saturation pressure, or during gas injection, or for condensate evaporation at low pressures. In many cases the ability to match field data with equilibrium model depends on simulation scale. The only method to account for non-equilibrium phase behavior adopted by the majority of flow simulators is the option of limited rate of gas dissolution (condensate evaporation) in black oil models. For compositional simulations no practical yet thermodynamically consistent method has been presented so far except for some upscaling techniques in gas injection problems. Previously reported academic non-equilibrium formulations have a common drawback of doubling the number of flow equations and unknowns compared to the equilibrium formulation. In the paper a unified thermodynamically-consistent formulation for compositional flow simulations with non-equilibrium phase behavior model is presented. Same formulation and a special scale-up technique can be used for upscaling of an equilibrium or non-equilibrium model to a coarse-scale non-equilibrium model. A number of test cases for real oil and gas-condensate mixtures are given. Model implementation specifics in a flow simulator are discussed and illustrated with test simulations. A non-equilibrium constant volume depletion algorithm is presented to simulate condensate recovery at low pressures in gas-condensate reservoirs. Results of satisfactory model matching to field data are reported and discussed.

A recent study demonstrated that noninvasive measurements of cortical hemodynamics and metabolism in the resting human prefrontal cortex can facilitate quantitative metrics of unilateral mitochondrial-hemodynamic coupling and bilateral connectivity in infraslow oscillation (ISO) frequencies in young adults (YA). The ISO includes three distinct vasomotions with endogenic (E), neurogenic (N), and myogenic (M) frequency bands. The goal of this study was to prove the hypothesis that there are significant differences between young and older adults (OA) in the unilateral coupling (uCOP) and bilateral connectivity (bCON) in the prefrontal cortex. Accordingly, we performed measurements from 24 OA (67.2 ± 5.9 years of age) using the same 2-channel broadband near-infrared spectroscopy (bbNIRS) setup and resting-state experimental protocol as those in the recent study (Shahdadian et al, Cerebral Cortex Communications, 2022). After quantification of uCOP and bCON in three E/N/M frequencies and statistical analysis, we demonstrated that OA had significantly weaker bilateral hemodynamic connectivity but significantly stronger bilateral metabolic connectivity than YA in the M band. Furthermore, OA exhibited significantly stronger unilateral coupling on both prefrontal sides in all E/N/M bands, particularly with a very large effect size in the M band (&gt; 1.9). These age-related results clearly support our hypothesis and were well interpreted following neurophysiological principles. The key finding of this paper is that the neurophysiological metrics of uCOP and bCON are highly associated with age and may have the potential to become meaningful features for human brain health and be translatable for future clinical applications, such as early detection of Alzheimer’s disease.

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and cochlear hypothalamic–pituitary–adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins, and Ca2+-linked transporters and voltage-gated channels. These findings suggest that pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss

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.

This study aimed to investigate whether non-fasting plasma triglycerides were associated with diabetes mortality. It included 7,312 US adult participants. Diabetes mortality data were obtained via linkage to the National Death Index (NDI) records. Hazard ratios of non-fasting plasma triglycerides for diabetes mortality were assessed using Cox proportional hazards models, adjusting for age, gender, ethnicity, obesity, poverty-income ratio, education levels, physical activity, alcohol consumption, cigarette smoking status, survey period, hypercholesterolemia, hypertension, diabetes, and family history of diabetes. Among these participants, 1,180 had diabetes. A total of 420 diabetes-caused deaths were recorded during a mean follow-up of 16.8 years. A 1-natural-log-unit increase in non-fasting plasma triglycerides was associated with a 41% higher diabetes mortality risk (hazard ratio, 1.41; 95% confidence interval, 1.19-1.67). Participants with non-fasting plasma triglycerides in the highest quintile, versus those in the lowest quintile, had a 144% higher diabetes mortality risk (hazard ratio, 2.44; 95% confidence interval, 1.49-4.02). The positive association of non-fasting plasma triglycerides with diabetes mortality was independent of diabetes status at the baseline. In conclusion, this study demonstrated that non-fasting plasma triglycerides were positively associated with diabetes mortality, independent of diabetes status at the baseline. Non-fasting triglycerides may be a therapeutic target for diabetes-related complications.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Meat serves as a vital component of the human diet, offering a rich source of protein and essential trace elements. China stands as both a significant producer and consumer of meat on a global scale, leading the world in terms of total meat production and consumption. As the standard of living within the country continues to rise, there is a growing emphasis on the nutritional value and safety of meat consumption. The tenderness of meat is a critical factor influencing its overall quality. Traditionally, tenderness has been assessed through shear force testing, a method that is inherently destructive, inefficient, and results in considerable sample wastage. In light of these drawbacks, non-destructive testing techniques have emerged as a preferred alternative, promising greater accuracy, efficiency, and convenience without compromising the integrity of the samples. This paper delves into the application of five advanced non-destructive testing technologies in the realm of meat tenderness assessment. These include near-infrared spectroscopy, hyperspectral imaging, Raman spectroscopy, airflow optical fusion detection, and nuclear magnetic resonance detection. Each technology is scrutinized for its respective strengths and limitations, providing a comprehensive overview of their current utility and potential for future development. Moreover, the integration of these techniques with the latest advancements in artificial intelligence (AI) technology is explored. The fusion of AI with non-destructive testing offers a promising avenue for the development of more sophisticated, rapid, and intelligent systems for meat tenderness evaluation. This integration is anticipated to significantly enhance the efficiency and accuracy of quality assessment in the meat industry, ensuring a higher standard of safety and nutritional value for consumers. The paper concludes with a set of technical recommendations aimed at guiding the future direction of non-destructive, AI-enhanced meat tenderness detection, thereby contributing to the ongoing improvement of the meat industry in China and beyond.

Despite significant milestones in armed conflict research generally and climate security research specifically, methodologically tight explanation of naturally caused armed conflict still leaves much to be desired. In this article we unpack the black box of the climate-security nexus and advance causal modelling of armed conflict. To infer effects of natural causes on armed conflict outcomes, we apply recent advances in causal methods to conflict outcomes that have been non-experimentally observed across Iraqi municipalities. Retrieval of an entire empirical causal structure of climate-conflict pathways allows us to corroborate the existence of a cause-and-effect relationship between climatological, environmental, and demographic variables and armed conflict. We confirm that soil temperature, population density, and variability of latent energy cause an increase in fatalities, while rice production decreases fatalities. We discuss our findings, their limitations, and future research directions, and reflect on their relevance for policy interventions.

Background: Despite scientific advances, the management of procedural pain in neonates remains suboptimal. Applying adequate therapy to control pain during the neonatal period is a moral and ethical act. In recent decades, ample evidence has accumulated regarding the risks, associated with both untreated pain and the use of more aggressive analgesic therapy. Thus, the emphasis in neonatal clinical practice is on non-aggressive pain management techniques, including homeopathic agents. The efficacy and safety of homeopathic agents for reducing procedural pain in neonates is the subject of the present study. Materials and Methods: Healthy full-term newborn babies with an average age of 72-84 hours were included. They were divided into three study groups: group (A) – not anesthetised, /n= 67/, group (B) – anesthetised with Arnica D30 /n=40/ and group (C)- anesthetised with Sol.Glucose 25% /n=40/. The severity of the pain was assessed using the multimodal - Neonatal Infant Pain Scale (NIPS) and the unimodal - Neonatal Facial Coding System (NFCS) scale. Assessments were done 30s before, 30 seconds after, and 5 minutes after the painful stimulus caused by the heel prick. Heart rate, transcutaneous oxygen saturation, respiratory rate and blood pressure were examined at the same intervals. The results obtained were processed statistically by descriptive analysis and ANOVA at a significance level of p&lt; 0.05. Results: 5 minutes after heel prick both scales showed a statistically significant lower score in those given Arnica D30, compared to those who received Sol.Glucose 25%. When monitoring the physiological indicators, we found a significant increase in the heart rate 30 seconds after the procedure.5 minutes after the heel prick we recorded significantly respiratory rate and systolic blood pressure in all three groups compared to pre-procedural values. Conclusions: Arnica D30 has better analgesic effects compared to Sol.Glucose 25% for newborn babies after heel prick tests.

Approximately 300 million non-cardiac surgeries are performed each year. Perioperative mortality after non-cardiac surgery is estimated at 2% in patients over 45 years of age . Half of these deaths are attributable to cardiovascular complications, and most to perioperative myocardial infarction (MINS). Before introduction of cardiac biomarkers the diagnosis of postoperative myocardial infarction was based on symptoms and electrocardiographic changes and its incidence was largely underestimated. The incidence of MINS when standard troponin assay is used ranges between 8 and 19% but increases to 20-30% whit high sensitivity troponin assays. Higher troponin values sugegsting myocardial injury , both with or without definite diagnosis of myocardial infarction, are associated with increased 30 day and 1-year mortality . Diagnostic and therapeutic strategies are reported .

Malnutrition problems are related to diets that lack one or more essential elements, which it is extremely important to food enrichment to improve the content of compounds effective for health. The objective of this study is to evaluate the effect of the addition of Ca2+, K+ and Mg2+ on the induction of nutraceutical quality in grafted tomatoes grown in the NFT (Nutrient Film Technique) system. In the experiment, two factors were evaluated: plants with and without grafting and the foliar application of 10 ml L−1 Ca2+, 4 ml L−1 K+ and 10 ml L−1 Mg2+ cations separately for each case, in addition to the control. The treatments were evaluated using a completely randomized design, with 5 repetitions per treatment. The interactive effects between grafting and foliar application of Ca2+ induced a greater content lycopene, β-carotene and total flavonoids in fruits of tomato. The interactive effects between the graft and the Mg2+ foliar applications obtained the best results in the phenol content. As regards, capacity DPPH and ABTS, the graft decreased concentration, increasing the content of these through foliar applications of calcium. Regarding the enzymatic variables, graft factor increased activity catalase, glutathione peroxidase and phenylalanine ammonium lyase, obtained the best results graft interaction and foliar application of calcium and magnesium. The results obtained demonstrate the influence of the use of grafts and foliar applications of cal-cium and magnesium as tools that could improve the nutraceutical quality content of tomato crop

Metformin is an oral antidiabetic agent with antimicrobial properties, excreted in an active and unmetabolized form. Like some non-antibiotic drugs, subinhibitory concentrations of metformin may contribute to the expression of microbial resistance in wild-type strains. This work aimed to evaluate the biofilm formation of Pseudomonas aeruginosa TGC04 exposed to 100 and 200 µg/mL of metformin, varying the Chemical Oxygen Demand (COD) and flow regime. Biofilms were quantified after 2 and 24 hours, observing reductions and increases in biofilm growth around 13 and 64%, respectively. The greatest biofilm growth occurred in cells exposed to 200 µg/mL of metformin. Both the flow regime and COD concentration were important for the development of the biofilm, whose cells were mostly weakly to moderately adhered. The study provides evidence that in polluted aquatic systems with turbulent regimes, the inhibitory concentration of metformin promoted the least disturbances to the biofilm.

In this review, we will cover a general overview of the current panorama on lncRNAs with an actual or potential role as biological markers in cancer. We will discuss examples of multi-omics approaches that integrates information on somatic aberrations, gene expression and epigenomics, with the scope of providing a more comprehensive view of the functional impact of lncRNA profiles and how these paradigm can be exploited for the discovery and selection of lncRNAs with a functional role and their use as variables informing on progression and prognostic and help guiding the selection of therapeutic strategies for cancers. Finally, we propose a perspective for future evolution of the study of lncRNAs and the discovery of their functional and harnessing their potential to assist in clinical management of malignancies.

Small bowel non-Meckelian diverticulosis is a rare condition with only few published cases despite being described over 200 years ago. In the midst of the COVID-19 pandemic, studies suggested that a lot of patients may experience gastrointestinal manifestations. Intestinal symptoms could worsen the inflammation and infection associated with small bowel diverticulitis. Here, we present two cases: one with inflammation and rupture in a COVID-19 patient and the other as an asymptomatic detection. Furthermore, we provide a mini-review of the literature to emphasize the importance of considering this entity in the differential diagnosis of an acute abdomen.

This publication delves into the intricate world of human communication, extending beyond the realm of spoken and written language to explore the profound influence of non-verbal communication. Focusing on body language—comprising gestures, facial expressions, postures, and movements—it reveals the pivotal role it plays in conveying emotions, intentions, and psychological states. The rapidly evolving fields of neuroscience and cognitive science are investigating the neural mechanisms and cognitive processes that underpin the interpretation and utilization of these non-verbal cues. Notably, the amygdala's involvement in processing emotional facial expressions has provided a neurological foundation for our emotional understanding in non-verbal communication. Concurrently, cognitive psychology sheds light on how perception, attention, and memory influence our interpretation of non-verbal cues and communication strategies.In our modern, technologically advancing society characterized by global interconnectivity and cultural diversity, the significance of non-verbal communication, especially in digital and virtual contexts, is paramount. The transformation of non-verbal expression into digital symbols like emoticons and emojis raises questions regarding its ability to maintain authenticity and emotional understanding. This publication endeavors to comprehensively explore the fundamental role of body language and non-verbal communication in contemporary society. By integrating insights from psychology, neuroscience, social sciences, and digital technologies, it aims to elucidate the underlying mechanisms guiding non-verbal communication. Additionally, it delves into the implications of non-verbal communication across diverse domains, including interpersonal communication, the workplace, politics, advertising, and the virtual world.The research presented herein strives to offer a thorough understanding of interpersonal dynamics, relationships, and social behavior, with the goal of promoting the development of more effective, conscious, and ethically guided communication strategies. Ultimately, this analysis aspires to inspire further interdisciplinary research and reflection, addressing emerging challenges and fully leveraging the potential of non-verbal communication in modern society. This, in turn, guides our path towards a communication landscape that is more inclusive, authentic, and empathetic.

Although adult spontaneous (non-diabetic) hypoglycaemia is rare, its recognition is important for the preventative or curative treatment of the underlying cause. Establishing Whipple’s triad; low blood glucose, neuroglycopaenia and resolution of neuroglycopaenia on increasing blood glucose levels to normal or above, is essential to verify hypoglycaemia. Awareness that hypoglycaemia may occur in severely ill patients is important for its prevention. Further investigation in such cases is unnecessary unless another cause of hypoglycaemia is suspected. Patients are often asymptomatic and normoglycaemic at review. History of medication, self-medication, access to hypoglycaemic drugs, alcohol and comorbidity may provide aetiological clues. The investigation involves obtaining blood samples during symptoms for laboratory glucose measurement or provoking fasting or postprandial hypoglycaemia as directed by symptoms. If confirmed, insulin, c-peptide, proinsulin, beta-hydroxybutyrate are analysed in hypoglycaemic samples. These will classify hypoglycaemia due to non-ketotic hyperinsulinaemia, non-ketotic hypoinsulinaemia and ketotic hypoinsulinaemia and direct investigations to identify the underlying cause. There are, however, many pitfalls, which may mislabel healthy individuals as “hypoglycaemic” or misdiagnose treatable or preventable causes of spontaneous hypoglycaemia. Clinical acumen and appropriate investigations will mostly identify hypoglycaemia and its cause.

This paper presents ConF, a novel deep learning model designed for accurate and efficient prediction of non-coding RNA families. NcRNAs are essential functional RNA molecules involved in various cellular processes, including replication, transcription, and gene expression. Identifying ncRNA families is crucial for comprehensive RNA research, as ncRNAs within the same family often exhibit similar functionalities. Traditional experimental methods for identifying ncRNA fam-ilies are time-consuming and labor-intensive. Computational approaches relying on annotated secondary structure data face limitations in handling complex structures like pseudoknots and have restricted applicability, resulting in suboptimal prediction performance. To overcome these chal-lenges, ConF integrates mainstream techniques such as residual networks with dilated convolutions and cross multi-head attention mechanisms. By employing a combination of dual-layer convolu-tional networks and BiLSTM, ConF effectively captures intricate features embedded within RNA sequences. This feature extraction process leads to significantly improved prediction accuracy compared to existing methods. Experimental evaluations conducted on a ten-fold publicly available dataset demonstrate the superiority of ConF in terms of accuracy, sensitivity, and other perfor-mance metrics. Overall, ConF represents a promising solution for accurate and efficient ncRNA family prediction, addressing the limitations of traditional experimental and computational methods.

Background: Chronic, non-cancer pain represents a serious public health and economic issue affecting approximately 20% of the global population. Chronic pain can affect many aspects of patient’s lives, including mental health, employment, and relationships. Current medical management is largely focussed on investigating and managing acute pain. Patients and clinicians are now increasingly aware of the potential benefits of combined treatments or complex interventions in alleviating chronic pain. These approaches include both physical interventions, such as exercise or yoga, as well as psychological support including cognitive behavioural therapy (CBT) and talking therapies. Methods: This study used network meta-analyses to explore the prevalence of complex interventions in pain management, and the effects of these interventions on quality of life, using outcome measures including intensity of chronic pain, assessment of functional disability and participant’s psychological state. Results: Psychological interventions were associated with improvements in pain intensity and depression. Exercise and manipulation technique-based treatments provided a statistically significant reduction in pain intensity. This effect was enhanced when exercise and CBT were combined. Mensendieck somatocognitive therapy (MSCT) plus standard gynaecological treatment (STGT) treatments appeared to have a better effect on chronic pain than multimodal exercise plus CBT treatment. Combined MSCT and STGT treatment, and multimodal exercise plus CBT treatments, reduced pain intensity, whilst MSCT+STGT treatments had a slightly better effect than exercise plus CBT treatment.Conclusions: Complex interventions have become more popular with patients as the risks associated with other interventions including surgery and pharmacological management have become better understood. These interventions can have a significant positive effect both on the physical and psychological health of patients. The analysis presented in this study suggests that further work is warranted in this area and that additional studies are required, both in more geographically diverse locations, and with larger cohorts.

Fermented food matrices, including beverages, can be defined as the result of the activity of complex microbial ecosystems where different microorganisms interact according to different biotic and abiotic factors. Certainly, in industrial production the technological processes aim to control the fermentation to place safe foods on the market. Therefore, if food safety is the essential prerogative, consumers are increasingly oriented towards a healthy and conscious diet driving the production and consequently the applied research towards natural processes. In this regard, the aim to guarantee safety, quality and diversify of products should be reached limiting or avoiding the addition of antimicrobials or synthetic additives using the biological approach. In this paper, following the recent re-evaluation of non-Saccharomyces yeasts (NSYs) has been re-viewed the bio-protectant and biocontrol activity with a particular focus on their antimicrobial power, probiotic features and promoting functional aspects. In this review, the authors would underline the contribution of NSYs in all food production chain and its role in the technological and fermentative features for their practical and useful use as biocontrol agent in food preparations.

The need to regulate the non-exhaust particulate emissions from vehicles has been discussed worldwide due to the toxicity to the human body as well as the atmosphere. In-depth studies have been conducted on precise analysis of the non-exhaust particulates, in particular, accurate measurement of tire-brake-road wear particles, and their proportion in the atmosphere. In this study, the influence of tire and road wear particles (TRWP) on particulate matter (PM) in the atmosphere was investigated through tire and PM samples. PM samples were collected from the atmosphere using a high-volume sampler equipped with a quartz filter. Additionally, polycyclic aromatic hydrocarbons (PAHs) and heavy metals in tire rubber were analyzed as markers by pyrolysis-gas chromatography/mass spectrometry (GC/MS), GC/MS, and inductively coupled plasma/mass spectrometry (ICP/MS). More vinylcyclohexene was detected than dipentene in the markers measured in the samples of tires equipped with vehicles driving on the road with the high-volume sampler installed, while more dipentene was detected in total suspended particles (TSP) samples. Among the PAHs measured in tire samples, pyrene exhibited the highest concentration. In TSP samples, benzo(b)fluoranthene showed the highest concentration. Among the heavy metals, zinc exhibited the highest concentration in all tire samples and calcium in TSP samples.

With the development of data science, more and more machine learning technologies have been designed to solve complicated and challenging real-world tasks containing a large volume of data. And many significant real-world datasets contain data in the form of networks or graphs. Graph Neural Networks is one of the powerful machine learning tools, which could provide a perfect solution to processing a large amount of non-Euclidean data. And because most bio information data in bioinformatics is in the non-Euclidean domain, Graph Neural Networks could then directly be applied to solve problems in bioinformatics. Much research has been done in the field of GNN, and there are also some surveys related to GNN and its applications. However, there has been little research focusing on GNN in bioinformatics, and we think in the future we could better utilize GNN in the field of biology, so we would like to write a literature review to help take a comprehensive look at GNN and their applications in the field of bioinformatics. In this paper, we would first introduce SOTA models in Graph Neural Networks, and second, introduce their applications in bio information. And then we would provide future directions of Graph Neural Networks in bioinformatics.

In this paper we use the additive thermodynamic formalism to obtain new bounds of the Hausdorff and box-counting dimension of certain non conformal hyperbolic repellers defined by piecewise smooth expanding maps on a $d$-dimensional smooth manifold $M$.

We suggest that the 14^th century scholar Nicholas of Autrecourt can be regarded as a precursor of the paraconsistent logics developed around 1950. We show how the Sorbonne licentiatus in theology provided in his few extant writings a refutation of both the principle of explosion and the law of non-contradiction, in accordance with the tenets of paraconsistent logics. This paves the way to the most advanced theories of truth in natural language and quantum dynamics.