Over the years, network analysis became a promising strategy to analyze complex system, i.e. systems composed by a large number of interacting elements. In particular, multilayer networks have emerged as a powerful framework for modelling and analysing complex systems with multiple types of interactions. Network analysis can be applied to pharmacogenomics to gain insights into the interactions between genes, drugs, and diseases. By integrating network analysis techniques with pharmacogenomic data, the goal consists to uncover complex relationships and identify key genes to use in pathway enrichment analysis to figure out biological pathways involved in drug response and adverse reactions. In this study, we model omics, diseases and drugs data together through the multilayer network representation. Then, we mined the multilayer network with a community detection algorithm by obtaining top communities. After that, we used the identified list of genes from the communities to perform pathway enrichment analysis (PEA) to figure out the biological function affected form the selected genes. The results show that the genes forming the top community have the multiple roles through different pathways.

In recent years, Nigeria is witnessing increasing frequency of flood occurrence with devastating impact translating into significant loss of lives (in Nigeria, over 300 people died in September 2022) and properties. Addressing flood disaster requires holistic approach from policy and governance perspectives, integration of policies and programs and synergies between institutions. Using synergies and eliminating trade-offs, flood governance and policy coherence integrate all relevant policy fields and institutions to achieve common policy outcomes. The objective of this study is to examine and understand how flood governance and policy coherence are approached, as well as institutional design and implementation for coherence in Nigeria. The findings revealed that there is no single flood policy in Nigeria. Due to this, there is no focus and no defined objectives for flood governance, prevention, control, and management, and no imperative for the government to seek both short-term and long-term flood solutions. There is no synergy and coordination among institutions for flood governance in the country. Since the country established the federal ministry of environment in 1999, the environment, floods, and climate-related hazards were given less priority. State and local governments handle most flood disasters and emergencies. Federal assistance is provided, however, when flood disasters exceed the capabilities of local and state governments. This study recommends that across the country, flood policy needs to be designed, formulated, and implemented while assigning governance responsibility and decentralizing policy to state and local governments.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-kB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-kB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that PKP2 and the LUBAC complex were required for EGFR-mediated NF-kB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IkB phosphorylation and subsequent NF-kB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-kB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-kB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR, and perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Current research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on the receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells. The results revealed that L-quebrachitol suppressed RANK-mediated signalling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of receptor activator of nuclear factor κB (RANK)-mediated signalling pathways. However, further exploration of L-quebrachitol's potential as a therapeutic approach for osteoporosis is warranted.

Multiple myeloma (MM) accounts for about 10 to 15% of all diagnosed hematologic malignancies and about 1-2% of all cancer cases. Approximately 80-90% of MM patients develop bone disease and the changes rarely regress. It is only possible to stop or slow their progression. A major role in bone destruction in MM is attributed to the Wnt signaling pathway, and its action can be modified by various types of interventions including training and diet. Therefore, the aim of this project was to evaluate the effects of a Nordic Walking (NW) training cycle and intermittent fasting (IF) on the levels of selected bone turnover markers associated with the Wnt pathway in patients with MM. Results from 35 patients divided into training (NW and IF NW) and non-training (IF and control) groups were included in the analysis. A 6-week training cycle involving 60-minute workouts 3 times a week was conducted. Body mass and composition and the levels of: vitamin D, calcium and phosphorus, beta2-microglobulin and albumin were examined before and after completion of training cycle. Markers of bone turnover were also determined: sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), osteoprotegrin (OPG), osteopontin (OPN) and Tartrate-resistant acid phos-phatase 5b (TRACP 5b). There was no negative effect of IF or combined training and fasting on the nutritional status of the patients (the level of albumines was unchanged). Both training groups showed an increase in serum concentrations of the active metabolite of vitamin D (IF NW and NW: p=0.001 and p=0.022, re-spectively). The change in the concentration of this vitamin negatively correlated with the con-centration of TRACP 5b (r=-0.413, p=0.014). Evaluating the concentrations of markers related to bone turnover, a reduction in the concentrations of SOST (time: p=0.026, time vs. group: p=0.033) and TRACP 5b (time: p

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

Cisplatin (CDDP), an important chemotherapeutic agent, could result in potential hepatotoxicity, but the precious molecular mechanisms remain unclear. In this study, the protective effect of ellagic acid (EA) on CDDP exposure-induced hepatotoxicity and underlying molecular mechanisms were investigated using a mouse model. Mice were randomly divided into control, CDDP model, EA100 (i.e., EA 100 mg/kg/day), and CDDP plus EA 25, 50, and 100 mg/kg/day. Mice in all CDDP-treated groups were intraperitoneally injected with CDDP 20 mg/kg/day for 2 days. In all EA co-treatments, mice were orally administrated with EA for 7 days. Our results found that, compared to the control group, CDDP treatment resulted in liver dysfunction, oxidative stress, and hepatocyte necrosis, which are effectively revised by EA supplementation in a dose-dependent manner. Meanwhile, EA supplementation inhibited CDDP-induced the elevation of caspases-9 and -3 activities in the liver tissues of mice. Furthermore, EA supplementation significantly downregulated CDDP exposure-induced the increases of NF-κB, IL-1β, TNF-α, and IL-6 proteins and mRNAs, while further upregulated the expression of Nrf2, and HO-1 proteins and mRNAs. Taken together, our results reveal that EA supplementation could ameliorate CCDP-induced liver injury in mice via the opposite regulation of Nrf2/HO-1 and NF-kB pathways.

Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial disfunction in adult human skin fibroblasts which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and ATP-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance which is associated with the molecular pathophysiology of MDD. The observed alterations in OXPHOS and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.

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

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance is a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister cells (DTP) are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study for cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after a single exposure to tyrosine kinase inhibitor TKIs (erlotinib or osimertinib). After establishing DTPs, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were found to be overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival of patients with lung cancer.

This comprehensive review delves into the multifaceted aspects of ERK signaling and the intricate mechanisms underlying distinct cellular fates. ERK1 and ERK2 (ERK) govern proliferation, transformation, epithelial-mesenchymal transition, differentiation, senescence, or cell death, con-tingent upon activation strength, duration, and context. The biochemical mechanisms underlying these outcomes are inadequately understood, shaped by signaling feedback and the spatial localization of ERK activation. Generally, ERK activation aligns with the Goldilocks principle in cell fate determination. Excessive or insufficient ERK activity inhibits growth, whereas moderated activation supports proliferation and survival. Unraveling the intricacies of how the degree of ERK activation dictates cell fate requires deciphering mechanisms encompassing protein stability, transcription factors downstream of ERK, and the chromatin landscape.

Metabolic pathways provide key information to achieve a better understanding of life and all its processes; this is useful information for the improvement of medicine, agronomy, pharmacy, and other similar areas. The main analysis tool used to study these pathways is based on the idea of pathway comparison, using graph data structures. Metabolic pathway comparison has been defined as a computationally complex task \cite{ay2011submap,abaka2013campways}. In previous work from 2017, two different approaches that simplify the problem of comparing pathways represented as graphs were introduced. The first algorithm consists of the transformation of a two-dimensional graph structure, representing a metabolic pathway, to a one-dimensional structure and thus aligning the corresponding data using a reduced 1 dimension string. The second algorithm consists of performing a paired analysis between reactions in pathways and thus eliminating all similarities, finally, showing these differences to the user. The suggestion is to use the information provided by these algorithms as a previous analysis to a deeper, more expensive, comparison tool use. Here we provide an extension of this work with more data and deeper analysis. These methods have shown to be an effective way to treat the problem of metabolic pathway comparison as listed in the discussion and results section. Our results show evidence of a quick, simple and effective way to resolve the described problem.

Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO₂) as under deprived oxygen (hypoxia) the transcription factor Hypoxia Inducible Factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established HIF-EPO axis, and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

On review of neuroscience literature extreme capsule considered as a whiter matter tract. Nevertheless it is not clear that extreme capsule itself is a association fiber pathway or is o bottleneck for passing other association fiber. By a systematic search with investigating anatomical position, dissection, connectivity and cognitive role of extreme capsule it can be argued that extreme capsule probably is a bottleneck for passing uncinated fasciculus (UF) and inferior fronto – occipital fasciculus(IFOF), And its different role of language processing is duo to different tract that passing it.

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

Activating mutations in the Epidermal Growth Factor Receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20-30% of patients do not respond or respond for a very short time (< 3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

Oxidative stress-mediated cell death is a major cause of dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson’s disease patients. Ergothioneine (ET), a natural dietary compound, has been shown to have cytoprotective functions, but neuroprotective actions against PD have not been well established. 6-Hydroxydopamine (6-OHDA) is a widely used neurotoxin to simulate the degeneration of dopaminergic (DA) neurons in Parkinson's disease. In this study, we investigated the protective effect of ET on 6-OHDA treated iPSC-derived dopaminergic neurons (iDAs) and further confirmed the protective effects in 6-OHDA treated human neuroblastoma SH-SY5Y cells. In 6-OHDA treated cells, metabolic stress in the form of decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mROS), reduced cellular ATP levels, and increased total protein carbonylation levels was observed. 6-OHDA treatment also significantly decreased tyrosine hydroxylase levels. These effects were significantly abrogated when ET was present. Verapamil hydrochloride (VHCL), a non-specific inhibitor of the ET transporter, OCTN1, abolished ET’s cytoprotective effects, indicative of an intracellular action. These results suggest that ET could be a potential therapeutic for Parkinson’s disease.

Following ischemic stroke, the degradation of myelin and other cellular membranes surpasses the lipid-processing capabilities of resident microglia and infiltrating macrophages. This imbalance leads to foam cell formation in the infarct and areas of secondary neurodegeneration, instigating sustained inflammation and furthering neurological damage. Given that mitochondria are the primary sites of fatty acid metabolism, augmenting mitochondrial biogenesis (MB) may enhance lipid processing, curtailing foam cell formation and post-stroke chronic inflammation. Previous studies have shown that the pharmacological activation of the β2-adrenergic receptor (β2-AR) stimulates MB. Consequently, our study sought to discern the effects of intensified β2-AR signal-ing on MB, the processing of brain lipid debris, and neurological outcome using a mouse stroke model. To achieve this goal, aged mice were treated with formoterol, a long-acting β2-AR ago-nist, daily for two and eight weeks following stroke. Formoterol increased MB in the infarct re-gion, modified fatty acid metabolism, and reduced foam cell formation. However, it did not re-duce markers of post-stroke neurodegeneration or improve recovery. Our findings suggest that boosting MB in myeloid cells is one component of a therapeutic avenue for improving brain lipid debris processing after stroke.

The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where is needed. Accordingly, the distribution of mitochondria is not even in neurons and is regulated by a dynamic balance between active transport and stable docking events. This system is finely tuned to respond to changes in environmental conditions and neuronal activity. In this review, we summarize the mechanisms by which mitochondria are selectively transported in different compartments taking into account the structure of the cytoskeleton, the molecular motors and the metabolism of neurons. Remarkably, the motor proteins driving the mitochondrial transport in axons have been shown to mediate also their transfer between cells. This so-named intercellular transport of mitochondria is opening new exciting perspectives in the treatment of multiple diseases.

When exposed to a viral infection, the attacked cells promptly set up defence mechanisms. Part of antiviral responses, the innate immune interferon pathway and associated interferon stimulated genes are notably allowing the production of proteins bearing an antiviral activity. Numerous viruses are able to evade the interferon response, highlighting the importance of controlling this pathway to ensure their efficient replication. Several viruses are also known to manipulate the metabolism of infected cells to optimize the availability of amino acids, nucleotides and lipids. They then benefit from a reprogramming of the metabolism that favours glycolysis instead of mitochondrial respiration. Given the increasingly discussed crosstalk between metabolism and innate immunity, we wondered whether this switch from glycolysis to mitochondrial respiration would be beneficial or deleterious for an efficient antiviral response. We used a cell based model of metabolic reprogramming. Interestingly, we showed that increased mitochondrial respiration was associated with an enhanced interferon response following poly:IC stimulation. This suggests that during viral infection, the metabolic reprogramming towards glycolysis is also part of the virus' strategies to inhibit the antiviral response.

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

In the present study, the complete mitochondrial genome of the New Zealand parasitic blowfly Lucilia sericata (green bottle blowfly) field strain NZ_LucSer_NP was generated using next-generation sequencing technology. The length of complete the mitochondrial genome is 15,938 bp, with 39.4% A, 13.0% C, 9.3% G, and 38.2% T nucleotide distribution. The complete mitochondrial genome consists of 13 protein-coding genes, two ribosomal RNAs, 22 transfer RNAs, and a and a 1,124 bp non-coding region, similar to most metazoan mitochondrial genomes. Phylogenetic analysis showed that L. sericata NZ_LucSer_NP forms a monophyletic cluster with the remaining six Lucilia species and the Calliphoridae are polyphyletic. This study provides the first complete mitochondrial genome sequence for a L. sericata blowfly species derived from New Zealand to facilitate species identification and phylogenetic analysis.

The superfamily Lauxanioidea is a significant dipteran clade including over 2500 known species in three families: Lauxaniidae, Celyphidae and Chamaemyiidae. We sequenced the first five (three complete and two partial) lauxanioid mitochondrial (mt) genomes, and used them to reconstruct the phylogeny of this group. The lauxanioid mt genomes are typical of the Diptera, containing all 37 genes usually present in bilaterian animals. A total of three conserved intergenic sequences have been reported across the Cyclorrhapha. The inferred secondary structure of 22 tRNAs suggested five substitution patterns among the Cyclorrhapha. The control region in the Lauxanioidea has apparently evolved very fast, but four conserved structural elements were detected in all three complete mt genome sequences. Phylogenetic relationships based on the mt genome data were inferred by Maximum Likelihood and Bayesian methods. The traditional relationships between families within the Lauxanioidea, (Chamaemyiidae + (Lauxaniidae + Celyphidae)), was corroborated, however, the higher level relationships between cyclorrhaphan superfamilies are mostly poorly supported.

Adamantinomatous Craniopharyngioma (ACP) is a rare epithelial tumor located in the craniopharyngeal duct, often associated with high morbidity and a high long-term recurrence rate. ACP is predominantly diagnosed in children below the age of 15 and accounts for a majority of Craniopharyngioma cases in the United States. It is most commonly caused by a mutation in exon 3 of the CTNNB1 gene, which promotes overaccumulation of β-Catenin in the WNT pathway. As β-Catenin accumulates, it over-activates the transcription factor, causing an over-transcription of WNT proteins and uncontrolled cell growth. Current methods of treatment for ACP are centered around surgical intervention and radiotherapy, including gross-total resection (GTR), subtotal resection (STR), and a combination of subtotal resection and adjuvant radiotherapy (STR+XTR). These methods of treatment are associated with high risk due to the proximity of ACP to critical structures near the craniopharyngeal duct. High recurrence rates and morbidity are closely associated with current methods of treatment and other methods have yet to be attempted in craniopharyngioma. This review will explore two possible methods of non-surgical and non-radiological therapeutic interventions. The use of RNAi therapy and CRISPR may provide insight and be a potential way to treat ACP with increased quality of life and decreased recurrence rates.

Blind image quality assessment (BIQA) aims to evaluate image quality in a way that closely matches human perception. To achieve this goal, the strengths of deep learning and the characteristics of human visual system (HVS) can be combined. In this paper, inspired by the ventral pathway and dorsal pathway of HVS, a dual-pathway convolutional neural network is proposed for BIQA task. The proposed method consists of two pathways: “what” pathway, which mimics the ventral pathway of HVS to extract the content features of distorted images, and the “where” pathway, which mimics the dorsal pathway of HVS to extract the global shape features of distorted images. Then, the features from the two pathways are fused and mapped to an image quality score. Additionally, the gradient images weighted by the contrast sensitivity are used as the input to the “where” pathway, allowing it to extract global shape features that are more sensitive to human perception. Moreover, a dual-pathway multi-scale feature fusion module is designed to fuse the multi-scale features of the two pathways, enabling the model to capture both global features and local details, thus improving the overall performance of the model. The experiments conducted on six databases show that the proposed method achieves the state-of-the-art performance.

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently nociplastic pain has been introduced as a descriptor of mechanism of pain, which is due to disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring participations of psychosocial and behavioral factors in central sensitization of diseases progressing into development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in ischemic condition is also presented.

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones - new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction, due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accom-panied with 90, 94, 88 and 87% decrease in the content of Complex I, II, III and IV proteins, respectively. The content of the FOF1-ATPase subunits decreased sharply by approximately 35% after 24 hours and remained unchanged up to 72 hours of incubation with TR-57. At the same time, a disappearance of the ATPIF1, natural inhibitor of mitochondrial FOF1-ATPase observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin had no effect on the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 hours retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that alt-hough TR-57 treatment lead to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of FOF1-ATPase supports mitochondrial polarization.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of disability and neurological damage. The present work evaluated LTL and mtDNA-CN in 75 relapsing-remittent MS (RRMS) patients 50 of whom had an Expanded Disability Status Scale (EDSS) 0 to 3 (mild-moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). Absolute LTL and absolute mtDNA-CN were measured via real-time polymerase chain reaction (qPCR). The LTL and mtDNA-CN were significantly lower in RRMS severe disability than in RRMS mild-moderate disability (3.924 ± 0.124 vs 2.854 ± 0.092, p<00001; 75.14 ± 1.77 vs 68.06 ± 1.608, p<0.00001, respectively). The LTL and mtDNA-CN showed a linear correlation in RRMS with mild-moderate disability (r=0.2986, p=0.0351). In addition, in a binary logistic regression model the LTL can predict severe disability (AUC=0.697, p=0.0031, cutoff ≤ 3.0875 Kb, sensitivity= 73.1%, specificity=62.5%), the prediction is improved by including age to the model (AUC=0.765, <0.0001, sensitivity=78.26%, specificity=81.25%). Aging is closely linked to the development of disability in RRMS and can be evaluated through LTL and mtDNA-CN absolute quantification.

Mitochondrial DNA copy number (mtDNAcn) is associated with mitochondrial function contributing various diseases. Understanding of the association between mtDNAcn and infant neurodevelopment, as well as the role of racial disparities, remains unknown. A cohort study was conducted with 55 preterm infants and a single blood sample was collected from each infant during their NICU stay to measure mtDNAcn. NICU Network Neurobehavioral Scale (NNNS) and Bayley Scale of Infant Developmental testing Edition III was assessed during NICU until 2 years of corrected age (CA). Linear regression models were performed to investigate the relationship between the clinical characteristics, neurobehavioral outcomes and mtDNAcn. Majority of our subjects were male, White, non-Hispanic, had C-section, and without preterm premature rupture of membrane (PPROM). Increased mtDNAcn was found associated with younger birth gestational age (GA), nonoptimal neurodevelopment. However, the opposite associations between mtDNAcn and neurodevelopmental outcomes were observed between Black and White infants up to 1 year of CA. Adverse early life experience, together with increased mtDNAcn in White infants, and decreased mtDNAcn in Black infants may be considered as significant positive predictors of poor early life neurodevelopmental outcomes in infants.

The agamid lizard Phrynocephalus melanurus, is restricted to the Northwest China (Dzungar Basin) and adjacent Eastern Kazakhstan (Zaisan and Alakol basins). To elucidate the phylogeography of P. melanurus, we obtained the mitochondrial DNA COI segments of 175 sampled lizards from 44 localities across the whole distribution range. Phylogenetic analyses revealed two main clades comprising six geographically structured lineages (I, IIa, IIb, IIc1, IIc2, and IIc3) that fits an isola-tion by distance (IBD) model. The divergence from the most recent ancestor was dated to ~1.86 million years ago (Ma). Demographic analyses demonstrated lineage-specific response to past climate change: stable population for Clade I, IIb and IIc2; while past population expansion for IIc1 and IIc3 since 0.02 Ma and 0.18 Ma, respectively. Bayesian phylogeographic diffusion anal-yses detected initial spreading at the Saur Mount vicinity approximately 1.8 Ma. Historical species distribution modeling (SDM) projected expansion of the suitable habitat in the last interglacial period and stepwise contraction in the Last Glacial Maximum and Holocene epochs. The SDM predicts a shrinkage and shift of suitable area eastward as a response to future climate change. Our findings suggest that the evolution of P. melanurus followed a parapatric divergence with subsequent dispersal and adaptation to cold and dry environments during the Quaternary. Moreover, future conservation strategies need to be taken to maintain the population of lineage IIc1.

Type 2 Diabetes Mellitus is being increasingly associated with dysfunction of cognition. Dementia, including vascular dementia and Alzheimer’s disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear in older patients primarily. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes which affect the brain and lead to dementia development. The connection between Diabetes Mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted mechanisms related to Diabetes Mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between type 2 diabetes and Dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s disease and helping to explain the potential mechanisms behind the disease process. The Google search for ‘Diabetes Mellitus and Dementia’ was carried out. Also, the search was done using ‘Diabetes Mellitus,’ ‘Vascular Dementia,’ ‘Alzheimer’s Disease.’ The literature search was done from Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the type 2 diabetes effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding different types of dementia and their relationship with diabetes.

Bacteria in the gut microbiome play an intrinsic part in immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. Gut microbiota communicates with the central nervous system (CNS) through the production of bile acids, short-chain fatty acids (SCFAs), glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin (5-HT) and histamine. A vast number of signals generated in the gastrointestinal tract (GIT) reaches the brain via afferent fibers of the vagus nerve (VN). Signals from the CNS are returned to entero-epithelial cells (EES) via efferent VN fibers and communicate with 100 to 500 million neurons in the submucosa and myenteric plexus of the gut wall, which is referred to as the enteric nervous system (ENS). Intercommunications between the gut and CNS regulate mood, cognitive behavior, and neuropsychiatric disorders such as autism, depression, and schizophrenia. The modulation, development, and renewal of nerves in the ENS, and changes in the gut microbiome alter the synthesis and degradation of neurotransmitters, which ultimately influence our mental health. The more we decipher the gut microbiome and understand its effect on neurotransmission, the closer we may get to the developing of novel therapeutic and psychobiotic compounds to improve cognitive functions and prevent mental disorders. In this review, the intricate control of entero-endocrine signaling and immune responses that keep the gut microbiome in a balanced state, and the influence that changing gut bacteria have on neuropsychiatric disorders are discussed.

This brief commentary challenges the use of the term "energy deficiency" in nutrition and metabolism, providing a critical examination of its scientific and philosophical aspects. It emphasizes the need to consider rare diseases associated with actual energy deficiency, which extend beyond the scope of everyday tiredness or fatigue. By analyzing energy balance and its complexities, this critique underscores the oversimplification associated with the term and its potential for misleading implications. It highlights the dynamic nature of energy metabolism and the intricate mechanisms involved in maintaining energy equilibrium, including the impact of rare genetic and physiological abnormalities. In addition to the discussion on energy balance, this commentary explores the manifestation of rare diseases that disrupt energy production, utilization, or hormonal regulation. Conditions such as mitochondrial diseases, glycogen storage diseases, adrenal insufficiency, and Prader-Willi syndrome are examined, shedding light on their profound impact on individuals' energy levels and overall health. The distinct time courses, underlying mechanisms, and clinical implications of protein deficiency, energy deficiency, and vitamin C deficiency are also compared, further emphasizing the complexity of energy metabolism and its relationship with various nutrient deficiencies. To foster a more comprehensive understanding of energy metabolism and enhance clarity in communication within the field, the commentary proposes the adoption of alternative terminology, such as "energy flux," to capture the multifaceted nature of energy balance more accurately. By reevaluating the terminology employed, researchers and healthcare professionals can better convey the intricate dynamics of energy metabolism and address the unique challenges faced by individuals with rare diseases causing actual energy deficiency. In conclusion, this commentary serves as a thought-provoking exploration of the concept of energy deficiency in nutrition and metabolism. It highlights the limitations of the term in capturing the complexities of energy balance, particularly in the context of rare diseases. By broadening the discussion to include these rare conditions, it encourages a more comprehensive understanding of energy metabolism and calls for precise and nuanced terminology to facilitate effective communication and advancements in the field.

The receptor Tyrosine Kinase (RTK) pathway and the downstream related Mitogen Activated Protein Kinase (MAPK) cascades are crucial signal transduction pathways that preside over various cellular processes, including proliferation, differentiation, apoptosis, and responses to stressors. They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. Germ cell tumors (GCTs) are relatively rare. However, they are the most diagnosed malignancies occurring in the testis (TGCT) among men aged between 15 and 40 years. Despite high aneuploidy and a paucity of somatic mutations, several genomic and transcriptomic assays have identified few significantly mutated somatic genes, primarily KIT and K-RAS, so affecting, at various levels, the KIT–RAS–RAF–MEK–ERK cascade. This review focuses on the most recent investigations about this signaling pathway in TGCTs concerning their development, natural history, response to standard chemotherapy protocols (i.e., cisplatin-based), and on the efforts being made to identify targetable markers for possible precision medicine approaches.

In a recent effort to mitigate harm from human pathogens, many biosynthetic pathways are extensively evaluated for their ability to inhibit pathogen growth and determine drug targets. Among those, one of the important products/targets of such pathways is isopentenyl diphosphate, the universal precursor of isoprenoids, which are essential for the normal functioning of microorganisms. In general, two biosynthetic pathways lead to the formation of isopentenyl diphosphate: 1) the mevalonate pathway in animals and 2) the non-mevalonate or methylerythritol phosphate (MEP) in many bacteria, some protozoa, and plants. Because the MEP pathway is not found in mammalian cells, it is considered an attractive target for the development of antimicrobials against a variety of human pathogens, including Mycobacterium tuberculosis (M.tb). In the MEP pathway, 4-diphosphocytidyl-2-c-methyl-d-erythritol kinase (IspE) phosphorylates 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDPME) to form 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDPME2P), followed by cyclization to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECPP) by 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF). A virtual high throughput screening was done by docking IspE protein with commercially available compounds and identified an active heterotricyclic compound. Hence, we designed, synthesized, and tested similar new heterotricyclic compounds. This study will provide the critical insight necessary for the ability to develop novel antimicrobials that target the MEP pathways in pathogens.

Cadmium (Cd) is a toxic non–essential element to plants, and its accumulation in crops has significant adverse effects on human health. The cross–talk between copper (Cu) and Cd has been reported, but the molecular mechanisms remain unknown. Here, the function of wheat Cu transporter 3D (TaCOPT3D) in Cd tolerance was investigated. The TaCOPT3D transcripts significantly accumulated in wheat roots under Cd exposure. To test whether TaCOPT3D was involved in response to Cd stress, overexpressing lines with altered expression of TaCOPT3D transporters were compared to wild–type (WT) plants. The results showed that, under 20 μM Cd treatment, TaCOPT3D–overexpression lines exhibited more biomass and lower Cd accumulation in roots, shoots, and grains compared to WT plants. In addition, the TaCOPT3D–overexpression lines demonstrated less reactive oxygen species (ROS) and a greater amount of active antioxidant enzymes under Cd conditions than WT plants. Moreover, TaCOPT3D–overexpression lines highly reduced Cd accumulation under exposure to 20 μM Cu. The regulation pathway of TaCOPT3D in response to Cd stress was investigated, and transcription factor (TF) TaWRKY22, which targeted the TaCOPT3D promoter, was identified. Therefore, TaCOPT3D can serve as a candidate gene for decreasing Cd accumulation in wheat through genetic engineering.

Lysine is the first limiting essential amino acid in rice because it is present in the lowest quantity compared to all the other amino acids. Amino acids are the building block of proteins and play an essential role in maintaining the human body’s healthy functioning. Rice is a staple food for large proportion of the global population, thus increasing the lysine content in rice will improve its nutritional value. In this paper, we studied the lysine biosynthesis pathway in rice (Oryza Sativa) to identify the regulators of the lysine reporter gene LYSA (LOC_Os02g24354). Genetically intervening at the regulators has the potential to increase the overall lysine content in rice. We modeled the lysine biosynthesis pathway in rice seedlings under normal and saline (NaCl) stress conditions using Bayesian networks. We estimated the model parameters using experimental data and identified the gene DAPF(LOC_Os12g37960) as a positive regulator of the lysine reporter gene LYSA under both normal and saline stress conditions. Based on this analysis, we conclude that the gene DAPF is a potent candidate for genetic intervention. Upregulating DAPF using methods such as CRISPR-Cas9 has the potential to upregulate the lysine reporter gene LYSA and increase the overall lysine content in rice.

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.

Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of the present analysis is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

Background and aims: Despite recent advances in advanced prostate cancer treatments, there are no clinically useful biomarkers or treatments for men with such cancers. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterize BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signaling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

For decades, neurologic and other extra glandular manifestations have been described in Sjögren’s syndrome (SS). More recently, neuropathic, psychological and cognitive alterations are being considered part of the disease. The lacrimal glands (LG), the ocular surface (OS), salivary glands (SG) and the central nervous system (CNS) are integrated to modulate the autonomic functions and, not just those organs, but also the hippocampus, which is linked to the autonomic nervous system, and modulate behavior responses appears to be compromised in the SS. Recent studies confirm that the tryptophan/kynurenine pathway (TKP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating the indoleamine-pyrrole 2,3-dioxygenase (IDO) in SS. This pathway interferes on serotonergic and glutamatergic neurotransmission, mostly in the hippocampus, and other structures of the CNS. Although not demonstrated, it is plausible that this constant interference induces clinical signs of SS, and contributes to the discrepancy between symptoms and signs, towards manifestations of hyperalgesia and depression in patients with SS. Therapeutic strategies are being reexamined and new options designed and tested to regulate the involved steps of the TKP. In the future, the application of this concept may offer a clue to the mosaic of manifestations of SS.

The magnesium ion is an essential cation in the human body and participates in numerous physiological activities. A deficiency in magnesium ions is closely associated with tumor development, and supplementation with magnesium ions has been shown to partially inhibit tumor growth. However, the specific mechanisms by which magnesium ions suppress tumor proliferation remain unclear. Currently, studies have revealed that mitochondria may serve as a crucial intermediate link in the regulation of tumors by magnesium ions. Mitochondria might intervene in the proliferation and invasion of tumor cells by modulating energy metabolism and oxidative stress levels. Therefore, this article provides a comprehensive review of the relationship between magnesium ions and tumors, the mechanisms by which magnesium ions regulate mitochondrial function, and the theoretical basis and prospects of magnesium ion regulation of mitochondrial function for tumor treatment. This review aims to offer insights for clinical tumor treatment strategies involving magnesium ion intervention.

Copepods are the most abundant metazoans on Earth, exhibit remarkable species diversity and global distribution. Accurate species identification of copepods presents a challenge due to their cryptic nature, necessitating meticulous examination and differentiation. To address this challenge, innovative approaches utilizing molecular markers have emerged, enabling more reliable and precise species identification. Mitochondrial genes, which are characterized by high variability, have proven invaluable in uncovering taxonomically significant variations among copepod species. In this study, we present the first complete mitochondrial genome analysis of the marine calanoid copepod Bestiolina similis (Sewell, 1914). Recent investigations employing whole mitochondrial genome-based phylogenetic analyses have generated considerable interest in exploring the deep branching patterns of arthropods. The complete mitochondrial genome of B. similis spans 23,704 base pairs and includes 13 protein-coding genes and 20 transfer RNA genes. The nucleotide composition of the mitochondrial genome is characterized by 43.42% adenine, 43.22% thymine, 6.48% guanine, and 6.88% cytosine. Maximum likelihood-based phylogenetic analysis of the mitochondrial genome were constructed of the available copepod species. Mitochondrial ge-nome-based phylogenies often reveal intriguing and distinctive topologies compared to traditional phylogenetic approaches. However, the sequencing of copepod mitochondrial genomes, particularly within the calanoid copepods remains limited. Therefore, this study aims to construct a phylogenetic tree based on the extracted mitochondrial genome, incorporating available data, to enhance our understanding of the evolutionary relationships among calanoid copepods.

Central metabolic pathways may play a major role in the virulence of pathogenic fungi. Here, we have investigated the susceptibility of a Candida parapsilosis mutant deficient in trehalase activity (atc1Δ/ntc1Δ strain) to the azolic compounds Fluconazole and Itraconazole. A time-course exposure to Itraconazole but not Fluconazole induced a significant degree of cell-killing in mutant cells compared to the parental strain. Flow cytometry determinations indicated that Itraconazole was able to induce a marked production of endogenous ROS together with a simultaneous increase in membrane potential, these effects being irrelevant after Fluconazole addition. Furthermore, only Itraconazole induced a significant synthesis of endogenous trehalose. The recorded impaired capacity of mutant cells to produce structured biofilms was further increased in the presence of both azoles, with Itraconazole being more effective than Fluconazole. Our results in the opportunistic pathogen yeast C. parapsilosis reinforce the study of trehalose metabolism as an attractive therapeutic target and allow extending the hypothesis that the generation of internal oxidative stress may be a component of the antifungal action exerted by the compounds currently available in medical practice.

Population genetic data underpin many studies of behavioral, ecological, and evolutionary processes in wild populations and contribute to effective conservation management. However, collecting genetic samples can be challenging when working with endangered, invasive, or cryptic species. Environmental DNA (eDNA) offers a way to sample genetic material non-invasively without requiring visual observation. While eDNA has been trialed extensively as a biodiversity and biosecurity monitoring tool with a strong taxonomic focus, it has yet to be fully explored as a means for obtaining population genetic information. Here, we review current research that employs eDNA approaches for the study of populations. We outline challenges facing eDNA-based population genetic methodologies, and suggest avenues of research for future developments. We advocate that with further optimizations, this emergent field holds great potential as part of the population genetics toolkit.

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.

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBC. We hypothesized that EZH2 inhibition in TNBC cells per se would exert anti-tumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2-knockout (KO) and overexpressing lines from parent (wild-type -WT) 4T1 cells, an established murine TNBC model. In vitro, EZH2 KO and OE cells showed little change in replicative capacity and invasiveness, but marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. On in vivo injection, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Our findings show a tumor-intrinsic role of EZH2 in the 4T1 TNBC model in regulating TIN/TIL poise, primary tumor progression and lung metastasis in vivo.

The intrinsic dynamic and static nature of the non-covalent Br-*-Br interactions in the neutral polybromine clusters is elucidated for Br4–Br12, applying QTAIM dual functional analysis (QTAIM-DFA). The asterisk (*) emphasizes the existence of the bond critical point (BCP) on the interaction in question. Data from the fully optimized structures correspond to the static nature of interactions. The intrinsic dynamic nature is originated from those of the perturbed structures generated using the coordinates derived from the compliance constants for the interactions and the fully optimized structures. The non-covalent Br-*-Br interactions in the L-shaped clusters of the Cs symmetry are predicted to have the typical hydrogen bond nature without covalency, although the first ones in the sequences have the vdW nature. The L-shaped clusters are stabilized by the n(Br)->σ*(Br–Br) interactions. The compliance constants for the corresponding non-covalent interactions are strongly correlated to the E(2) values based on NBO. Indeed, the MO energies seem not contribute to stabilize Br4 (C2h) and Br4 (D2d), but the core potentials stabilize them, relative to the case of 2Br2, maybe due to the reduced nuclear-electron distances in the average for the dimmers.

Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80 % of them surpassed +3SD, all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.

Flavonoids are polyphenolic phytochemical compounds found in many plants, fruits, vegetables, and leaves. They have a multitude of medicinal applications due to their anti-inflammatory, anti-oxidative, anti-viral, and anti-carcinogenic properties. Furthermore, they also have neuroprotective and cardioprotective effects. Their biological properties depend on the chemical structure of flavonoids, their mechanism of action, and their bioavailability. The flavonoid’s beneficial effects have been proven for a variety of diseases. In the last few years, it is demonstrated that flavonoids’ effects are mediated by inhibiting the NF-κB (Nuclear Factor-κB) pathway. In this review, we have summarized the effects of some flavonoids on the most common diseases such as cancer, cardiovascular, and neurodegenerative human diseases. In particular, here we collected all recent studies describing plant-derived flavonoids’ protective and prevention role, by specifically focusing their action on the NF-κB signaling pathway.

Wnt/β-catenin signaling pathway plays an established role in various diseases and is considered a hallmark of endometrial cancer (EC). Special AT-rich sequence-binding protein 1 and 2 (SATB1 and SATB2) are nuclear matrix-associated proteins involved in chromatin remodeling and regulation of gene expression. SATB1 promotes the progression of numerous types of cancers, whereas SATB2 acts as a tumor suppressor. Despite a recent progress in our knowledge about EC, the exact mechanisms that control their proliferation and metastatic potential still remain unknown. The aim of our study was to investigate the association between Wnt3A, β-catenin, SATB1 and SATB2 protein level and the clinicopathological features of EC patients. 92 EC patients, aged 37-84, were enrolled to our study. The immunoexpression of WNT3A was found in specimens from all EC patients, β-catenin was expressed in 97% of the cases, SATB1 in 87%. The significant association between Wnt3a expression and tumor grade was found; moreover mean IRS for Wnt3a turned out to be significantly lower in high-grade tumors than in low-grade malignancies (p=0.038). In turn, immunoexpression of β-catenin varied significantly across FIGO stages and was associated with the presence of lymph node metastases. Mean IRS for β-catenin in patients with lymph node metastases was significantly lower than in those without (p = 0.028). The Kaplan-Meier analyses demonstrated a stepwise impairment of cancer overall survival with increasing SATB1 expression. In conclusion, both Wnt/β-catenin signaling pathway and SATB1 contribute to progression of EC. Downregulation of β-catenin may predispose to lymphatic spread of EC. In turn, downregulation of Wnt3a seems to be characteristic for high-grade tumors, but probably does not play a role in formation of lymph node metastases. The important role of SATB1 as a predictor of poor survival and could be helpful in establishing a more accurate prognosis in endometrial cancer patients.

The Coronavirus 2 (SARS-CoV-2) infection is a global pandemic that has affected millions of people worldwide. The advent of vaccines, however, has permitted some restitution. Aside from the respiratory complications of the infection, there is also a thrombotic risk attributed to both the disease alongside the vaccine. There are no reliable data for the risk of thromboembolism in SARS-CoV-2 infection in patients managed out with the hospital setting. A literature review was performed to identify the pathophysiological mechanism of thrombosis from the SARS-CoV-2 infection including the role of Angiotensin-Converting Enzyme receptors. The impact of the vaccine and likely mechanisms from thrombosis following vaccination was also clarified. Finally, the utility of the vaccines available against the multiple variants is also highlighted. The systemic response to SARS-CoV-2 infection is still relatively poorly understood, but several risk factors have been identified. The roll-out of the vaccines worldwide has also allowed the lifting of lockdown measures and a reduction in the spread of the disease. The experience of the SARS-CoV-2 infection, however, has highlighted the crucial role of epidemiological research and the need for ongoing studies within this field.

Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin on wound healing in vitro and in vivo. Visfatin enhanced the proliferation and migration of human dermal fibroblasts (HDFs) and keratinocytes, and significantly increased the expression of wound healing-related vascular endothelial growth factor (VEGF) in vitro and in vivo. Treatment of HDFs with visfatin induced activation of both extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in a time-dependent manner. Inhibition of ERK1/2 and JNK1/2 led to a significant decrease in visfatin-induced proliferation and migration of HDFs. Importantly, blocking VEGF with its neutralizing antibodies suppressed the visfatin-induced proliferation and migration of HDFs and human keratinocytes, indicating that visfatin induces the proliferation and migration of HDFs and human keratinocytes via increased VEGF expression. Moreover, visfatin effectively improved wound repair in vivo, which was comparable to the wound healing activity of epidermal growth factor (EGF). Taken together, we demonstrate that visfatin promotes the proliferation and migration of HDFs and human keratinocytes by inducing VEGF expression and can be used as a potential novel therapeutic agent for wound healing.

Background and objectives: Diabetes mellitus is a disease of insulin deficiency or its inability of usage by the target tissues leading to impairment of carbohydrate, lipid, and protein metabolisms. Resveratrol, having robust anti-inflammatory and anti-oxidant properties, has a high potential to treat or prevent the pathogenesis of diseases. This study was conducted to reveal the relationship between diabetes-induced oxidative stress and tissue inflammation with changes in main enzymatic antioxidants (cat, sod, gpx, and gst) and the components of the insulin signaling pathway (insulin Rβ, irs-1, pi3k, akt, mtor) in kidney tissues. Additionally, the effects of resveratrol on these parameters were evaluated. Materials and Methods: Male Wistar rats were randomly divided into four groups; (1) control/vehicle; (2) control/20 mg/kg resveratrol; (3) diabetic/vehicle; (4) diabetic/20 mg/kg resveratrol. Gene and protein expressions of antioxidant enzymes and insulin signaling elements were evaluated in renal tissues. Results: Downregulation of antioxidant enzymes’ gene expression in the kidney tissues of diabetic rats was demonstrated and this situation was devoted partially to the reduced gene expression of nfκb. Moreover, the components of renal insulin signaling elements were upregulated at both gene and protein expression levels in diabetic rats, and resveratrol treatment decreased this sensitization towards the control state. Conclusion: Resveratrol partially improved diabetes-induced renal oxidative stress and inflammation due to healing action on renal antioxidant enzymes and insulin signaling pathway components.

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.

Hyperlipidemia is the fat particles excess in the serum. Hyperlipidemia increases the mortality rate that occurs with other metabolic disorders. Hyperlipidemia is classified into familial and acquired subgroups. Moreover, Hyperlipidemia etiology is based on environmental or genetic factors. For instance, abnormal HMG-CoA regulation down-regulates ubiquitin ligase and targets variable oxidative stress-related condition proteins. There has been proven reactive oxygen species (ROS) overshoot happens during hyperlipidemia occurrence. OS, directly and indirectly, regulates molecular cascades within the cell and leads to gene expression alteration. At this molecular juncture, AMPK is affected by ROS. AMPK is a serine-threonine kinase and a critical energy balance. Low energy conditions result in AMPK activation due to the down-regulation of protein and lipid synthesis. Furthermore, ER stress and activated unfolded protein proteasomal response and autophagy are AMPK mediated. Polyphenols are widespread dietary plant-based compounds that regulate gene expression and signal conduction. Through the hyperlipidemic state, FFAs releasing indirectly connect to AMPK/NF-κB pathway then polyphenols target them. AMPK, during this FFA exposure, down-regulates de novo lipid molecules generation. Likewise, if AMPK/mTOR pathway failure is prolonged, the hyperlipidemic state may be explicit, activated by natural herbal mediators, e.g., polyphenols. Polyphenols activate the AMPK signaling pathway and influence lipid metabolism. Polyphenol-mediated AMPK activation results in lipogenesis inhibition and lipophagy. Cholesterol efflux mediated polyphenols lipid-lowering effects, accessing LXR pathway. All these clues persist on direct or indirect AMPK-related polyphenolic anti-hyperlipidemic effects.

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10.000 different secretory and membrane proteins. The membrane insertion of proteins, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid metabolism for membrane lipids including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein folding-imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

The capsid precursor P1 constitutes the N-terminal part of the enterovirus poly-protein. It is processed into VP0, VP3, and VP1 by the viral proteases, and VP0 is cleaved autocatalytically into VP4 and VP2. We observed that poliovirus VP0 is recognized by an antibody against a cellular autophagy protein LC3A. The LC3A-like epitope overlapped the VP4/VP2 cleavage site. Individually expressed VP0-EGFP and P1 strongly colocalized with a marker of selective autophagy p62/SQSTM1. To assess the role of capsid proteins in autophagy development we infected different cells with poliovirus or encapsidated polio replicon coding for only the replication proteins. We analyzed the processing of LC3B and p62/SQSTM1, markers of the initiation and completion of the autophagy pathway, and systematically investigated the association of the viral antigens with these au-tophagy proteins in infected cells. We observed cell-type specific development of autophagy upon infection and found that only the virion signal strongly co-localized with p62/SQSTM1 early in infection. Collectively, our data suggest that activation of autophagy is an antiviral response, and that capsid proteins con-tain determinants targeting them to p62/SQSTM1-dependent sequestration. Such a strategy may control the level of capsid proteins so that viral RNAs are not re-moved from the replication/translation pool prematurely.

Background. Wnt-pathway proteins play a vital role in kidney development and defects in the Wnt-pathway are associated with kidney disorders. However, the knowledge on the role of Wnt/β-catenin pathway proteins in end-stage renal disease (ESRD) is limited.Aim of the study. To delineate the association of ESRD and Wnt-proteins including the agonistR-spondin 1, the transducer β-catenin and the antagonists Dickkopf-related protein 1 (DKK1) and sclerostin.Methods. Serum Wnt-pathway proteins levels were measured by ELISA, while other biochemicals were measured spectrophotometrically in 60 ESRD patients and 30 normal controls.Results. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-Sponin-1 / DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Logistic regression analysis showed that ESRD was significantly predicted by increased levels of DDK1 and sclerostin and lowered β-catenin (p<0.001). eGFR was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r=0.468, p<0.001). DKK1 levels were significantly and positively correlated with urea, creatinine, and copper. DKK1 and sclerostin were inversely associated with hemoglobin and packet cell volume. Catenin was significantly negatively associated with copper, urea and creatinine.Conclusion. Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists and, therefore, attenuated Wnt/β-catenin pathway activity. The latter is associated with lowered eGFR and increased serum copper levels. Wnt/β-catenin pathway proteins are possible drug targets to treat ESRD or its consequences.

In recent years, marine, freshwater and terrestrial pollution with microplastics has been discussed extensively, whereas atmospheric microplastic transport has been largely overlooked. Here, we present the first global simulation of atmospheric transport of microplastic particles produced by road traffic (TWPs – tire wear particles and BWPs – brake wear particles), a major source that can be quantified relatively well. We find a high transport efficiency of these particles to remote regions, such as the Arctic Ocean (14%). About 34% of the emitted coarse TWPs and 30% of the emitted coarse BWPs (100 kt yr^-1 and 40 kt yr^-1 respectively) were deposited in the World Ocean. These amounts are of similar magnitude as the total estimated terrestrial and riverine transport of TWPs and fibres to the ocean (64 kt yr^-1). Atmospheric transport of microplastics is thus an underestimated threat to global terrestrial and marine ecosystems and affects air quality on a global scale, especially considering that other large but highly uncertain emissions of microplastics to the atmosphere exist. High latitudes and the Arctic are highlighted as an important receptor of mid-latitude emissions of road microplastics, which may imply a future climatic risk, considering their affinity to absorb solar radiation and accelerate melting.

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.

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.

.Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating specific signaling pathways in the cells. Disruption of the retinoic acid signaling pathway can result in neuroinflammation, ox-idative stress, mitochondrial dysfunction and neurodegenerative processes, and has been asso-ciated with a range of neurodegenerative diseases. The present study explores the potential therapeutic application of our innovative synthetic retinoid, Ellorarxine, also known as DC645 and NVG0645, for the treatment of neurodegenerative disorders in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehy-drogenase (LDH) assay, enzyme-linked immunosorbent assay (ELISA), senescence-associated (SA) β-galactosidase (β-gal) staining and immunofluorescence staining were performed. The re-sults showed that no cytotoxicity was detected at the experimental concentrations of Ellorarxine. Ellorarxine significantly reduced cell death, increased mitochondrial viability, reduced the num-ber of senescent cells, modulated cytokine release and regulated cellular autophagy. Furthermore, Ellorarxine also increased Cyp26 and selectively RARβ expression. These results make Ellorarxine a promising drug candidate that should be further investigated in the treatment of neurodegenerative diseases. .

Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress, and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune sentinels of the central nervous system capable of initiating an innate and adaptive immune response. Nevertheless, the pathological mechanisms underlying the initiation and spread of inflammation in the brain are still poorly described. Recently, a new mechanism of intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs are nanosized particles (30-150 nm) with a bilipid membrane that carries cell-specific bioactive cargos that participate in physiological or pathological processes. Damage-associated molecular patterns (DAMPs) are cellular components recognized by the immune receptors of microglia, inducing or aggravating neuroinflammation in neurodegenerative disorders. Diverse evidence links mitochondrial dysfunction and inflammation mediated by mitochondrial-DAMPs (mtDAMPs) such as mitochondrial DNA, TFAM and cardiolipin, among others. Mitochondrial-derived vesicles (MDVs) are a subtype of EVs produced after mild damage to mitochondria and, upon fusion with multivesicular bodies (MVBs), are released as EVs to the extracellular space. MDVs are particularly enriched in mtDAMPs which can induce an immune response and the release of pro-inflammatory cytokines. Importantly, growing evidence supports the association between mitochondrial dysfunction, EVs release and inflammation. Here, we describe the role of extracellular vesicles-associated mtDAMPS in physiological conditions and as neuroinflammation activators contributing to neurodegenerative disorders.

leaf beetle (BLB) (Ootheca mutabilis) has emerged as an important bean pest in Uganda, leading to devastating crop losses. There is limited information on the population genetic structure of BLB despite their importance. In this study, novel microsatellite markers and the partial mitochondrial cytochrome oxidase subunit I (mtCOI) gene sequences were used to analyze the spatial population genetic structure, genetic differentiation, gene flow and haplotype diversity of 87 O. mutabilis samples from five populations. We identified 19,356 simple sequence repeats (SSRs) (mono, di, tri, tetra, penta, and hexa-nucleotides) of which 81 di, tri and tetra-nucleotides were selected for primer synthesis. Five highly polymorphic SSR markers (4-21 alleles, heterozygosi-ty 0.59-0.84, polymorphic information content (PIC) 50.13-83.14%) were used for this study. Analyses of the five O. mutabilis populations with these five novel SSRs found 89% of genetic variation occurring within individuals, 9% among individuals and 2% among populations. Genetic differentiation was low but significant for SSR and insignificant for mtCOI partial sequence data while gene flow was high across the populations. There was no evidence of isolation by distance between geographical and genetic distances. Bayesian clustering identified signature of admixture that suggests genetic contributions from two ancestral genetic lineages, and the median-joining haplotype network showed low differentiation of many different haplotypes from the most common haplotype. Low genetic differentiation and high gene flow indicates unrestricted migrations between populations. This information will contribute to the design of BLB control strategies.

Mitochondrial dysfunctions remained a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria which is also known as the power-generating set of the cell, have a dominant role in several processes associated with the genomic integrity and cellular equilibrium maintenance. They are involved in maintaining optimal cells functioning and guidance from possible DNA damage which could lead to mutations and onset of diseases. Conversely, system perturbations which could be due to environmental factors or senescence induce changes in the physiological balance and result in the mitochondrial functions impairment. The focal point of this review focuses on mitochondrial dysfunction as a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria which are common amongst the most recurring neurodegenerative diseases including Alzheimers and Parkinsons disease. Do mitochondrial dysfunctions represent an early event in causing a shift towards neuropathological processes?

Mitochondrial Encephalohepatopathy (MEH) is an autosomal recessive neurodevelopmental disorder usually accompanied by microcephaly, white matter changes, cardiac and hepatic failure. Here, we applied the whole-exome sequencing (WES) framework on a trio family data with unaffected non-consanguineous parents and proband (neonate girl) with this inherited disorder. A total of 2,928,402 variants were observed with 2,613,746 SNPs, 112,336 multiple nucleotide polymorphisms (MNPs), 72,610 insertions, 113,207 deletions and 16,503 mixed variants. These variations are responsible for 82,813,631 effects on various genomic regions. Our pipeline uncovered candidate gene mutations from these variants and retained a handful of 5,277 variants harboring 3,598 genes, out of which, 8 genes codes for non-coding RNA while 178 genes are those with high impact severity. Among these 178 variants, 125 are de-novo variants that are not previously reported in the ClinVar database. Consistent to previous studies, the leftover high impact severity genes are involved in encephalopathy, Leigh syndrome, Charcot–Marie–Tooth disease, global developmental disorder, seizures, spastic paraplegia, premature ovarian failure, mitochondrial myopathy-cerebellar, ataxia-pigmentary, retinopathy syndrome, ocular and retinal degeneration, deafness, intellectual disability, cardiofacioneurodevelopmental syndrome etc. All these clinical features were also observed in the patient studied. The current analysis highlights and expands the genetic architecture of the MEH phenotype. Furthermore, this pipeline on trio family data significantly broadens the concept of its usefulness as a first-tier diagnostic method in the detection of complex multisystem phenotypic disorders.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function with neuronal damage. Although the precise pathobiology of AD is still elusive, accumulating evidences suggest that mitochondrial dysfunction is one of the underlying causes of AD. Mutations of mitochondrial or nuclear DNA that encode mitochondrial constituents may cause mitochondrial dysfunctions. In particular, dysfunction of electron transport chain complexes along with interactions of mitochondrial pathological proteins are associated with mitochondrial dysfunctions in AD. Mitochondrial dysfunction causes an imbalance in reactive oxygen species, leading to oxidative stress (OS) and vice-versa. Neuroinflammation is another potential contributory factor to induce mitochondrial dysfunction. Phytochemicals or other natural compounds have the potential to scavenge oxygen free radicals and enhance cellular antioxidant defense system, and thereby protect against OS-mediated cellular damage. Phytochemicals can also modulate other cellular processes, including autophagy and mitochondrial biogenesis. Pharmacological intervention through neuroprotective phytochemicals can, therefore, be a potential strategy to combat mitochondrial dysfunctions as well as AD. This review focuses on the role of phytochemicals to mitigate mitochondrial dysfunction in the therapy of AD pathogenesis.

Burn-induced cardiac dysfunction is thought to involve mitochondrial dysfunction although the mechanisms responsible are unclear. In this study, we used our established model of in vivo burn injury to understand the genetic evidence of burn-induced mitochondrial metabolism confusion by describing cardiac mitochondrial metabolism-related gene expression after burn. Cardiac tissue was collected at 24 hours after burn injury. An O2K respirometer system was utilized to measure cardiac mitochondrial function. Oxidative phosphorylation complex activities were determined using enzyme activity assays. RT Profiler PCR array was used to identify differential regulation of genes involved in mitochondrial biogenesis and metabolism. Quantitative qPCR and Western Blotting were applied to validate differentially expressed genes. Burn-induced cardiac mitochondrial dysfunction was supported by the finding of decreased state 3 respiration and decreased mitochondrial electron transport chain activity in complex I, III, IV, and V following burn injury. Eighty-four mitochondrial metabolism-related gene profiles were measured. The mitochondrial gene profile showed that one third of genes related to mitochondrial energy and metabolism was differentially expressed. Of these 28 genes, 15 were more than 2-fold upregulated and 13 were more than 2-fold downregulated. All genes were validated using qPCR; 4 genes had a protein level which correlated with the observed change in gene expression. This study provides preliminary evidence that a large percentage of mitochondrial metabolism-related genes in cardiomyocytes were significantly affected by burn injury.

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

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.

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.

Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

A rapid and appropriate genetic and metabolic acclimation, which is crucial for plants’ survival in a changing environment, is maintained due to the coordinated action of plant hormones and cellular degradation mechanisms influencing proteostasis. The plant hormone abscisic acid (ABA) rapidly accumulates in plants in response to environmental stress and plays a pivotal role in the reaction to various stimuli. Increasing evidence demonstrates a significant role of autophagy in controlling ABA signaling. This field has been extensively investigated and new discoveries are constantly being provided. We present updated information on the components of the ABA signaling pathway, particularly on transcription factors modified by different E3 ligases. Then, we focus on the role of selective autophagy in ABA pathway control and review novel evidence on the involvement of autophagy in different parts of the ABA signaling pathway that are important for crosstalk with other hormones, particularly cytokinins and brassinosteroids.

Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies de-scribing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonautes proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases and an atypical ribonuclease III (RNaseIII). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.

The description of the genus Leishmania as causative agents of leishmaniasis occurred during this modern age. But evolutionary studies suggest that the origin of Leishmania can be traced back to the Mesozoic era. Subsequently, during its evolutionary process, it sustained a worldwide dispersion predating the breakup of the Gondwana supercontinent. It is assumed that this parasite evolved from monoxenic Trypanosomatidae. Phylogenetic studies locate the dixenous Leishmania in a well-supported clade, recently named subfamily Leishmaniinae, which includes also monoxenous trypanosomatids. Virus-Like Particles were reported in many species of this family. So far, several Leishmania species have been reported as infected by Leishmania RNA Virus (LRV) and Leishbunyavirus (LBV). Since the first descriptions of LRV decades ago, differences in its genomic structure have been highlighted, leading to the designation of a LRV1 in L. (Viannia) species and a LRV2 in other L. (Leishmania) species. There are strong indications of virus infecting Leishmania spp. ability to enhance parasitic survival both in human and experimental infections, through highly complex and specialized mechanisms. Phylogenetic analyzes of these viruses have shown that their genomic differences correlate with the infected parasite species, suggesting a coevolutionary process. Herein, we will present unpublished results regarding the relationship Leishmania – endosymbiotic Leishmania viruses and will explore what has been described in the literature, and what is known about this association that could contribute to discussions about the worldwide dispersion of Leishmania.

Anthropogenic activities have increased the amount of urban wastewater discharged into natural aquatic reservoirs confining in them a high amount of nutrients and organics contaminants. Several studies have reported that an alternative to reduce those contaminants is using consortiums of microalgae and endogenous bacteria. In this research, a genome-scale biochemical reaction network is reconstructed for the co-culture between the microalga Chlorella vulgaris and the bacterium Pesudomonas aeruginosa. Metabolic Pathway Analysis (MPA), is applied to understand the metabolic capabilities of the co-culture and to elucidate the best conditions in removing nutrients such as Phosphorus (inorganic phosphorous and phosphate) and Nitrogen (nitrates and ammonia). Theoretical yields for Phosphorus removal under photoheterotrophic conditions are calculated, determining their values as 0.042 mmol of PO₄/ g DW of C. vulgaris, 19.53 mmol of inorganic Phosphorus /g DW of C. vulgaris and 4.90 mmol of inorganic Phosphorus/ g DW of P. aeruginosa. Similarly, according to the genome-scale biochemical reaction network the theoretical yields for Nitrogen removal are 10.3 mmol of NH₃/g DW of P. aeruginosa and 7.19 mmol of NO₃ /g DW of C. vulgaris. Thus, this research proves the metabolic capacity of these microorganisms in removing nutrients and their theoretical yields are calculated.

This research investigates the relationship among human knowledge, behavior, and risk as they relate to urban chicken husbandry in the U.S. Concern over zoonotic diseases has been on the rise, especially with increasing contact. In particular, avian influenza, or bird flu, Salmonella enterica (salmonella), and Escherichia coli (E. coli), can all cross species lines between people and poultry. This study analyzed knowledge and practices in urban chicken husbandry to assess how they relate to risk of disease acquisition, hypothesizing that certain practices associated with a lessened knowledge base may heighten the risk. This study used social surveys to examine the self-reported knowledge base of individuals involved in chicken husbandry as they relate to beliefs and behaviors associated with the care of these animals. These results identify key factors that may heighten the risk of disease transmission, and demonstrate that an increased knowledge base could act to lessen this risk.

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.

In this study, we resequenced the mitogenomes of P. megacephalus from different regions using a “primer bridging” approach with Sanger sequencing technologies. The mitogenome of this species was found to contain two copies of the ND5 genes and three copies of the control regions. Furthermore, multiple tandem repeats were identified in the control regions. Notably, we observed that there was no correlation between the distribution of species and their genetic distance. However, our research revealed the discovery of the “missing” ATP8 gene in P. megacephalus as well as three other previously published Polypedates, as a result of manual data curation. Using the mitogenome, gene expression analysis was performed via RT-qPCR of liver samples and determined that COIII, ND2, ND4, and ND6 were reduced to 0.64±0.24, 0.55±0.34, 0.44±0.21 and 0.65±0.17 under the low-temperature stress (8℃), respectively, as compared with controls (P<0.05). Remarkably, the transcript of long non-coding RNA (LncRNA) between positions 8029 and 8612 decreased significantly with exposure to low-temperature stress (8℃). Antisense ND6 gene expression showed a downward trend but this was not significant. These results reveal that modulations of protein-coding mitogenomes genes and lncRNAs of P. megacephalus play a crucial part in the molecular response to cold stress.

Thyroid hormones are essential for regulating the metabolic rate, growth, development, and maintenance of many physiological processes in vertebrates. They are synthesized by the thyroid gland, which is an ancient organ that evolved early in vertebrate evolution. This study aims to characterize the evolutionary path of polymorphic variants associated with the hypothalamus-pituitary-thyroid (HPT) axis by comparing ancient DNA (aDNA) sequences of Late Pleistocene-Holocene hominin populations with those of modern humans. We evaluated the genetic sequences of several populations, including Neanderthals, Denisovans, Palaeolithic hunter-gatherers from European Russia and Sunghir, and Neolithic hunter-gatherers/farmers from Anatolia focusing on genes involved in the development of the thyroid gland and thyroid hormone (TH) biosynthesis, secretion, and transport. Results showed interesting variants in the DIO2 (rs225014), TPO (rs4927611), and TG (rs2069556 and rs1133076) genes. All SNPs seemed to confirm that Neanderthals, and in part Denisovas, were physiologically hypothyroidic. Probably they had lower T3 levels due to defective production or peripheral conversion. From the moment that the most favourable alleles in terms of T3 production appear during the Paleolithic, we are inclined to assume that their selection was linked to environmental pressure.Our study supports insight into the evolutionary history of the endocrine system and can help in providing understanding into the evolution of physiological systems and their adaptation to changing environments. Understanding the evolution of thyroid hormones can also shed light on the mechanisms underlying thyroid disorders in humans.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system and their interplay and therefore potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Benzylsuccinate is generated in anaerobic toluene degradation by radical addition of toluene to fumarate and further degraded to benzoyl-CoA by a beta-oxidation pathway. Using metabolic modules for benzoate transport and activation to benzoyl-CoA and the enzymes of benzylsuccinate beta-oxidation, we established an artificial pathway for benzylsuccinate production in Escherichia coli, which is based of its degradation pathway running in reverse. Benzoate is supplied to the medium, but needs to be converted to benzoyl-CoA by an uptake transporter and a benzoate-CoA ligase or CoA-transferase. In contrast, the second substrate succinate is endogenously produced from glucose under anaerobic conditions, and the constructed pathway includes a succinyl-CoA:benzylsuccinate CoA-transferase that activates it to the CoA-thioester. We present first evidence for the feasibility of this pathway and explore product yields under different growth conditions. Compared to aerobic cultures, the product yield increased more than 1000-fold in anaerobic glucose-fermenting cultures and showed further improvement under fumarate-respiring conditions. An important bottleneck to overcome appears to be product excretion, based on much higher recorded intracellular concentrations of benzylsuccinate, compared to those excreted. While no export system is known for benzylsuccinate, we observed an increased product yield after adding an unspecific mechanosensitive channel to the constructed pathway.

Cloud computing has become a widespread technology due to ICT advancements. It allows businesses to move and take advantage of the pay-as-you-go price model. Enterprises pay for what they use and don't have to buy, setup, or maintain resources. However, outsourcing core resources such as storage, servers, operating systems, and software applications from a third party needs careful decisions to take advantage of cloud facilities. Choice of appropriate service provider, deployment and service model must be aligned with business needs and goals. In this paper, we will present cloud computing benefits, cloud deployment methods, services, state-of-the-art migration methods, tools and techniques and will conclude with the role of SDN in cloud computing.

This article explores the intersection of innovative leadership and climate change, aiming to provide outstanding contributions to the existing body of knowledge in this field. The article identifies the critical role of innovative leadership in driving sustainable solutions and strategies for addressing climate change. It examines the defining characteristics and behaviors of innovative leaders and explores how their transformative leadership approaches can create a positive impact on climate change mitigation and adaptation efforts. The article also highlights the importance of fostering innovation within organizations and societies to tackle the complex challenges posed by climate change. Through a comprehensive review of relevant literature and case studies, this article presents novel insights, theoretical frameworks, and practical implications for policymakers, organizations, and individuals involved in climate change leadership.

Bone Morphogenetic Proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-β superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidences are emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here we identified the zebrafish bmp4 ortholog, whose expression is up-regulated by challenge with virus or its mimic poly(I:C). Overexpression of bmp4 in EPC cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 runs an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.

Notch signaling is a highly conserved pathway which occurs between adjacent cells to distinguish them. The Notch signaling cascade operates in a simple mechanism, yet Notch plays remarkably diverse roles in development to regulate cell fate determination, organ growth and tissue patterning. Originally isolated and characterized in the model insect Drosophila melanogaster, recent studies in various insect species have revealed that Notch signaling is broadly involved in the construction of insect tissues. This review focuses on providing a molecular mechanistic and developmental picture regarding the roles of Notch pathway in insects. The functions of Notch in the formation and patterning of insect embryo, wing, leg, ovary and several specific structures as well as in stress responses are summarized. These results are discussed in developmental context with an eye toward understanding the functionality of Notch signaling pathway in different insect species.

The yeast Saccharomyces cerevisiae is widely used in food and nonfood industries. During industrial fermentations yeast are exposed to fluctuations in oxygen concentration, osmotic pressure, pH, ethanol concentration, nutrient availability and temperature. Fermentation performance depends on the ability of different yeast strains to adapt to these changes. Suboptimal growth conditions trigger responses to these external stimuli to allow cellular homeostasis to be maintained. Stress-specific signaling pathways are activated to coordinate changes in tran-scription, translation, protein function, and metabolic fluxes while a transient arrest of growth and cell cycle progression occur. cAMP-PKA, HOG-MAPK and CWI signalling pathways are signal transduction pathways turned on during stress re-sponse. Comprehension of the mechanisms involved in the responses and in the adaptation to these stresses during fermentation is key to improving this industrial process. The scope of this review is to outline the advancement of knowledge about the cAMP-PKA signalling and the crosstalk of this pathway with the CWI and HOG-MAPK cascades in response to the environmental challenges heat and hy-perosmotic stress.

Chronic high glucose (HG) exposure increases methylglyoxal (MG)-derived AGEs and is involved in the onset of pathological conditions, such as diabetes, atherosclerosis and chronic‐degenerative diseases. Under physiologic condition the harmful effects of MG are contrasted by glyoxalase system that is involved in the detoxification of Reactive Carbonyl Species (RCS) and maintain the homeostasis of the redox environment of the cell. Polyphenols are the most abundant antioxidants in the diet and present various health benefits. The study aimed at investigating the role of polyphenols extracted from an apple high in polyphenols (Calville White Winter), on glyco-oxidative stress induced by chronic HG-exposure. Intestinal Caco-2 cells were treated in physiological glucose condition (25mM) as a control and in HG condition (50mM) with or without apple extract for one week. Our data demonstrated that HG-treatment triggers glyco-oxidation stress with a significantly increase in ROS, lipid peroxidation, AGEs and Glyoxalase I (GlxI) activity with a significant decrease in total antioxidant intracellular defense. Treatment with polyphenols under HG condition restores to the control levels GlxI activity, decreases Glyoxalase II (GlxII) in relation to the control and induces a drop of glyco-oxidative damage. This paper seeks to highlight the roles of polyphenols in glyco-oxidative stress.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, is associated with aggressive tumor behavior and poor prognosis. This study aimed to assess its impact on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of The Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, emphasizing a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.

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.

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.

The World Health Organization has developed the Integrated Care of Older People (ICOPE) strategy, a program based on the measurement of intrinsic capacity (IC) as “the composite of all physical and mental attributes on which an individual can draw”. Multicomponent interventions appear to be the most effective approach to enhance IC and to prevent frailty and disability, since adapted physical activity is the preventive intervention that has shown most evidence in the treatment of frailty and risk of falls. Our paper describes the development of a multi-domain group-based intervention addressed to older people living in the community, aimed at improving and/or maintaining intrinsic capacity by means of promoting physical activity, healthy nutrition, and psychological wellbeing in older people. The process of intervention development is described following the Guidance for reporting intervention development studies in health research (GUIDED. The result of this study is the AMICOPE intervention (Aptitude Multi-domain group-based intervention to improve and/or maintain IC in Older PEople) built upon the ICOPE framework and described following the Template for Intervention Description and Replication (TIDieR) guidelines. This study represents the first stage of the UK Medical Research Council framework for developing and evaluating a complex intervention. The next step should be carrying out a feasibility study for the AMICOPE intervention, and in a later stage, assessing the effectiveness in a randomized controlled trial.

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