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Ca2+ imaging is the most frequently used technique to study glial cell physiology. While chemical Ca2+ indicators served to visualize and measure changes in glial cell cytosolic Ca2+ concentration for several decades, genetically encoded Ca2+ indicators (GECIs) have become state of the art in recent years. Great improvements have been made since the development of the first GECI and a large number of GECIs with different physical properties exist, rendering it difficult to select the optimal Ca2+ indicator. This review discusses some of the most frequently used GECIs and their suitability for glial cell research. [ABSTRACT FROM AUTHOR]

This document is an editorial published in the journal Frontiers in Cell & Developmental Biology. The editorial discusses the topic of metabolic modulation of cellular function. It highlights the role of metabolites in regulating cell function, fate, and structure, and how metabolic changes can impact cell signaling and cell death pathways. The editorial also explores the connection between metabolic reprogramming and cell fate determination, diseases caused by metabolic dysfunction, drug discovery, embryonal development, aging, and the impact of environmental stressors on metabolic diseases. The papers presented in this Research Topic demonstrate the importance of understanding the metabolic machinery in deciphering biological processes in health and disease. [Extracted from the article]

This document is an editorial published in the journal Frontiers in Cell & Developmental Biology. The editorial discusses the topic of metabolic modulation of cellular function. It highlights the role of metabolites in regulating cell function, fate, and structure, and how metabolic changes can impact cell signaling and cell death pathways. The editorial also includes papers that explore the connection between metabolic reprogramming and cell fate, diseases caused by metabolic dysfunction, drug discovery, and the impact of environmental stressors on metabolic diseases. Overall, the editorial emphasizes the importance of understanding the metabolic machinery in deciphering biological processes in health and disease. [Extracted from the article]

Introduction: B cells play a pivotal role in adaptive immunity which has been extensively characterised primarily via flow cytometry-based gating strategies. This study addresses the discrepancies between flow cytometry-defined B cell subsets and their high-confidence molecular signatures using single-cell multiomics approaches. Methods: By analysing multi-omics single-cell data from healthy individuals and patients across diseases, we characterised the level and nature of cellular contamination within standard flow cytometric-based gating, resolved some of the ambiguities in the literature surrounding unconventional B cell subsets, and demonstrated the variable effects of flow cytometric-based gating cellular heterogeneity across diseases. Results: We showed that flow cytometric-defined B cell populations are heterogenous, and the composition varies significantly between disease states thus affecting the implications of functional studies performed on these populations. Importantly, this paper draws caution on findings about B cell selection and function of flow cytometric-sorted populations, and their roles in disease. As a solution, we developed a simple tool to identify additional markers that can be used to increase the purity of flow-cytometric gated immune cell populations based on multi-omics data (AlliGateR). Here, we demonstrate that additional non-linear CD20, CD21 and CD24 gating can increase the purity of both naïve and memory populations. Discussion: These findings underscore the need to reconsider B cell subset definitions within the literature and propose leveraging single-cell multi-omics data for refined characterisation. We show that single-cell multi-omics technologies represent a powerful tool to bridge the gap between surface marker-based annotations and the intricate molecular characteristics of B cell subsets. [ABSTRACT FROM AUTHOR]

Counting and analyzing of blood cells, as well as their subcellular structures, are indispensable for understanding biological processes, studying cell functions, and diagnosing diseases. In this paper, we combine digital holographic microscopy with cell segmentation guided by the Sobel operator using Dice coefficients for automatic threshold selection and aimed to automatic counting and analysis of blood cells in flow and different kinds of cells in the static state. We demonstrate the proposed method with automatic counting and analyzing rat red blood cells (RBCS) flowing in a microfluidic device, extracting quickly and accurately the size, concentration, and dry mass of the sample in a label-free manner. The proposed technique was also demonstrated for automatic segmentation of different cell types, such as COS7 and Siha. This method can help us in blood inspection, providing pathological information in disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Up to now, the physiology, pathology, and recovery of beta-cells have been intensively studied and made great progress, and these are of major significance for the treatment of related diseases. Nevertheless, a comprehensive and objective report on the status of beta-cell research is lacking. Therefore, this study aims to conduct a bibliometric analysis to quantify and identify the current status and trending issues in beta-cell research. Methods: The articles and reviews related to beta-cell were obtained from the Web of Science Core Collection on August 31, 2022. Two scientometric software (CiteSpace 6.1.R3 and VOSviewer 1.6.18) were used to perform bibliometric and knowledge-map analysis. Results: A total of 4098 papers were published in 810 academic journals in 2938 institutions from 83 countries/regions. The number of beta-cell-related publications was increasing steadily. The United States was the most productive country, while Universite libre de Bruxelles, University of Toronto and University of Geneva were the most active institutions. Diabetes published the most beta-cell studies and received the largest number of co-citations. Decio I Eizirik published the most papers and had the most co-citations. Twelve references on reviews and mechanisms were regarded as the knowledge base. Four major aspects of betacell research included the pathological mechanism of beta-cell failure, the recovery of beta cells, the risk factor related to beta cells, and the physiology of beta cells. Endoplasmic reticulum stress and oxidative stress have been core elements throughout the research in this field. In addition, beta-cell dedifferentiation, inflammation, autophagy, miRNA, and lncRNA are hot topics nowadays. Additionally, stem cell replacement therapies might be the alternative way to reverse beta-cell failure. Restoring beta-cell mass and function will remain a research goal in the future. Conclusion: This study provided a comprehensive overview of beta-cell research through bibliometric and visual methods. The information would provide helpful references for scholars focusing on beta cells. [ABSTRACT FROM AUTHOR]

PLC-β is widely distributed in eukaryotic cells and is the key enzyme in phosphatidylinositol signal transduction pathway. The cellular functions regulated by its four subtypes (PLC-β1, PLC-β2, PLC-β3, PLC-β4) play an important role in maintaining homeostasis of organism. PLC-β and its related signals can promote or inhibit the occurrence and development of cancer by affecting the growth, differentiation and metastasis of cells, while targeted intervention of PLC-β1-PI3K-AKT, PLC-β2/CD133, CXCR2-NHERF1-PLC-β3, Gaq-PLC-β4-PKC-MAPK and so on can provide new strategies for the precise prevention and treatment of malignant tumors. This paper reviews the mechanism of PLC-β in various tumor cells from four aspects: proliferation and differentiation, invasion and metastasis, angiogenesis and protective measures. [ABSTRACT FROM AUTHOR]

This article, titled "Editorial: Current state of male physiological research and the impacts of environment and fetal programming in livestock," discusses the importance of male fertility in livestock production and its impact on reproductive efficiency and the health of offspring. The article highlights the influence of the male's environment, nutrition, and stress on the quality of sperm and the subsequent performance of progeny. It also explores the role of seminal plasma composition in sperm quality and the effects of the paternal environment on offspring. The article presents research papers that investigate various aspects of male physiological research in livestock. [Extracted from the article]

Introduction: The potential mechanisms governing drug induced osteonecrosis of the jaw (ONJ) is not well understood, and is one of the objectives of this study. Thus, we tested the release of IFN-g within different immune compartments including bone marrow and gingivae upon treatment with zoledronic acid (ZOL) and denosumab which are known to induce ONJ in susceptible individuals. Methods: We used humanized-BLT mouse model for the in-vivo studies reported in this paper. To determine the effects of zoledronic acid and denosumab on IFN-g secretion and NK cell-mediated cytotoxicity; peripheral blood, bone marrow, spleen and gingiva were obtained after the injection of ZOL and denosumab in mice. Results: Percentages of B cells are much higher in wild-type mice whereas the proportions of immune subsets in humans and reconstituted hu-BLT peripheralblood are similar. Therefore, hu-BLT mice are preferable model to study human disease, in particular, immune-pathologies induced by ZOL and denosumab. Both agents resulted in a severe suppression of IFN-g in the gingiva, whereas they heightened the release of IFN-g and NK cell-mediated cytotoxicity by the BMderived immune cells. ZOL increased the IFN-g secretion by the spleen and peripheral blood immune cells, whereas denosumab decreased the release IFNg by these cells significantly. Discussion: ZOL and denosumab may likely suppress IFN-g secretion in gingiva through different mechanisms. In addition, to the suppression of IFN-g secretion, denosumab mediated effect could in part be due to the decrease in the bone resorptive function of osteoclasts due to the induction of antibody dependent cellular cytotoxicity and lysis of osteoclasts, whereas ZOL is able to mediate cell death of osteoclasts directly. Suppression of IFN-gamma in gingiva is largely responsible for the inhibition of immune cell function, leading to dysregulated osteoblastic and osteoclastic activities. Restoration of IFN-gamma in the local microenvironment may result in establishment of homeostatic balance in the gingiva and prevention of osteonecrosis of jaw. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and coinhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology. [ABSTRACT FROM AUTHOR]

TP53-induced glycolysis and apoptosis regulator (TIGAR) mainly regulates pentose phosphate pathway by inhibiting glycolysis, so as to synthesize ribose required by DNA, promote DNA damage repair and cell proliferation, maintain cell homeostasis and avoid body injury. Its physiological functions include anti-oxidative stress, reducing inflammation, maintaining mitochondrial function, inhibiting apoptosis, reducing autophagy etc. This paper reviews the research of TIGAR in neurological diseases, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), seizures and brain tumors, aiming to provide reference for the development of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Food allergy is a serious public health problem because of its high incidence and risk. Probiotics can induce immune regulation in patients with allergic diseases, but its mechanism is not fully clear. In this paper, b-lactoglobulin (bLG)-sensitized mice were used as models to explore the mechanism of Bifidobacterium animalis KV9 (KV9) and Lactobacillus vaginalis FN3 (FN3) on reducing allergic reactions and regulating immune cell function. The results showed that oral administration of KV9 and FN3 significantly reduced the scores of allergic symptoms, hypothermia symptoms, and serum levels of bLG-specific immunoglobulins E (b-LG-sIgE), histamine, and mast cell protease in allergic mice. Flow cytometry analysis of intestinal dendritic cells (DCs) showed that the proportion of CD11c+major histocompatibility complex (MHC)-II+DCs, CD11c+CD80+DCs, and CD11c+ CD86+DCs increased after KV9 and FN3 intervention, indicating that the strains induced immature DCs and decreased the antigen-presenting capacity of DCs. Meanwhile, the toll-like receptor 4 (TLR4)-NF-kB signaling pathway was activated in DCs. The secretion of interleukin-12 (IL-12) was significantly increased, while interleukin-4 (IL-4) was decreased by DCs after KV9 and FN3 intervention, indicating that DCs have the potential to promote T-cell differentiation into T helper type 1 (Th1) cells. Furthermore, the proportion of CD3+CD8−IFN-g+ T cells in the spleen increased, while CD3+CD8−IL-4+T cells decreased after oral administration of KV9 and FN3, correcting the T helper type 2 (Th2)-skewed immune responses. These results indicate that KV9 and FN3 reduce b-LGinduced allergic symptoms in mice, and suggest that the two potential probiotics might be used as an alternative therapeutic agent for mitigating food allergy. [ABSTRACT FROM AUTHOR]

For the skin immune system, γδ T cells are important components, which help in defensing against damage and infection of skin. Compared to the conventional αβ T cells, γδ T cells have their own differentiation, development and activation characteristics. In adult mice, dendritic epidermal T cells (DETCs), Vγ4 and Vγ6 γδ T cells are the main subsets of skin, the coordination and interaction among them play a crucial role in wound repair. To get a clear overview of γδ T cells, this review synopsizes their derivation, development, colonization and activation, and focuses their function in acute and chronic wound healing, as well as the underlining mechanism. The aim of this paper is to provide cues for the study of human epidermal γδ T cells and the potential treatment for skin rehabilitation. [ABSTRACT FROM AUTHOR]

Stroke's secondary damage, such as inflammation, oxidative stress, and mitochondrial dysfunction, are thought to be crucial factors in the disease's progression. Despite the fact that there are numerous treatments for secondary damage following stroke, such as antiplatelet therapy, anticoagulant therapy, surgery, and so on, the results are disappointing and the side effects are numerous. It is critical to develop novel and effective strategies for improving patient prognosis. The ubiquitin proteasome system (UPS) is the hub for the processing and metabolism of a wide range of functional regulatory proteins in cells. It is critical for the maintenance of cell homeostasis. With the advancement of UPS research in recent years, it has been discovered that UPS is engaged in a variety of physiological and pathological processes in the human body. UPS is expected to play a role in the onset and progression of stroke via multiple targets and pathways. This paper explores the method by which UPS participates in the linked pathogenic process following stroke, in order to give a theoretical foundation for further research into UPS and stroke treatment. [ABSTRACT FROM AUTHOR]

The EhVps23 protein, an orthologue of the yeast Vps23 and the mammalian TSG101 proteins, is the single member of the ESCRT-I complex of Entamoeba histolytica identified and characterized until now. EhVps23 actively participates in vesicular trafficking and phagocytosis, which influence several cellular events. In this paper, we investigated the role of EhVps23 in virulence-related functions, including the invasive capacity of trophozoites, using transfected trophozoites. Trophozoites overexpressing the EhVps23 protein (Neo-EhVps23) presented helical arrangements in the cytoplasm, similar to the ones formed by EhVps32 for scission of vesicles. By confocal and transmission electron microscopy, EhVps23 was detected in multivesicular bodies, vesicles, and the extracellular space. It was secreted in vesicles together with other proteins, including the EhADH adhesin. Probably, these vesicles carry molecules that participate in the prey capture or in cell-cell communication. Mass spectrometry of precipitates obtained using α-EhVps23 antibodies, evidenced the presence of proteins involved in motility, phagocytosis, vesicular trafficking and secretion. The study of cellular functions, revealed that Neo-EhVps23 trophozoites exhibit characteristics similar to those described for mammalian transformed cells: they grew 50% faster than the control; presented a significant higher rate of phagocytosis, and migrated five-fold faster than the control, in concordance with the low rate of migration exhibited by Ehvps23 -knocked down trophozoites. In addition, Neo-EhVps23 trophozoites produced dramatic liver abscesses in experimental animals. In conclusion, our results showed that EhVps23 overexpression gave to the trophozoites characteristics that resemble cancer cells, such as increased cell proliferation, migration, and invasion. The mutant that overexpresses EhVps23 can be a good study model to explore different events related to the transformation of malignant cells. [ABSTRACT FROM AUTHOR]

Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells. [ABSTRACT FROM AUTHOR]

Integrins, a family of adhesion molecules generally exist on the cell surface, are essential for regulating cell growth and its function. As a bi-directional signaling molecule, they mediate cell-cell and cell-extracellular matrix interaction. The recognitions of their key roles in many human pathologies, including autoimmunity, thrombosis and neoplasia, have revealed their great potential as a therapeutic target. This paper focuses on the activation of integrins, the role of integrins in tumorigenesis and progression, and advances of integrin-dependent tumor therapeutics in recent years. It is expected that understanding function and signaling transmission will fully exploit potentialities of integrin as a novel target for tumors. [ABSTRACT FROM AUTHOR]

Inflammation is a type of defense response against tissue damage, and can be mediated by lymphocytes and macrophages. Fibrosis is induced by tissue injury and inflammation, which leads to an increase in fibrous connective tissue in organs and a decrease in organ parenchyma cells, finally leading to organ dysfunction or even failure. The vascular niche is composed of endothelial cells, pericytes, macrophages, and hematopoietic stem cells. It forms a guiding microenvironment for the behavior of adjacent cells, and mainly exists in the microcirculation, including capillaries. When an organ is damaged, the vascular niche regulates inflammation and affects the repair of organ damage in a variety of ways, such as via its angiocrine function and transformation of myofibroblasts. In this paper, the main roles of vascular niche in the process of organ fibrosis and its mechanism of promoting the progress of fibrosis through inflammatory immunoregulation are summarized. It was proposed that the vascular niche should be regarded as a new therapeutic target for organ fibrosis, suggesting that antifibrotic effects could be achieved by regulating macrophages, inhibiting endothelial-mesenchymal transition, interfering with the angiocrine function of endothelial cells, and inhibiting the transformation of pericytes into myofibroblasts, thus providing new ideas for antifibrosis drug research. [ABSTRACT FROM AUTHOR]

The extensive literature dealing with the Golgi system emphasizes its role in protein secretion and modification, usually without specifying from which evolutionary ancient cell physiological necessity such secretion originated. Neither does it specify which functional requirements the secreted proteins must meet. From a reinterpretation of some classical and recent data gained mainly, but not exclusively, from (insect) endocrinology, the view emerged that the likely primordial function of the rough endoplasmic reticulum (RER)–Golgi complex in all eukaryotes was not the secretion of any type of protein but the removal of toxic excess Ca2+ from the cytoplasm. Such activity requires the concurrent secretion of large amounts of Ca2+-carrying/transporting proteins acting as a micro-conveyor belt system inside the RER–Golgi. Thus, (fitness increasing) protein secretion is subordinate to Ca2+ removal. Milk with its high content of protein and Ca2+ (60–90 mM vs. 100 nM in unstimulated mammary gland cells) is an extreme example. The sarco(endo)plasmatic reticulum Ca2+-ATPases (SERCAs) and SPCA1a Ca2+/Mn2+ transport ATPases are major players in Ca2+ removal through the Golgi. Both are blocked by the sesquiterpenoid thapsigargin. This strengthens the hypothesis (2014) that endogenous farnesol-like sesquiterpenoids (FLSs) may act as the long sought for but still unidentified agonist (s) for Ca2+-pumps in both the ER and Golgi. A second putative function also emerges. The fusion of both the incoming and outgoing transport vesicles, respectively, at the cis - and trans - side of Golgi stacks, with the membrane system requiring high flexibility and fast self-closing of the involved membranes. These properties may—possibly partially—be controlled by endogenous hydrophobic membrane "fluidizers" for which FLSs are prime candidates. A recent reexamination of unexplained classical data suggests that they are likely synthesized by the Golgi itself. This game-changing hypothesis is endorsed by several arguments and data, some of which date from 1964, that the insect corpus allatum (CA), which is the major production site of farnesol-esters, has active Golgi systems. Thus, in addition to secreting FLS, in particular juvenile hormone(s), it also secretes a protein(s) or peptide(s) with thus far unknown function. This paper suggests answers to various open questions in cell physiology and general endocrinology. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics. [ABSTRACT FROM AUTHOR]

The article gives a brief description of geroprotection and rejuvenation methods known to date, presenting their main mechanisms and limitations. To overcome the main limitations of the process of rejuvenation, it is possible to use a process called "cell autocloning." The principle of the proposed method of rejuvenation is as follows: a periodic process of autocloning of the cell nucleus is initiated in the cellular genome with the formation of one unstable daughter copy and its subsequent self-elimination. In this case, the process of cell division stops in the phase of nuclei divergence without subsequent physical separation of the cell itself. This is especially important for postmitotic cells, where the looping of the "unidirectional" line of the ontogenesis program into a "ring" will mean their transition into renewable cells. The prototype for autocloning mechanisms could be the already known ways in which cells adapt to the increasing amount of their damage over time. These are polyploidy and asymmetric cell division, relying on which it is possible to obtain a renewable process of cell nuclei division, when only the original nucleus remains as a result of division. Although this is not a simple task, there are possible pathways to its solution using approaches that can suggest modern knowledge from the field of molecular and cell biology and genetics. The realization of such a goal will require a lot of work, but the expected result justifies it. [ABSTRACT FROM AUTHOR]

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism’s ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway. [ABSTRACT FROM AUTHOR]

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice. [ABSTRACT FROM AUTHOR]

Farnesol, the sesquiterpenoid precursor of insect juvenile hormones (JH) that itself has JH activity, existed already long before animals and their hormones came into being. Although it is omnipresent in all eukaryotes, this molecule remains a "noble unknown" in cell physiology. It is neither documented as a hormone nor as another type of signaling molecule. To date, its function as an intermediate in the synthesis of squalene-cholesterol-steroids in chordates/vertebrates, and of the insect/arthropod JHs, esters of farnesol, in the mevalonate biosynthetic pathway is assumed to be the only one. This assumption neglects that already two decades ago, farnesol has been shown to be a potent endogenous inhibitor of N-type voltage-gated Ca2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca2+ channels originated early in eukaryotic evolution, and has since been well conserved, "promoting" it as a ubiquitous player in Ca2+ homeostasis in all eukaryotes. This paper accentuates how this drastic change in thinking gained momentum after the discovery by Paroulek and Sláma that the huge amounts of JH I in male accessory glands of the Cecropia moth, are actually synthesized in these glands themselves and not in the corpora allata, the hitherto assumed unique synthesis site of such compounds. In addition, MAG-JHs have no hormonal- but an exocrine function. Here we hypothesize that MAG-JHs may function in protecting the spermatozoa against toxic Ca2+ concentrations, and in enabling their flagellum to undulate. They may do so by acting through membrane receptors. Our novel paradigm assigns to farnesol/JHs a function of flexible hydrophobic molecular valves for restricting untimely Ca2+-passage through some types of canonical Ca2+channels, using covalently bound farnesyl- or geranyl-geranyl group attachment as well as GPCRs-G proteins all containing a prenyl group. The high rotatable bond count, and their horseshoe-shape are instrumental to their valve function. In our paradigm, Met/Tai and Gce, to date generally thought to be the (only) functional (nuclear) receptors for JHs, are classified as probable Ca2+-sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed. [ABSTRACT FROM AUTHOR]

In silico representation of cellular systems needs to represent the adaptive dynamics of biological cells, recognizing a cell's multi-objective topology formed by temporally cohesive intracellular structures. The design of these models needs to address the hierarchical and concurrent nature of cellular functions and incorporate the ability to self-organize in response to transitions between healthy and pathological phases, and adapt accordingly. The functions of biological systems are constantly progressing, due to the ever changing demands of their environment. Biological systems meet these demands by pursuing objectives, aided by their constituents, giving rise to biological functions. A biological cell is organized into an objective/task hierarchy. These objective hierarchy corresponds to the nested nature of temporally cohesive structures and representing them will facilitate in studying pleiotropy and polygeny by modeling causalities propagating across multiple interconnected intracellular processes. Although biological adaptations occur in physiological, developmental and reproductive timescales, the paper is focused on adaptations that occur within physiological timescales, where the biomolecular activities contributing to functional organization, play a key role in cellular physiology. The paper proposes a multi-scale and multi-objective modeling approach from the bottom-up by representing temporally cohesive structures for multi-tasking of intracellular processes. Further the paper characterizes the properties and constraints that are consequential to the adaptive dynamics in biological cells. [ABSTRACT FROM AUTHOR]

The intestinal barrier, consisting of the vascular endothelium, epithelial cell lining, and mucus layer, covers a surface of about 400 m2. The integrity of the gut wall is sustained by transcellular proteins forming tight junctions between the epithelial cells. Protected by three layers of mucin, the gut wall forms a non-permeable barrier, keeping digestive enzymes and microorganisms within the luminal space, separate from the blood stream. Microorganisms colonizing the gut may produce bacteriocins in an attempt to outcompete pathogens. Production of bacteriocins in a harsh and complex environment such as the gastro-intestinal tract (GIT) may be below minimal inhibitory concentration (MIC) levels. At such low levels, the stability of bacteriocins may be compromised. Despite this, most bacteria in the gut have the ability to produce bacteriocins, distributed throughout the GIT. With most antimicrobial studies being performed in vitro , we know little about the migration of bacteriocins across epithelial barriers. The behavior of bacteriocins in the GIT is studied ex vivo , using models, flow cells, or membranes resembling the gut wall. Furthermore, little is known about the effect bacteriocins have on the immune system. It is generally believed that the peptides will be destroyed by macrophages once they cross the gut wall. Studies done on the survival of neurotherapeutic peptides and their crossing of the brain–blood barrier, along with other studies on small peptides intravenously injected, may provide some answers. In this review, the stability of bacteriocins in the GIT, their effect on gut epithelial cells, and their ability to cross epithelial cells are discussed. These are important questions to address in the light of recent papers advocating the use of bacteriocins as possible alternatives to, or used in combination with, antibiotics. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stressinduced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatinbased cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy. [ABSTRACT FROM AUTHOR]

Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and energy provision. Lipid metabolism is necessary for the maintenance of life since it regulates the balance between the processes of synthesis and breakdown. Increasing evidence suggests that cancer cells exhibit abnormal lipid metabolism, significantly affecting their malignant characteristics, including self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. Prominent oncogenic signaling pathways that modulate metabolic gene expression and elevate metabolic enzyme activity include phosphoinositide 3- kinase (PI3K)/AKT, MAPK, NF-kB, Wnt, Notch, and Hippo pathway. Conversely, when metabolic processes are not regulated, they can lead to malfunctions in cellular signal transduction pathways. This, in turn, enables uncontrolled cancer cell growth by providing the necessary energy, building blocks, and redox potentials. Therefore, targeting lipid metabolism-associated oncogenic signaling pathways could be an effective therapeutic approach to decrease cancer incidence and promote survival. This review sheds light on the interactions between lipid reprogramming and signaling pathways in cancer. Exploring lipid metabolism as a target could provide a promising approach for creating anticancer treatments by identifying metabolic inhibitors. Additionally, we have also provided an overview of the drugs targeting lipid metabolism in cancer in this review. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastics and titaniumdioxide nanoparticles arewidely spread in all environments, often coexisting within identical frameworks. Both these contaminants can induce negative effects on cell and plant physiology, giving concerns on their possible interaction which could increase each other's harmful effects on plants. Despite the urgency of this issue, there is very little literature addressing it. To evaluate the potential risk of this co-contamination, lentil seeds were treated for five days with polystyrene nanoplastics and titanium dioxide nanoparticles (anatase crystalline form), alone and in co-presence. Cytological analyses, and histochemical and biochemical evaluation of oxidative stress were carried out on isolated shoots and roots. TEM analysis seemed to indicate the absence of physical/chemical interactions between the two nanomaterials. Seedlings under cotreatment showed the greatest cytotoxic and genotoxic effects and high levels of oxidative stress markers associated with growth inhibition. Even if biochemical data did not evidence significant differences between materials treated with polystyrene nanoplastics alone or in copresence with titanium dioxide nanoparticles, histochemical analysis highlighted a different pattern of oxidative markers, suggesting a synergistic effect by the two nanomaterials. In accordance, the fluorescence signal linked to nanoplastics in root and shoot was higher under cotreatment, perhaps due to the well-known ability of titanium dioxide nanoparticles to induce root tissue damage, in this way facilitating the uptake and translocation of polystyrene nanoplastics into the plant body. In the antioxidant machinery, peroxidase activity showed a significant increase in treated roots, in particular under cotreatment, probably more associated with stress-induced lignin synthesis than with hydrogen peroxide detoxification. Present results clearly indicate the worsening by metal nanoparticles of the negative effects of nanoplastics on plants, underlining the importance of research considering the impact of cotreatments with different nanomaterials, which may better reflect the complex environmental conditions. [ABSTRACT FROM AUTHOR]

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPStreated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin- NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a complex three-dimensional structure composed of proteins, glycans, and proteoglycans, constituting a critical component of the tumor microenvironment. Complex interactions among immune cells, extracellular matrix, and tumor cells promote tumor development and metastasis, consequently influencing therapeutic efficacy. Hence, elucidating these interaction mechanisms is pivotal for precision cancer therapy. T lymphocytes are an important component of the immune system, exerting direct anti-tumor effects by attacking tumor cells or releasing lymphokines to enhance immune effects. The ECM significantly influences T cells function and infiltration within the tumor microenvironment, thereby impacting the behavior and biological characteristics of tumor cells. T cells are involved in regulating the synthesis, degradation, and remodeling of the extracellular matrix through the secretion of cytokines and enzymes. As a result, it affects the proliferation and invasive ability of tumor cells as well as the efficacy of immunotherapy. This review discusses the mechanisms underlying T lymphocyte-ECM interactions in the tumor immune microenvironment and their potential application in immunotherapy. It provides novel insights for the development of innovative tumor therapeutic strategies and drug. [ABSTRACT FROM AUTHOR]

Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field. [ABSTRACT FROM AUTHOR]

Recent experimental observations suggest that cells can show relatively precise and reliable responses to external signals even though substantial noise is inevitably involved in the signals. An intriguing question is the way how cells can manage to do it. One possible way to realize such response for a cell is to evolutionary develop and optimize its intra-cellular signaling pathways so as to extract relevant information from the noisy signal. We recently demonstrated that certain intracellular signaling reactions could actually conduct statistically optimal information processing. In this paper, we clarify that such optimal reaction operates near bifurcation point. This result suggests that critical-like phenomena in the single-cell level may be linked to efficient information processing inside a cell. In addition, improving the performance of response in the single-cell level is not the only way for cells to realize reliable response. Another possible strategy is to integrate information of individual cells by cell-to-cell interaction such as quorum sensing. Since cell-to-cell interaction is a common phenomenon, it is equally important to investigate how cells can integrate their information by cell-to-cell interaction to realize efficient information processing in the population level. In this paper, we consider roles and benefits of cell-to-cell interaction by considering integrations of obtained information of individuals with the other cells from the viewpoint of information processing. We also demonstrate that, by introducing cell movement, spatial organizations can spontaneously emerge as a result of efficient responses of the population to external signals. [ABSTRACT FROM AUTHOR]

As the first line of defense against invading pathogen, intestinal epithelium produces various antimicrobial proteins (AMP) that help in clearance of pathogen. Bactericidal/permeability-increasing protein (BPI) is a 55 kDa AMP that is expressed in intestinal epithelium. Dysregulation of BPI in intestinal epithelium is associated with various inflammatory diseases like Crohn's Disease, Ulcerative colitis, and Infectious enteritis's. In this paper, we report a direct correlation between intestinal damage and BPI expression. In Caco-2 cells, we see a significant increase in BPI levels upon membrane damage mediated by S. aureus infection and pore-forming toxins (Streptolysin and Listeriolysin). Cells detect changes in potassium level as a Danger-associated molecular pattern associated with cell damage and induce BPI expression in a p38 dependent manner. These results are further supported by in vivo findings that the BPI expression in murine intestinal epithelium is induced upon infection with bacteria which cause intestinal damage (Salmonella Typhimurium and Shigella flexneri) whereas mutants that do not cause intestinal damage (STM ΔfliC and STM ΔinvC) did not induce BPI expression. Our results suggest that epithelial damage associated with infection act as a signal to induce BPI expression. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinomas (HNSCC) are highly heterogeneous tumors. In the harsh tumor microenvironment (TME), metabolic reprogramming and mitochondrial dysfunction may lead to immunosuppressive phenotypes. Aerobic glycolysis is needed for the activation of cytotoxic T-cells and the absence of glucose may hamper the full effector functions of cytotoxic T-cells. To test the effect of mitochondrial dysfunction on cytotoxic T cell function, slice cultures (SC) of HNSCC cancer were cultivated under different metabolic conditions. Methods: Tumor samples from 21 patients with HNSCC were collected, from which, SC were established and cultivated under six different conditions. These conditions included high glucose, T cell stimulation, and temporarily induced mitochondrial dysfunction (MitoDys) using FCCP and oligomycin A with or without additional T cell stimulation, high glucose and finally, a control medium. Over three days of cultivation, sequential T cell stimulation and MitoDys treatments were performed. Supernatant was collected, and SC were fixed and embedded. Granzyme B was measured in the supernatant and in the SC via immunohistochemistry (IHC). Staining of PD1, CD8/Ki67, and cleavedcaspase3 (CC3) were performed in SC. Results: Hematoxylin eosin stains showed that overall SC quality remained stable over 3 days of cultivation. T cell stimulation, both alone and combined with MitoDys, led to significantly increased granzyme levels in SC and in supernatant. Apoptosis following T cell stimulation was observed in tumor and stroma. Mitochondrial dysfunction alone increased apoptosis in tumor cell aggregates. High glucose concentration alone had no impact on T cell activity and apoptosis. Apoptosis rates were significantly lower under conditions with high glucose and MitoDys (p=0.03). Conclusion: Stimulation of tumor-infiltrating lymphocytes in SC was feasible, which led to increased apoptosis in tumor cells. Induced mitochondrial dysfunction did not play a significant role in the activation and function of TILs in SC of HNSCC. Moreover, high glucose concentration did not promote cytotoxic T cell activity in HNSCC SC. [ABSTRACT FROM AUTHOR]

Objectives: Adrenal tumors are common, but adrenocortical carcinomas (ACCs) are a rare and challenging form of cancer to diagnose and manage. This study aimed to explore the critical role of mitochondrial quality in maintaining cellular function and the implications of the abnormal expression of mitochondrial metabolism-related proteins observed in ACC patients. We focused on identifying the connection between mitochondrial quality and the development of ACC at molecular and genomic levels. Methods: We compared mitochondrial quality-related genes (MQRGs) across ACC subtypes using overall survival (OS) and disease-free survival (DFS) as evaluation indicators. Furthermore, a novel MQRG score was developed to predict clinical prognosis and guide immunotherapy responses accurately. Results: The majority of MQRGs were upregulated in the ACC samples, correlating to poor prognosis. The MQRG score was confirmed as an independent prognostic factor for ACC, with the high-risk MQRG score group showing a significantly shorter overall survival period. Conclusions: Multilayer alterations in MQRGs are associated with patient prognosis and immune cell infiltration characteristics. This comprehensive analysis of MQRGs can contribute to a deeper understanding of potential differences in ACC patients' tumor microenvironment. This can influence clinical decision-making and advanced prognosis prediction, thereby offering new insights into personalized treatments in ACC. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are a unique subset of T cells that recognizes metabolites derived from the vitamin B2 biosynthetic pathway. Since the identification of cognate antigens for MAIT cells, knowledge of the functions of MAIT cells in cancer, autoimmunity, and infectious diseases has been rapidly expanding. Recently, MAIT cells have been found to contribute to visual protection against autoimmunity in the eye. The protective functions of MAIT cells are induced by T-cell receptor (TCR)-mediated activation. However, the underlying mechanisms remain unclear. Thus, this mini-review aims to discuss our findings and the complexity of MAIT cell-mediated immune regulation in the eye. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has made impressive advances in improving the outcome of patients affected by malignant diseases. Nonetheless, some limitations still need to be tackled to more efficiently and safely treat patients, in particular for those affected by solid tumors. One of the limitations is related to the immunosuppressive tumor microenvironment (TME), which impairs antitumor immunity. Efforts to identify targets able to turn the TME into a milieu more auspicious to current immuno-oncotherapy is a real challenge due to the high redundancy of the mechanisms involved. However, the insulin-like growth factor 1 receptor (IGF1R), an attractive drug target for cancer therapy, is emerging as an important immunomodulator and regulator of key immune cell functions. Here, after briefly summarizing the IGF1R signaling pathway in cancer, we review its role in regulating immune cells function and activity, and discuss IGF1R as a promising target to improve anti-cancer immunotherapy. [ABSTRACT FROM AUTHOR]

In chickens, γδ T cells represent a large fraction of peripheral T cells; however, their function remains largely unknown. Here, we describe the selective in vitro expansion of γδ T cells from total splenocytes by stimulation with the cytokines IL-2 and IL-12. Under these conditions, γδ T cells proliferated preferentially and reached frequencies of >95% within three weeks. Although IL-2 alone also triggered proliferation, an increased proliferation rate was observed in combination with IL-12. Most of the expanded cells were γδ TCR and CD8 double-positive. Splenocytes sorted into TCR1+CD8+, TCR1highCD8-, and TCR1lowCD8- subsets proliferated well upon dual stimulation with IL-2/IL-12, indicating that none of the three γδ T cell subsets require bystander activation for proliferation. TCR1+CD8+ cells maintained CD8 surface expression during stimulation, whereas CD8- subpopulations showed varied levels of CD8 upregulation, with the highest upregulation observed in the TCR1high subset. Changes in the γδ T-cell receptor repertoire during cell culture from day 0 to day 21 were analyzed by next-generation sequencing of the γδ variable regions. Overall, long-term culture led to a restricted g and d chain repertoire, characterized by a reduced number of unique variable region clonotypes, and specific V genes were enriched at day 21. On day 0, the d chain repertoire was highly diverse, and the predominant clonotypes differed between animals, while the most frequent g-chain clonotypes were shared between animals. However, on day 21, the most frequent clonotypes in both the g and d chain repertoires were different between animals, indicating that selective expansion of dominant clonotypes during stimulation seems to be an individual outcome. In conclusion, IL-2 and IL-12 were sufficient to stimulate the in vitro outgrowth of γδ T cells. Analyses of the TCR repertoire indicate that the culture leads to an expansion of individual T cell clones, which may reflect previous in vivo activation. This system will be instrumental in studying γδ T cell function. [ABSTRACT FROM AUTHOR]

Salinity is known to have a greater impact on shoot growth than root growth. Na+ buildup in plant tissue under salt stress has been proposed as one of the main issues that causes growth inhibition in crops via ionic imbalances, osmotic stress and pH disturbances. However, the evidence for apoplastic Na+ buildup and the role of silicon in Na+ accumulation at the subcellular level is still enigmatic. The current study focuses on the accumulation of Na+ in the apoplast and symplast of younger and older leaves of two maize varieties (Iqbal as salt-tolerant and Jalal as salt-sensitive) using hydroponic culture along with silicon supplementation under short-term salinity stress. Subcellular ion analysis indicated that silicon nutrition decreased Na+ concentration in both apoplastic washing fluid and symplastic fluid of maize under salt stress. The addition of silicon under NaCl treatment resulted in considerable improvement in fresh biomass, relative water content, chlorophyll content, and concentration of important subcellular ions (i.e., Ca2+, Mg2+, and K+). Knowledge of subcellular ion analysis is essential for solving the mechanisms underlying vital cellular functions e.g. in the current study, the soluble Na+ concentration in the apoplast of older leaves was found to be significantly greater (36.1 mM) in the salt-sensitive variety under NaCl treatment, which was 42.4% higher when compared to the Na+ concentration in the salt-tolerant variety under the same treatment which can influence permeability of cell membrane, signal transduction pathways and provides insights into how ion compartmentalization can contributes to salt tolerance. Calcium silicate enrichment can contribute to increased growth and improved ionic homeostasis by minimizing leaf electrolyte leakage, improving mechanical functions of cell wall and reducing water loss, and improved photosynthetic function. In current investigation, increased water content and intracellular ionic homeostasis along with reduced concentration of Na+ in the maize leaf apoplast suggest that calcium silicate can be used to ameliorate the adverse effects of salt stress and obtain yield using marginal saline lands. [ABSTRACT FROM AUTHOR]

The minimal cell concept represents a pragmatic approach to the question of how few genes are required to run a cell. This is a helpful way to build a parts-list, and has been more successful than attempts to deduce a minimal gene set for life by inferring the gene repertoire of the last universal common ancestor, as few genes trace back to this hypothetical ancestral state. However, the study of minimal cellular systems is the study of biological outliers where, by practical necessity, coevolutionary interactions are minimized or ignored. In this paper, we consider the biological context from which minimal genomes have been removed. For instance, some of the most reduced genomes are from endosymbionts and are the result of coevolutionary interactions with a host; few such organisms are "free-living." As few, if any, biological systems exist in complete isolation, we expect that, as with modern life, early biological systems were part of an ecosystem, replete with organismal interactions. We favor refocusing discussions of the evolution of cellular systems on processes rather than gene counts. We therefore draw a distinction between a pragmatic minimal cell (an interesting engineering problem), a distributed genome (a system resulting from an evolutionary transition involving more than one cell) and the looser coevolutionary interactions that are ubiquitous in ecosystems. Finally, we consider the distributed genome and coevolutionary interactions between genomic entities in the context of early evolution. [ABSTRACT FROM AUTHOR]

Grasping the concept of integrated, complementary responses that underpin the role of angiotensin II in body fluid regulation is critical for my laboratory's studies of estrogen effects on body fluid regulation. Keywords: angiotensin II; estrogen; body fluid balance; graduate training; medical education EN angiotensin II estrogen body fluid balance graduate training medical education 1 3 3 12/15/21 20211213 NES 211213 Summary This brief article is a personal perspective on the importance of integrative physiology education and research, using angiotensin II as an example of how integrative physiology occurs and why it matters. Having been trained in behavioral neuroscience by advisors with an appreciation for and encyclopedic knowledge of the physiological underpinnings of body fluid balance, integrative physiology was an integral part of my graduate training and research. Angiotensin II, estrogen, medical education, body fluid balance, graduate training. [Extracted from the article]

The tripartite motif (TRIM) protein family members have been implicated in a multitude of physiologies and pathologies in different tissues. With diverse functions in cellular processes including regulation of signaling pathways, protein degradation, and transcriptional control, the impact of TRIM dysregulation can be multifaceted and complex. Here, we focus on the cellular and molecular roles of TRIMs identified in the brain in the context of a selection of pathologies including cancer and neurodegeneration. By examining each disease in parallel with described roles in brain development, we aim to highlight fundamental common mechanisms employed by TRIM proteins and identify opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear thatmutations alone can explain the later stages of cancer. Can a different type of molecular change do better? Here, I introduce the "permissive binding theory" of cancer, which proposes that novel protein binding interactions are the key causal and explanatory entity in invasion and metastasis. It posits that binding is more abundant at baseline than we observe because it is restricted in normal physiology; that any large perturbation to physiological state revives this baseline abundance, unleashing many new binding interactions; and that a subset of these cause the cellular functions at the heart of oncogenesis, especially invasion and metastasis. Significant physiological perturbations occur in cancer cells in very early stages, and generally become more extreme with progression, providing interactions that continually fuel invasion and metastasis. The theory is compatible with, but not limited to, causal roles for the diverse molecular changes observed in cancer (e.g. gene expression or epigenetic changes), as these generally act causally upstream of proteins, and so may exert their effects by changing the protein binding interactions that occur in the cell. This admits the possibility that molecular changes that appear quite different may actually converge in creating the same few protein complexes, simplifying our picture of invasion and metastasis. If correct, the theory offers a concrete therapeutic strategy: targeting the key novel complexes. The theory is straightforwardly testable by large-scale identification of protein interactions in different cancers. [ABSTRACT FROM AUTHOR]

Intrauterine fetal demise (IUFD) – fetal loss after 20 weeks – affects 6 pregnancies per 1,000 live births in the United States, and the majority are of unknown etiology. Maternal systemic regulatory T cell (Treg) deficits have been implicated in fetal loss, but whether mucosal immune cells at the maternal-fetal interface contribute to fetal loss is under-explored. We hypothesized that the immune cell composition and function of the uterine mucosa would contribute to the pathogenesis of IUFD. To investigate local immune mechanisms of IUFD, we used the CBA mouse strain, which naturally has mid-late gestation fetal loss. We performed a Treg adoptive transfer and interrogated both pregnancy outcomes and the impact of systemic maternal Tregs on mucosal immune populations at the maternal-fetal interface. Treg transfer prevented fetal loss and increased an MHC-IIlow population of uterine macrophages. Single-cell RNAsequencing was utilized to precisely evaluate the impact of systemic Tregs on uterine myeloid populations. A population of C1q+, Trem2+, MHC-IIlow uterine macrophages were increased in Treg-recipient mice. The transcriptional signature of this novel uterine macrophage subtype is enriched in multiple studies of human healthy decidual macrophages, suggesting a conserved role for these macrophages in preventing fetal loss. [ABSTRACT FROM AUTHOR]

Aims: The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Methods: Adults with CF (=18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Results: Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. Conclusions: The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response. [ABSTRACT FROM AUTHOR]

In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or proresolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumormicroenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer. [ABSTRACT FROM AUTHOR]