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Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1-GIP or GLP1-glucagon and triple GLP1-GIP-glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP-GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology., (© 2024. Springer Nature Limited.)

Background: The skin is the largest organ in the human body, not only resisting the invasion of harmful substances, but also preventing the loss of moisture and nutrients. Maintaining skin homeostasis is a prerequisite for the proper functioning of the body. Any damage to the skin can lead to a decrease in local homeostasis, such as ultraviolet radiation, seasonal changes, and air pollution, which can damage the skin tissue and affect the function of the skin barrier., Objective: This article reviews the maintenance mechanism and influencing factors of skin homeostasis and the symptoms of homeostasis imbalance., Methods: We searched for articles published between 1990 and 2022 in English and Chinese using PubMed, Web of Science, CNKI, and other databases in the subject area of dermatology, using the following search terms in various combinations: "skin homeostasis," "skin barrier," and "unstable skin." Based on our results, we further refined our search criteria to include a series of common skin problems caused by the destruction of skin homeostasis and its treatments. Limitations include the lack of research on dermatological and cosmetic problems triggered by the disruption of skin homeostasis., Results: This study describes the neuroendocrine-immune system, skin barrier structure, and skin metabolic system that maintain skin homeostasis. In addition, we discuss several common symptoms that occur when skin homeostasis is out of balance, such as dryness, redness, acne, sensitivity, and aging, and explain the mechanism of these symptoms., Conclusion: This article provides an update and review for students and practitioners, and provides a theoretical basis for the development of skin care products for the maintenance and repair of skin homeostasis., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Dynamic cerebral autoregulation (dCA) is the mechanism that describes how the brain maintains cerebral blood flow approximately constant in response to short-term changes in arterial blood pressure. This is known to be impaired in many different pathological conditions, including ischaemic and haemorrhagic stroke, dementia and traumatic brain injury. Many different approaches have thus been used both to analyse and to quantify this mechanism in a range of healthy and diseased subjects, including data-driven models (in both the time and the frequency domain) and biophysical models. However, despite the substantial body of work on both biophysical models and data-driven models of dCA, there remains little work that links the two together. One of the reasons for this is proposed to be the discrepancies between the time constants that govern dCA in models and in experimental data. In this study, the processes that govern dCA are examined and it is proposed that the application of biophysical models remains limited due to a lack of understanding about the physical processes that are being modelled, partly due to the specific model formulation that has been most widely used (the equivalent electrical circuit). Based on the analysis presented here, it is proposed that the two most important time constants are arterial transit time and feedback time constant. It is therefore time to revisit equivalent electrical circuit models of dCA and to develop a more physiologically realistic alternative, one that can more easily be related to experimental data. KEY POINTS: Dynamic cerebral autoregulation is governed by two time constants. The first time constant is the arterial transit time, rather than the traditional 'RC' time constant widely used in previous models. This arterial transit time is approximately 1 s in the brain. The second time constant is the feedback time constant, which is less accurately known, although it is somewhat larger than the arterial transit time. The equivalent electrical circuit model of dynamic cerebral autoregulation should be replaced with a more physiologically representative model., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

The analysis of genetic variation underlying local adaptation in natural populations, together with the response to different external stimuli, is currently a hot topic in forest sciences, with the aim of identifying genetic markers controlling key phenotypic traits of interest for their inclusion in restoration and breeding programs. In Europe, one of the main tree species is Norway spruce (Picea abies (L.) H.Karst.). Using the MassARRAY® platform, 568 trees from North Rhine-Westphalia (Germany) were genotyped with 94 single nucleotide polymorphisms (SNPs) related to circadian and growth rhythms, and to stress response. The association analysis of the selected markers with health status and elevation was performed using three different methods, and those identified by at least two of these were considered as high confidence associated SNPs. While just five markers showed a weak association with health condition, 32 SNPs were correlated with elevation, six of which were considered as high confidence associated SNPs, as indicated by at least two different association methods. Among these genes, thioredoxin and pseudo response regulator 1 (PRR1) are involved in redox homeostasis and ROS detoxification, APETALA2-like 3 (AP2L3), a transcription factor, is involved in seasonal apical growth, and a RPS2-like is a disease resistance gene. The function of some of these genes in controlling light-dependent reactions and metabolic processes suggests signatures of adaptation to local photoperiod and the synchronization of the circadian rhythm. This work provides new insights into the genetic basis of local adaptation over a shallow elevation gradient in Norway spruce., (© 2024 The Authors. Plant Biology published by John Wiley & Sons Ltd on behalf of German Society for Plant Sciences, Royal Botanical Society of the Netherlands.)

Calcium and magnesium ions are highly abundant and important cations in human body. At the same time, both dyscalcemia and dysmagnesemia are frequently encountered in the clinical practice. As deficiency or excess of Ca(II) or Mg(II) can cause severe symptoms, determining these ions in serum is of great importance. Concentration of these ions in biological samples is typically assayed in clinical laboratories with the use of expensive and specialized equipment. Since those methods cannot be easily adapted for self-diagnosis purposes, there is a great need to develop a convenient tool for reliable determination of calcium and magnesium in serum at the point-of-care. The colorimetric methods employed for calcium and magnesium analysis were o -cresophtalein complexone assay and xylidyl blue assay, respectively. Analytical signal acquisition was accomplished using an ordinary flatbed scanner or smartphone and free software. For increased user-friendliness the device was optimized to perform simultaneous determination of calcium and magnesium ions in only 10 min. In the optimized conditions, the limit of detection for calcium ions was 0.09 mmol L−1, while for magnesium it was 0.04 mmol L−1. Determination of both ions requires only 4 μL of serum sample. The developed paper-based sensors were validated with control human serum samples and the obtained relative errors for majority of samples were below 20 %. In this paper, a microfluidic paper-based analytical device for simultaneous determination of calcium and magnesium ions in human serum is reported for the first time. Additionally, this is also the first report on colorimetric determination in serum of any of these ions in paper-based format. Simultaneous detection of both ions allows for fast and user-friendly screening of disturbance in calcium and magnesium homeostasis. [Display omitted] • Paper-based sensor for simultaneous Ca2+ and Mg2+ determination is reported. • Cations recognition relies on their reaction with appropriate dyes. • HSV color space channels were used as analytical signal. • The sensors were validated with human serum samples. [ABSTRACT FROM AUTHOR]

Narrative: In this paper I give the principles for each of the three Categories applied within Sacro Occipital Technique (SOT) and show how these relate to each of the three primary systems of the body DeJarnette was a researcher, author, teacher and developer of the SOT systems method of Chiropractic and the principles he gave underpin a clinically solid and successful approach to patient care. A system strives for equilibrium, a point of balance, a state in which all components of the system are in a state of harmony. The SOT practitioner strives to achieve harmony and balance amongst these three systems of the body. [ABSTRACT FROM AUTHOR]

Purpose: Chronic inflammation is one of the key mechanisms of depression. Wenyang-Tianjin-Jie Decoction (WTJD) is an effective antidepressant found in the course of diagnosis and treatment, but the mechanism of therapeutic effect is not clear. The study aimed to evaluate the efficacy of WTJD in the kidney yang deficiency (KYD) type of depression rats and reveal its mechanisms. Materials and Methods: We selected forty 6-week-old male Sprague-Dawley rats for the study. We established a KYD [Phellodendron amurense Rupr (Huangbai) solution oral gavage and 4°C environments; 8 weeks] type of depression (chronic unpredictable mild stimulus; 6 weeks) rat model first. After successful modeling, we used WTJD or fluoxetine on rats for 3 weeks. Then we evaluated the depression and KYD behavior. Finally, we observed the expression of key inflammatory factors and proteins in peripheral blood and hippocampus, and further investigated the immune balance of Th17/Treg and Th1/Th2 cells and the activity of their main regulatory pathways JAK2/STAT3 and TLR4/TRAF6/NF-κB. Results: The imbalance of Th17/Treg and Th1/Th2 cells in rats were related to KYD and depressive symptoms. Through this study, we found that WTJD can inhibit the activity of JAK2/STAT3 and TLR4/TRAF6/NF-κB pathways, balance Th17/Treg and Th1/Th2 cell homeostasis, regulate the levels of inflammatory factors in the hippocampus and peripheral blood, and reverse KYD and depression. Conclusion: This study confirmed that WTJD had a reliable effect on depression rats with KYD, and its mechanism was to regulate the immune homeostasis of hippocampal T cells and related inflammatory factors to improve KYD and depression symptoms in rats. [ABSTRACT FROM AUTHOR]

Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate whether ASA VI controls osteoarthritis (OA) by regulating mitochondrial function., Methods: Primary chondrocytes were isolated and cultured from rat knee joints. The chondrocytes were treated with ASA VI and interleukin-1β (IL-1β) to simulate the inflammatory environment of OA. Cell viability, apoptosis, inflammatory cytokine levels, and extracellular matrix (ECM) component levels were assessed. Mitochondrial function, including ATP levels, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and mitochondrial DNA content, was evaluated. The expression of Sirtuin 3 (Sirt3), a key regulator of mitochondrial homeostasis, was examined. Additionally, a rat OA model was established by destabilizing the medial meniscus, and the effects of ASA VI on cartilage degeneration were assessed., Results: ASA VI treatment improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α levels in IL-1β-induced chondrocytes. ASA VI also upregulated Collagen II and Aggrecan expression, while downregulating ADAMTS5 and MMP-13 expression. Furthermore, ASA VI mitigated IL-1β-induced mitochondrial dysfunction by increasing ATP levels, restoring mitochondrial membrane potential, reducing ROS production, and preserving mitochondrial DNA content. These effects were accompanied by the activation of Sirt3. In the rat OA model, ASA VI treatment increased Sirt3 expression and alleviated cartilage degeneration., Conclusion: ASA VI exerts chondroprotective and anti-inflammatory effects on IL-1β-induced chondrocytes by improving mitochondrial function through Sirt3 activation. ASA VI also attenuates cartilage degeneration in a rat OA model. These findings suggest that ASA VI may be a potential therapeutic agent for the treatment of osteoarthritis by targeting mitochondrial dysfunction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Thimerosal (THI) has become a significant source of organic mercury pollutants in aquatic ecosystems, but there is limited information regarding its adverse effects on fish. In this study, zebrafish embryos were exposed to THI at 0 (control), 5.0, and 50 ng/L from 0-5 days post fertilization (dpf), and variations in their survival, development, behavior, free amino acid contents, and the biochemical responses involved in monoaminergic systems were examined. Although THI exposure did not significantly affect the survival, heart rate, or hatching time of zebrafish embryos, it substantially increased swimming velocity (136-154 % of the control) and reduced exploratory behavior (141-142 % of the control) in zebrafish larvae at 5 dpf. Exposure also significantly altered the amino acid contents (51-209 % of the control) and monoamine levels (70-154 % of the control) in zebrafish larvae, some of which displayed significant correlations with behavioral traits. THI significantly elevated dopamine receptor gene expression and monoamine oxidase activity in zebrafish larvae. Adding extra phenylalanine or tryptophan to the E3 medium facilitates the recovery of zebrafish larvae from the abnormal behaviors induced by THI. These findings reveal for the first time that THI exposure at the level of ng/L is sufficient to induce neurobehavioral toxic effects in the early life stages of zebrafish, and disrupting amino acid homeostasis is a critical underlying mechanism. This study provides valuable insights into the toxicity of THI to fish and highlights the importance of assessing its potential risks to aquatic ecosystems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Flooding intensity significantly alters the availability of iron (Fe), zinc (Zn), and cadmium (Cd) in paddy soil. However, the influence of arbuscular mycorrhizal fungi (AMF) on the uptake and transfer of Cd and micronutrients (Fe and Zn) under Cd stress in varying flooding conditions is not well understood. A pot experiment was conducted to investigate the micronutrient homeostasis and Cd uptake and transfer in rice cultivated in Cd-contaminated soil with AMF inoculation under continuous and intermittent flooding conditions. Compared to non-inoculation controls, mycorrhizal inoculation decreased Cd concentration in rice plants under continuous and intermittent flooding, and improved grain yield by 39.2 % for early season rice and 21.1 % for late season rice under continuous flooding. Mycorrhizal inoculation balanced the availability of Zn and Fe and decreased the availability of Cd in soil, lowering the ratios of soil-available Cd to both soil-available Zn and soil Fe 2+ . These changes led to a redistribution of Zn and Fe concentrations in rice, thereby reducing Cd acquisition in a soil-rice system. Structural equation model (SEM) analysis revealed that mycorrhizal inoculation had a strong direct negative effect on the expression of Zn and Fe-related genes OsNRAMP1, OsIRT1, and OsIRT2 in the roots of rice, which in turn directly affected root Cd concentration. Furthermore, mycorrhizal colonization decreased Cd transfer coefficients from leaves to grains under continuous flooding and from nodes and leaves to grains under intermittent flooding. In the nodes, the Fe concentration and the expression of genes OsIRT1 and OsHMA2 were associated with Cd transfer from the nodes to grains. Similarly, in the leaves, the expression of genes OsZIP1 and OsMTP1 corresponded with Cd transfer from leaves to grains. This study provides insights into the role of AMF in affecting micronutrient concentrations and Cd uptake in rice under varying flooding conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Trained Immunity is defined as a biological process normally induced by exogenous or endogenous insults that triggers epigenetic and metabolic reprogramming events associated with long-term adaptation of innate immune cells. This trained phenotype confers enhanced responsiveness to subsequent triggers, resulting in an innate immune "memory" effect. Trained Immunity, in the past decade, has revealed important benefits for host defense and homeostasis, but can also induce potentially harmful outcomes associated with chronic inflammatory disorders or autoimmune diseases. Interestingly, evidence suggest that the "trainers" prompting trained immunity are frequently glycans structures. In fact, the exposure of different types of glycans at the surface of pathogens is a key driver of the training phenotype, leading to the reprogramming of innate immune cells through the recognition of those glycan-triggers by a variety of glycan-binding proteins (GBPs) expressed by the immune cells. β-glucan or mannose-enriched structures in Candida albicans are some of the examples that highlight the potential of glycans in trained immunity, both in homeostasis and in disease. In this review, we will discuss the relevance of glycans exposed by pathogens in establishing key immunological hubs with glycan-recognizing receptors expressed in immune cells, highlighting how this glycan-GBP network can impact trained immunity. Finally, we discuss the power of glycans and GBPs as potential targets in trained immunity, envisioning potential therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Glyphosate and glyphosate-based herbicides (GBH), widely used globally, were initially considered harmless to humans. Experimental studies have suggested that these substances can disrupt iron homeostasis by interfering with iron uptake or triggering inflammatory responses. However, their potential impact on human iron homeostasis remains underexplored., Approach and Results: We analyzed data from 5812 participants aged three and older from the 2013 to 2018 NHANES. We investigated the relationships between urinary glyphosate levels, oral iron intake, and markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor. Higher urinary glyphosate levels were positively associated with oral iron intake (β = 1.310, S.E. = 0.382, P = 0.001). A one-unit increase in the natural logarithm (ln)-glyphosate was associated with lower serum iron (β = - 4.236, 95 % CI = - 6.432 to - 2.039, P < 0.001) and ferritin (β = - 9.994, 95 % CI = - 17.342 to - 2.647, P = 0.009), and higher UIBC (β = 5.431, 95 % CI = 1.061-9.800, P = 0.018) and transferrin receptor levels (β = 0.139, 95 % CI = 0.015-0.263, P = 0.029). Increasing glyphosate exposure was associated with significant decreases in serum iron and ferritin across exposure quintiles (trend P-values = 0.003 and 0.018, respectively)., Conclusions: Higher glyphosate exposure is associated with reduced iron availability, suggesting potential disruptions in iron absorption. These findings underscore the need for further research into the health implications of glyphosate exposure on iron homeostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on calcium phosphate homeostasis in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remain uncertain., Methods: A retrospective observational cohort study of patients with T2DM at CKD stage G3b-5ND who received SGLT2i as compared to control from 1 January 2015 through 31 December 2021 was recruited. Propensity score assignment at 1:3 ratio by logistic regression was done. All patients were followed for 12 months. Outcomes were changes in phosphate level., Results: We analyzed 1,450 SGLT2i users and 4,350 control subjects. At the 12 th month, SGLT2i users had a slower increase in phosphate levels (absolute change: -0.01 ± 0.28 vs + 0.14 ± 0.34 mmol/L; percentage change: -0.74 % ± 25.56 vs + 10.88 ± 28.15 %, P for both < 0.001). The proportion of patients with high phosphate was lower with SGLT2i (8.2 % vs 24.6 % increase). In the generalized estimating equation, SGLT2i was linked to a longitudinal reduction in phosphate (B -0.039, P<0.001)., Conclusions: SGLT2i can effectively slow down the progression of phosphate retention in advanced CKD with T2DM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Being the first line of defense, intestinal mucosal immunity serves as in maintaining immune homeostasis among organisms. This study investigated the impact of the areca inflorescence polysaccharide (AFP) on intestinal mucosal immunity and elucidated the mechanisms responsible for the immunomodulatory effects of AFP. The immunosuppression mouse model was established using the cyclophosphamide. The intestinal mucosal status was evaluated based on the intestinal integrity, chemical and mucosal immune barriers, and intestinal flora. According to the findings, AFP enhances intestinal integrity by up-regulating the expression of tight junction proteins and reinforcing the chemical barrier through increased mucin-2, β-defensins, and SIgA expression and secretion. Furthermore, AFP restores the mucosal immune barrier by regulating immune cells within Peyer's patches and lamina propria. AFP also reverses the intestinal flora balance and regulates its metabolism. Additionally, AFP effectively modulates the immune response in the spleen and peripheral blood. Together, these results indicated that AFP repairs mucosal damage and restores mucosal immunity, thereby preserving the immune homeostasis of organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Experimental and clinical research has reported beneficial effects of polyphenol intake on high prevalent diseases such as type 2 diabetes and obesity. These phytochemicals are ligands of taste 2 receptors (T2Rs) that have been recently located in a variety of organs and extra-oral tissues. Therefore, the interaction between polyphenol and T2Rs in brain structures can play a direct effect on appetite/satiety regulation and food intake. T2Rs are also expressed along the digestive tract, and their interaction with polyphenols can induce the release of gastrointestinal hormones (e.g., ghrelin, GLP-1, CCK) influencing appetite, gastrointestinal functionally, and glycemia control. Intestinal microbiota can also influence on network effects of polyphenols-T2Rs interaction and vice versa, impacting innate immune responses and consequently on gut functionally. Furthermore, polyphenols binding to T2Rs present important effects on adipose tissue metabolism. Interestingly, T2R polymorphism could, at least partially, explain the inter-individual variability of the effects of polyphenols on glucose and body weight homeostasis. Together, these factors can contribute to understand the beneficial effects of polyphenol-rich diets but also might aid in identifying new pharmacological pathway targets for the treatment of diabetes and obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Male sterility is used in the production of hybrid seeds and can improve the breeding efficiency of cotton hybrids. Reactive oxygen species is closely associated with the tapetum and pollen development, but their relationship in cotton male fertility remains unclear. In this study, we comprehensively compared the cytology and proteome of the anthers from an Upland cotton (Gossypium hirsutum) material, Shida 98 (WT), and its nearly-isogenic male sterile line Shida 98A (MS). Cytology indicated delayed PCD in the tapetum and defects in microspores in MS anthers. And further studies revealed disruption of ROS homeostasis. Proteomic analysis identified proteins with differential abundance mainly being related to redox homeostasis, protein folding, and apoptotic signaling pathways. GhAPX1 interacted with GhHSP70 and played a crucial role in the development of cotton anthers. Exogenous application of HSP70 inhibitor increased H 2 O 2 content and decreased the activity of APX1 and pollen viability. The GhAPX1 mutants generated by CRISPR/Cas9-mediated gene editing exhibited premature degradation of the tapetum, significant decrease in pollen viability, and significant increase in H 2 O 2 content. Altogether, our results imply HSP70 and APX1 being the key players jointly regulating male fertility by mediating ROS homeostasis. These results provide insights into the proteins associated with male fertility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Carotenoids are lipophilic plant molecules with antioxidant properties. Some carotenoids such as β-carotene also serve as vitamin A precursors, playing a key role in human health. Carotenoids are transported in lipoproteins with other lipids such as cholesterol, however, the mechanisms responsible for carotenoid storage in tissues and their non-enzymatic elimination remain relatively unexplored. The goal of this study was to examine the contribution of the low-density lipoprotein receptor (LDLR) in the bodily distribution and disposal of carotenoids., Methods: We employed mice lacking one or both carotenoid-cleaving enzymes as suitable models for carotenoid accumulation. We examined the contribution of LDLR in carotenoid distribution by crossbreeding these mice with Ldlr-/- mice or overexpressing LDLR in the liver., Results: Our results show that LDLR plays a dual role in carotenoid homeostasis by simultaneously favoring carotenoid storage in the liver and adipose tissue while facilitating their fecal elimination., Conclusions: Our results highlight a novel role of the LDLR in carotenoid homeostasis, and unveil a previously unrecognized disposal pathway for these important bioactive molecules., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Antibiotic residues, such as tetracycline (TET), in aquatic environments have become a global concern. The liver and gut are important for immunity and metabolism in aquatic organisms. In this study, juvenile groupers were subjected to 1 and 100 μg/L TET for 14 days, and the physiological changes of these fish were evaluated from the perspective of gut-liver axis. After TET exposure, the liver showed histopathology, lipid accumulation, and the elevated ALT activity. An oxidative stress response was induced in the liver and the metabolic pattern was disturbed, especially pyrimidine metabolism. Further, intestinal health was also affected, including the damaged intestinal mucosa, the decreased mRNA expression levels of tight junction proteins (ZO-1, Occludin, and Claudin-3), along with the increased gene expression levels of inflammation (IL-1β, IL-8, TNF-α) and apoptosis (Casp-3 and p53). The diversity of intestinal microbes increased and the community composition was altered, and several beneficial bacteria (Lactobacillus, Bacteroidales S24-7 group, and Romboutsia) and harmful (Aeromonas, Flavobacterium, and Nautella) exhibited notable correlations with hepatic physiological indicators and metabolites. These results suggested that TET exposure can adversely affect the physiological homeostasis of groupers through the gut-liver axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Versican is a large chondroitin sulfate proteoglycan in the extracellular matrix. It plays a pivotal role in the formation of the provisional matrix. S100a4, previously known as fibroblast-specific protein, functions as a calcium channel-binding protein. To investigate the role of versican expressed in fibroblasts, we generated conditional knockout mice in which versican expression is deleted in cells expressing S100a4. We found that S100a4 is expressed in adipose tissues, and these mice exhibit obesity under a normal diet, which becomes apparent as early as five months. The white adipose tissues of these mice exhibited decreased expression levels of S100a4 and versican and hypertrophy of adipocytes. qRT-PCR showed a reduced level of UCP1 in their white adipose tissues, indicating that the basic energy metabolism is diminished. These results suggest that versican in adipose tissues maintains the homeostasis of adipose tissues and regulates energy metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pregnancy is extremely vulnerable to external environmental influences. Bisphenol A, an endocrine-disrupting chemical, poses a significant environmental hazard to individuals of all ages and stages, particularly during pregnancy. The placenta is a temporary organ facilitating the connection between the mother and fetus. While it can detoxify certain exogenous substances, it is also vulnerable to the impacts of endocrine disruptors. Likewise, the intestinal flora is highly sensitive to exogenous stresses and environmental pollutants. The regulation of gut microbiota plays a crucial role in ensuring the health of both the mother and the fetus. The gut-placental axis connects the gut, gut microbes, placenta, and fetus. Exploring possible effects on placental function and fetal development involves analyzing changes in gut microbiota composition. Given that bisphenol A may cross the intestine and affect intestinal function, gut microorganisms, and their metabolites, as well as its potential impact on the placenta, resulting in impaired placental function and fetal development, this study aims to establish a link between bisphenol A exposure, intestinal microorganisms, placental function, and fetal development. This paper seeks to analyze the effects of maternal exposure to bisphenol A during pregnancy on the balance of the maternal gut microbiota, placental function, and fetal development, considering the key role of the gut-placental axis. Additionally, this paper proposes potential directions for future research emphasizing the importance of mitigating the adverse outcomes of bisphenol A exposure during pregnancy in both human and animal studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The skeletal system maintains a delicate balance known as bone homeostasis, which is essential for the lifelong preservation of bone mass, shape, and integrity. This equilibrium relies on a complex interplay between bone marrow mesenchymal stem cells (BMSCs), osteoblasts, osteocytes, and osteoclasts. Galectin-3 (Gal-3), a chimeric galectin with a unique N-terminal tail and a conserved carbohydrate recognition domain (CRD) at its C-terminus, has emerged as a critical regulator in bone homeostasis. The CRD of Gal-3 mediates carbohydrate binding, while its N-terminal tail is implicated in oligomerization and phase separation, which are vital for its functionality. Gal-3's multivalency is central to its role in a range of cellular activities, including inflammation, immune response, apoptosis, cell adhesion, and migration. Imbalances in bone homeostasis often arise from disruptions in osteoblast differentiation and activity, increased osteoclast differentiation and activity. Gal-3's influence on these processes suggests its significant role in the regulation of bone remodeling. This review will examine the molecular mechanisms through which Gal-3 contributes to bone remodeling and discuss its potential as a therapeutic target for the treatment of bone-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Minocycline, a broad-spectrum tetracycline antibiotic, has been shown to possess anti-inflammatory and antioxidative effects in various neurodegenerative diseases. However, its specific effects on retinitis pigmentosa (RP) have not been thoroughly investigated. Therefore, the objective of this study was to explore the potential role of minocycline in treating RP. In this investigation, we used rd1 to explore the antioxidant effect of minocycline in RP. Minocycline therapy effectively restored retinal function and structure in rd1 mice at 14 days postnatal. Additionally, minocycline inhibited the activation of microglia. Moreover, RNA sequencing analysis revealed a significant downregulation in the expression of mitochondrial genes within the retina of rd1 mice. Further KEGG and GO pathway analysis indicated impaired oxidative phosphorylation and electron transport chain processes. TEM confirmed the presence of damaged mitochondria in photoreceptors, while JC-1 staining demonstrated a decrease in mitochondrial membrane potential, accompanied by an increase in mitochondrial reactive oxygen species (ROS) levels. However, treatment with minocycline successfully reversed the abnormal expression of mitochondrial genes and reduced the levels of mitochondrial ROS, thereby providing protection against photoreceptor degeneration. Collectively, minocycline demonstrated the ability to rescue photoreceptor cells in RP by effectively modulating mitochondrial homeostasis and subsequently inflammation. These findings hold significant implications for the development of potential therapeutic strategies for RP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bone homeostasis is a homeostasis process constructed by osteoblast bone formation and osteoclast bone resorption. Bone homeostasis imbalance and dysfunction are the basis for the development of various orthopedic diseases such as osteoporosis, osteoarthritis, and steroid-induced avascular necrosis of femoral head. Previous studies have demonstrated that ferroptosis can induce lipid peroxidation through the generation of reactive oxygen species, activate a number of signaling pathways, and participate in the regulation of osteoblast bone formation and osteoclast bone resorption, resulting in bone homeostasis imbalance, which is an important factor in the pathogenesis of many orthopedic diseases, but the mechanism of ferroptosis is still unknown. In recent years, it has been found that, in addition to iron metabolism and intracellular antioxidant system imbalance, organelle dysfunction is also a key factor affecting ferroptosis. This paper takes this as the starting point, reviews the latest literature reports at home and abroad, elaborates the pathogenesis and regulatory pathways of ferroptosis and the relationship between ferroptosis and various organelles, and summarizes the mechanism by which ferroptosis mediates bone homeostasis imbalance, with the aim of providing new directions for the research related to ferroptosis and new ideas for the prevention and treatment of bone and joint diseases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

During pregnancy, the maternal body undergoes a series of adaptative physiological changes, leading to a slight increase in serum bile acid (BA) levels. Although the fetal liver can synthesize BAs since the first trimester through the alternative pathway, the BA metabolic system is immature in the fetus. Compared to adults, the fetus has a distinct composition of BA pool and limited expression of BA synthesis enzymes and transporters. Besides, the "enterohepatic circulation" of BAs is absent in fetus. Thus, fetal BAs need to be transported to the mother through the placenta for further metabolism and excretion, and maternal BAs can also be transported to the fetus. That is what we call the "fetal-placental-maternal BA circulation". Various BA transporters and nuclear receptors are essential for maintaining the balance of this BA circulation to ensure normal fetal development. However, prenatal adverse environments can alter fetal BA metabolism, resulting in intrauterine developmental abnormalities and susceptibility to a variety of adult chronic diseases. This review summarizes the current understanding of the fetal-placental-maternal BA circulation and discusses the effects of prenatal adverse environments on this particular BA circulation, aiming to provide a theoretical basis for exploring early prevention and treatment strategies for BA metabolism-associated adverse pregnancy outcomes and long-term impairments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Type I collagen (Col I) and hyaluronic acid (HA), derived from the extracellular matrix (ECM), have found widespread application in cartilage tissue engineering. Nevertheless, the potential of cell-free collagen-based scaffolds to induce in situ hyaline cartilage regeneration and the related mechanisms remain undisclosed. Here, we chose Col I and HA to construct Col I hydrogel and Col I-HA composite hydrogel with similar mechanical properties, denoted as Col and ColHA, respectively. Their potential to induce cartilage regeneration was investigated. The results revealed that collagen-based hydrogels could regenerate hyaline cartilage without any additional cells or growth factors. Notably, ColHA hydrogel stood out in this regard. It elicited a moderate activation, recruitment, and reprogramming of macrophages, thus efficiently mitigating local inflammation. Additionally, ColHA hydrogel enhanced stem cell recruitment, facilitated their chondrogenic differentiation, and inhibited chondrocyte fibrosis, hypertrophy, and catabolism, thereby preserving cartilage homeostasis. This study augments our comprehension of cartilage tissue induction theory by enriching immune-related mechanisms, offering innovative prospects for the design of cartilage defect repair scaffolds. STATEMENT OF SIGNIFICANCE: The limited self-regeneration ability and post-injury inflammation pose significant challenges to articular cartilage repair. Type I collagen (Col I) and hyaluronic acid (HA) are extensively used in cartilage tissue engineering. However, their specific roles in cartilage regeneration remain poorly understood. This study aimed to elucidate the functions of Col I and Col I-HA composite hydrogels (ColHA) in orchestrating inflammatory responses and promoting cartilage regeneration. ColHA effectively activated and recruited macrophages, reprogramming them from an M1 to an M2 phenotype, thus alleviating local inflammation. Additionally, ColHA facilitated stem cell homing, induced chondrogenesis, and concurrently inhibited fibrosis, hypertrophy, and catabolism, collectively contributing to the maintenance of cartilage homeostasis. These findings underscore the clinical potential of ColHA for repairing cartilage defects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Recent research has highlighted the ecological risk posed by microplastics (MPs) from mulching film and heavy metals to soil organisms. However, most studies overlooked real environmental levels of MPs and heavy metals. To address this gap, pristine and aged polyethylene (PE) mulching film-derived MPs (PMPs, 500 mg/kg; AMPs, 500 mg/kg) were combined with cadmium (Cd, 0.5 mg/kg) to assess the acute toxicity to earthworms and investigate associated molecular mechanisms (oxidative stress, osmoregulation pressure, gut microbiota, and metabolic responses) at environmentally relevant concentrations. Compared to Cd alone and Cd + PMPs treatments (11.15 ± 4.19 items/g), Cd + AMPs treatment resulted in higher MPs bioaccumulation (23.73 ± 13.14 items/g), more severe tissue lesions, and increased cell membrane osmotic pressure in earthworms' intestines. Cd + AMPs induced neurotoxicity through elevated levels of glutamate and acetylcholinesterase. Earthworm intestines (0.98 ± 0.49 to 3.33 ± 0.37 mg/kg) exhibited significantly higher Cd content than soils (0.19 ± 0.01 to 0.51 ± 0.06 mg/kg) and casts (0.15 ± 0.01 to 0.25 ± 0.05 mg/kg), indicating PE-MPs facilitated Cd transport in earthworms' bodies. Metabolomic analysis showed Cd + AMPs exposure depleted energy and nucleotide metabolites, disrupted cell homeostasis more profoundly than Cd and Cd + PMPs treatments. Overall, co-exposure to AMPs + Cd induced more severe neurotoxicity and disruption of homeostasis in earthworm than Cd and PMPs + Cd treatments. Our study, using Cd and MPs with environmental relevance, underscores MPs' role in amplifying Cd accumulation and toxicity in earthworms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epithelial homeostasis is fundamental for the physiological functions of colon tissue. Dysregulation of colon epithelial structure leads to abnormal immune responses and diseases such as inflammatory bowel disease. In this work we found long non-coding RNA DANCR was a novel regulator to colon epithelial homeostasis. Silencing DANCR resulted in decreased expression of epithelial barrier proteins and enhanced susceptibility to TNFα stimulation, which was accompanied by hyperactivation of the NF-κB pathway. Mechanistical studies revealed DANCR modulated the expression of a protein methyltransferase SET7 to suppress responses to TNFα, as well as the activity of NF-κB pathway. In summary, DANCR regulated colon epithelial homeostasis through modulating the TNFα/NF-κB axis. These findings cast light on the discovery of novel regulators to colon epithelial homeostasis and added new evidence to the physiological functions of DANCR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ability of Mycobacterium tuberculosis (Mtb) to tolerate nitric oxide ( • NO) and superoxide (O 2 •- ) produced by phagocytes contributes to its success as a human pathogen. Recombination of • NO and O 2 •- generates peroxynitrite (ONOO - ), a potent oxidant produced inside activated macrophages causing lethality in diverse organisms. While the response of Mtb toward • NO and O 2 •- is well established, how Mtb responds to ONOO - remains unclear. Filling this knowledge gap is important to understand the persistence mechanisms of Mtb during infection. We synthesized a series of compounds that generate both • NO and O 2 . RNA-sequencing with Mtb revealed that CJ067 induces antioxidant machinery, sulphur metabolism, metal homeostasis, and a 4Fe-4S cluster repair pathway (suf operon). CJ067 impaired the activity of the 4Fe-4S cluster-containing TCA cycle enzyme, aconitase, and diminished bioenergetics of Mtb. Work with Mtb strains defective in SUF and IscS involved in Fe-S cluster biogenesis pathways showed that both systems cooperatively protect Mtb from intracellular ONOO •- , which should combine to produce ONOO - and targeting Fe-S cluster homeostasis is expected to promote iNOS-dependent host immunity against tuberculosis (TB).- levels. CJ067-exposed Mtb strains, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates, exhibited dose-dependent, long-lasting oxidative stress and growth inhibition. In contrast, Mycobacterium smegmatis (Msm), a fast-growing, non-pathogenic mycobacterial species, maintained redox balance and growth in response to intracellular ONOO - . RNA-sequencing with Mtb revealed that CJ067 induces antioxidant machinery, sulphur metabolism, metal homeostasis, and a 4Fe-4S cluster repair pathway (suf operon). CJ067 impaired the activity of the 4Fe-4S cluster-containing TCA cycle enzyme, aconitase, and diminished bioenergetics of Mtb. Work with Mtb strains defective in SUF and IscS involved in Fe-S cluster biogenesis pathways showed that both systems cooperatively protect Mtb from intracellular ONOO - in vitro and inducible nitric oxide synthase (iNOS)-dependent growth inhibition during macrophage infection. Thus, Mtb is uniquely sensitive to intracellular ONOO - and targeting Fe-S cluster homeostasis is expected to promote iNOS-dependent host immunity against tuberculosis (TB)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Methyl viologen (MV), also known as paraquat, is a widely used herbicide but has also been reported as highly toxic to different life forms. The mode of its operation is related to superoxide radical (O 2 .- ) production and consequent oxidative damage. However, besides the damage to key macromolecules, reactive oxygen species (ROS; to which O 2 .- belongs) are also known as regulators of numerous ion transport systems located at cellular membranes. In this study, we used MV as a tool to probe the role of O 2 .- in regulating membrane-transport activity and systemic acquired tolerance in halophytic Chenopodium quinoa and glycophytic spinach plants. Both plant species showed growth reduction in terms of reduced shoot length, lower shoot fresh and dry weight, photosynthesis rate, and chlorophyll contents; however, quinoa showed less reduction in growth compared with spinach. This whole plant response was further examined by measuring the ion concentration, gene expression of ion transporters, activation of antioxidants, and osmolyte accumulation. We observed that at the mechanistic level, the differences in growth in response to MV were conferred by at least four complementary physiological mechanisms: (1) higher K + loss from spinach leaves resulted from higher expression of MV-induced plasma membrane-based depolarization-activated K + efflux GORK channel, (2) higher activation of high-affinity K + uptake transporter HAK5 in quinoa, (3) higher antioxidant production and osmolyte accumulation in quinoa as compared with spinach, and (4) maintaining a higher rate of photosynthesis due to higher chlorophyll contents, and efficiency of photosystem II and reduced ROS and MDA contents. Obtained results also showed that MV induced O 2 .- significantly reduced N contents in both species but with more pronounced effects in glycophytic spinach. Taken together this study has shown the role of O 2 .- in regulating membrane ion transport and N metabolism in the leaves of halophyte vs. glycophyte in the context of oxidative stress tolerance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Theabrownin (TB) is a dark brown pigment from Pu-erh tea or other dark teas. It is formed by further oxidization of theaflavins and thearubigins, in combination with proteins, polysaccharides, and caffeine etc. TB is a characteristic ingredient and bioactive substance of Pu-erh tea. However, the effects of TB on ulcerative colitis (UC) remains unclear., Purpose: This study aims to elucidate the mechanism of TB on UC in terms of recovery of intestinal homeostasis and regulation of toll-like receptor (TLR) 2&4 signaling pathway., Methods: The colitis models were established by administering 5% dextran sulfate sodium (DSS) to C57BL/6 mice for 5 days to evaluate the therapeutic and preventive effects of TB on UC. Mesalazine was used as a positive control. H&E staining, complete blood count, enzyme-linked immunosorbent assay, immunohistochemistry, flow cytometry, and 16S rRNA sequencing were employed to assess histological changes, blood cells analysis, content of cytokines, expression and distribution of mucin (MUC)2 and TLR2&4, differentiation of CD4 + T cells in lamina propria, and changes in intestinal microbiota, respectively. Western blot was utilized to study the relative expression of tight junction proteins and the key proteins in TLR2&4-mediated MyD88-dependent MAPK, NF-κB, and AKT signaling pathways., Results: TB outstanding alleviated colitis, inhibited the release of pro-inflammatory cytokines, reduced white blood cells while increasing red blood cells, hemoglobin, and platelets. TB increased the expression of occludin, claudin-1 and MUC2, effectively restored intestinal barrier function. TB also suppressed differentiation of Th1 and Th17 cells in the colon's lamina propria, increased the fraction of Treg cells, and promoted the balance of Treg/Th17 to tilt towards Tregs. Moreover, TB increased the Firmicutes to Bacteroides (F/B) ratio, as well as the abundance of Akkermansia, Muribaculaceae, and Eubacterium&#95;coprostanoligenes&#95;group at the genus level. In addition, TB inhibited the activation of TLR2&4-mediated MAPK, NF-κB, and AKT signaling pathways in intestinal epithelial cells of DSS-induced mice., Conclusion: TB acts in restoring intestinal homeostasis and anti-inflammatory in DSS-induced UC, and exhibiting a preventive effect after long-term use. In a word, TB is a promising beverage, health product and food additive for UC., Competing Interests: Declaration of competing interest The authors declare that they have no known conflict of interest or individual connections that could have appeared to impact the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The ataxia telangiectasia mutated (ATM) protein kinase is best known as a master regulator of the DNA damage response. However, accumulating evidence has unveiled an equally vital function for ATM in sensing oxidative stress and orchestrating cellular antioxidant defenses to maintain redox homeostasis. ATM can be activated through a non-canonical pathway involving intermolecular disulfide crosslinking of the kinase dimers, distinct from its canonical activation by DNA double-strand breaks. Structural studies have elucidated the conformational changes that allow ATM to switch into an active redox-sensing state upon oxidation. Notably, loss of ATM function results in elevated reactive oxygen species (ROS) levels, altered antioxidant profiles, and mitochondrial dysfunction across multiple cell types and tissues. This oxidative stress arising from ATM deficiency has been implicated as a central driver of the neurodegenerative phenotypes in ataxia-telangiectasia (A-T) patients, potentially through mechanisms involving oxidative DNA damage, PARP hyperactivation, and widespread protein aggregation. Moreover, defective ATM oxidation sensing disrupts transcriptional programs and RNA metabolism, with detrimental impacts on neuronal homeostasis. Significantly, antioxidant therapy can ameliorate cellular and organismal abnormalities in various ATM-deficient models. This review synthesizes recent advances illuminating the multifaceted roles of ATM in preserving redox balance and mitigating oxidative insults, providing a unifying paradigm for understanding the complex pathogenesis of A-T disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Glucose metabolic disorders, prevalent in numerous metabolic diseases, have become a pressing global public health concern. Artemisinin (ART) and its derivatives, including artesunate (ARTs) and artemether (ARTe), have shown potential as metabolic regulators. However, the specific effects of ART and its derivatives on glucose metabolism under varying nutritional conditions and the associated molecular mechanisms remain largely unexplored. In this study, we examined the impact of ART, ARTs, and ARTe on glucose homeostasis using a mouse model subjected to different dietary regimens. Our findings revealed that ART, ARTs, and ARTe increased blood glucose levels in mice on a normal-chow diet (ND) while mitigating glucose imbalances in high-fat diet (HFD) mice. Notably, treatment with ART, ARTs, and ARTe had contrasting effects on in vivo insulin signaling, impairing it in ND mice and enhancing it in HFD mice. Moreover, the composition of gut microbiota underwent significant alterations following administration of ART and its derivatives. In ND mice, these treatments reduced the populations of bacteria beneficial for improving glucose homeostasis, including Parasutterella, Alloprevotella, Bifidobacterium, Ileibacterium, and Alistipes. In HFD mice, there was an increase in the abundance of beneficial bacteria (Alistipes, Akkermanisia) and a decrease in bacteria known to negatively impact glucose metabolism (Coprobacillus, Helicobacter, Mucispirillum, Enterorhabdus). Altogether, ART, ARTs, and ARTe exhibited distinct effects on the regulation of glucose metabolism, depending on the nutritional context, and these effects were closely associated with modifications in gut microbiota composition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Flavins and their associated proteins have recently emerged as compelling players in the landscape of cancer biology. Flavins, encompassing flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), serve as coenzymes in a multitude of cellular processes, such as metabolism, apoptosis, and cell proliferation. Their involvement in oxidative phosphorylation, redox homeostasis, and enzymatic reactions has long been recognized. However, recent research has unveiled an extended role for flavins in the context of cancer. In parallel, riboflavin transporters (RFVTs), FAD synthase (FADS), and riboflavin kinase (RFK) have gained prominence in cancer research. These proteins, responsible for riboflavin uptake, FAD biosynthesis, and FMN generation, are integral components of the cellular machinery that governs flavin homeostasis. Dysregulation in the expression/function of these proteins has been associated with various cancers, underscoring their potential as diagnostic markers, therapeutic targets, and key determinants of cancer cell behavior. This review embarks on a comprehensive exploration of the multifaceted role of flavins and of the flavoproteins involved in nucleus-mitochondria crosstalk in cancer. We journey through the influence of flavins on cancer cell energetics, the modulation of RFVTs in malignant transformation, the diagnostic and prognostic significance of FADS, and the implications of RFK in drug resistance and apoptosis. This review also underscores the potential of these molecules and processes as targets for novel diagnostic and therapeutic strategies, offering new avenues for the battle against this relentless disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Elevated levels of NEFA caused by negative energy balance in transition cows induce cellular dyshomeostasis. Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) can maintain cellular homeostasis and act as a critical regulator of stress responses besides functioning in the ubiquitin-like system. The objective of this study was to elucidate the UFL1 working mechanism on promoting cellular adaptations in bovine mammary epithelial cells (BMECs) in response to NEFA challenge, with an emphasis on the ER and mitochondrial function. The results showed that exogenous NEFA and UFL1 depletion resulted in the disorder of ER and mitochondrial homeostasis and the damage of BMEC integrity, overexpression of UFL1 effectively alleviated the NEFA-induced cellular dyshomeostasis. Mechanistically, our study found that UFL1 had a strong interaction with IRE1α and could modulate the IRE1α/XBP1 pathway of unfolded protein response in NEFA-stimulated BMECs, thereby contributing to the modulation of cellular homeostasis. These findings imply that targeting UFL1 may be a therapeutic alternative to relieve NEB-induced metabolic changes in perinatal dairy cows., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) are used in consumer products; however, their toxic effects on intestinal epithelium remain largely unknown. In this study, we combined intestinal organoids and single-cell RNA sequencing to investigate the impact of BPA and BHPF exposure on intestinal cell composition, differentiation, and function. Both compounds inhibited the growth of small intestinal organoids, with BHPF exhibiting a more potent inhibitory effect. BPA and BHPF did not significantly alter the overall cell type composition; however, they led to different alterations in cell-cell communications. Gene Ontology enrichment analysis showed that BPA and BHPF exposures affected various biological processes, such as glutathione transferase activity, antioxidant activity, and lipid metabolism, in cell type-specific and compound-dependent manners. Trajectory analysis demonstrated that BPA and BHPF altered the differentiation trajectory of the intestinal cells. To further connect the cellular mechanism to the phenotypic impact in vivo, we constructed a mouse model exposed to BPA or BHPF and observed significant alterations in intestinal morphology, including reduced crypt depth and villus length and impaired stem cell proliferation and self-renewal. These results provide novel insights into the cell type-specific effects of BPA and BHPF on the intestinal epithelium and highlight the potential risks of exposure to these compounds. Our findings underscore the importance of evaluating the safety of BPA substitutes and contribute to a better understanding of the effects of environmental chemicals on gut health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Increasing the seed germination potential and seedling growth rates play a pivotal role in increasing overall crop productivity. Seed germination and early vegetative (seedling) growth are critical developmental stages in plants. High-power microwave (HPM) technology has facilitated both the emergence of novel applications and improvements to existing in agriculture. The implications of pulsed HPM on agriculture remain unexplored. In this study, we have investigated the effects of pulsed HPM exposure on barley germination and seedling growth, elucidating the plausible underlying mechanisms. Barley seeds underwent direct HPM irradiation, with 60 pulses by 2.04 mJ/pulse, across three distinct irradiation settings: dry, submerged in deionized (DI) water, and submerged in DI water one day before exposure. Seed germination significantly increased in all HPM-treated groups, where the HPM-dry group exhibited a notable increase, with a 2.48-fold rise at day 2 and a 1.9-fold increment at day 3. Similarly, all HPM-treated groups displayed significant enhancements in water uptake, and seedling growth (weight and length), as well as elevated levels of chlorophyll, carotenoids, and total soluble protein content. The obtained results indicate that when comparing three irradiation setting, HPM-dry showed the most promising effects. Condition HPM seed treatment increases the level of reactive species within the barley seedlings, thereby modulating plant biochemistry, physiology, and different cellular signaling cascades via induced enzymatic activities. Notably, the markers associated with plant growth are upregulated and growth inhibitory markers are downregulated post-HPM exposure. Under optimal HPM-dry treatment, auxin (IAA) levels increased threefold, while ABA levels decreased by up to 65 %. These molecular findings illuminate the intricate regulatory mechanisms governing phenotypic changes in barley seedlings subjected to HPM treatment. The results of this study might play a key role to understand molecular mechanisms after pulsed-HPM irradiation of seeds, contributing significantly to address the global need of sustainable crop yield., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sodium nitroprusside (SNP) is a potent nitric oxide (NO) donor that enhances plant tolerance to various abiotic stresses. This research aims to assess the effect of SNP application on rice seedlings subjected to individual and combined exposure to two abiotic stresses viz., low-temperature (LT) and chromium (Cr). Exposure to LT, Cr, and LT+Cr caused severe oxidative damage by stimulating greater production and accumulation of reactive oxygen species (ROS) leading to lipid peroxidation and cell membrane instability. The combined LT+CR stress more intensly increased the cellular oxidative stress and excessive Cr uptake that in turn deteriorated the chlorophyll pigments and photosynthesis, as well as effected the level of tetrapyrrole biosynthesis in rice plants. The reduction in rice seedling growth was more obvious under LT+Cr treatment than their individual effects. The exogenous application of SNP diminished the toxic impact of LT and Cr stress. This was attributed to the positive role of SNP in regulating the endogenous NO levels, free amino acids (FAAs) contents, tetrapyrrole biosynthesis and antioxidants. Consequently, SNP-induced NO decreased photorespiration, ROS generation, lipid peroxidation, and electrolyte leakage. Moreover, exogenous SNP diminished the Cr uptake and accumulation by modulating the ionic homeostasis and strengthening the heavy metals detoxification mechanism, thus improving plant height, biomass and photosynthetic indexes. Essentially, SNP boosts plant tolerance to LT and Cr stress by regulating antioxidants, detoxification mechanism, and the plant's physio-biochemical. Hence, applying SNP is an effective method for boosting rice plant resilience and productivity in the face of escalating environmental stresses and pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objectives: In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance., Methods: We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice., Results: In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice., Conclusions: These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Homeostasis is a self-regulatory process, wherein an organism maintains a specific internal physiological state. Homeostatic reinforcement learning (RL) is a framework recently proposed in computational neuroscience to explain animal behavior. Homeostatic RL organizes the behaviors of autonomous embodied agents according to the demands of the internal dynamics of their bodies, coupled with the external environment. Thus, it provides a basis for real-world autonomous agents, such as robots, to continually acquire and learn integrated behaviors for survival. However, prior studies have generally explored problems pertaining to limited size, as the agent must handle observations of such coupled dynamics. To overcome this restriction, we developed an advanced method to realize scaled-up homeostatic RL using deep RL. Furthermore, several rewards for homeostasis have been proposed in the literature. We identified that the reward definition that uses the difference in drive function yields the best results. We created two benchmark environments for homeostasis and performed a behavioral analysis. The analysis showed that the trained agents in each environment changed their behavior based on their internal physiological states. Finally, we extended our method to address vision using deep convolutional neural networks. The analysis of a trained agent revealed that it has visual saliency rooted in the survival environment and internal representations resulting from multimodal input., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Caries and pulpitis remain a major global disease burden and affect the quality of life of patients. Odontoblasts are key players in the progression of caries and pulpitis, not only secreting and mineralizing to form dentin, but also acting as a wall of defense to initiate immune defenses. Mitochondrion is an information processor for numerous cellular activities, and dysregulation of mitochondrion homeostasis not only affects cellular metabolism but also triggers a wide range of diseases. Elucidating mitochondrial homeostasis in odontoblasts can help deepen scholars' understanding of odontoblast-associated diseases. Articles on mitochondrial homeostasis in odontoblasts were evaluated for information pertinent to include in this narrative review. This narrative review focused on understanding the complex interplay between mitochondrial homeostasis in odontoblasts under physiological and pathological conditions. Furthermore, mitochondria-centered therapeutic strategies (including mitochondrial base editing, targeting platforms, and mitochondrial transplantation) were emphasized by resolving key genes that regulate mitochondrial function. Mitochondria are involved in odontoblast differentiation and function, and act as mitochondrial danger-associated molecular patterns (mtDAMPs) to mediate odontoblast pathological progression. Novel mitochondria-centered therapeutic strategies are particularly attractive as emerging therapeutic approaches for the maintenance of mitochondrial homeostasis. It is expected to probe key events of odontoblast differentiation and advance the clinical resolution of dentin formation and mineralization disorders and odontoblast-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study aims to explore the effects of long-term high fructose intake (LHFI) on the structure, functionality, and physiological homeostasis of mouse extra-orbital lacrimal glands (ELGs), a critical component of ocular health. Our findings reveal significant reprogramming of the circadian transcriptome in ELGs following LHFI, alongside the activation of specific inflammatory pathways, as well as metabolic and neural pathways. Notably, LHFI resulted in increased inflammatory infiltration, enhanced lipid deposition, and reduced nerve fiber density in ELGs compared to controls. Functional assessments indicated a marked reduction in lacrimal secretion following cholinergic stimulation in LHFI-treated mice, suggesting impaired gland function. Overall, our results suggest that LHFI disrupts lacrimal gland homeostasis, potentially leading to dry eye disease by altering its structure and secretory function. These insights underscore the profound impact of dietary choices on ocular health and highlight the need for strategies to mitigate these risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Kale is a functional food with anti-cancer, antioxidant, and anemia prevention properties. The harmful effects of the emerging pollutant microplastic (MP) on plants have been widely studied, but there is limited research how to mitigate MP damage on plants. Numerous studies have shown that Se is involved in regulating plant resistance to abiotic stresses. The paper investigated impact of MP and Se on kale growth, photosynthesis, reactive oxygen species (ROS) metabolism, phytochemicals, and endogenous hormones. Results revealed that MP triggered a ROS burst, which led to breakdown of antioxidant system in kale, and had significant toxic effects on photosynthetic system, biomass, and accumulation of secondary metabolites, as well as a significant decrease in IAA and a significant increase in GA. Under MP supply, Se mitigated the adverse effects of MP on kale by increasing photosynthetic pigment content, stimulating function of antioxidant system, enhancing secondary metabolite synthesis, and modulating hormonal networks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored., Experimental Design: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism., Results: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism., Conclusions: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ability to maintain cellular metabolic homeostasis is critical to life, in which mTOR plays an important role. This kinase integrates upstream nutrient signals and performs essential functions in physiology and metabolism by increasing metabolism and suppressing autophagy. Thus, dysregulation of mTOR activity leads to diseases, especially metabolic diseases such as cancer, type 2 diabetes and neurological disorders. Therefore, inhibition of overactivated mTOR becomes a rational approach to treat a variety of metabolic diseases. In this review, we discuss how mTOR responds to upstream signals and how mTOR regulates metabolic processes, including protein, nucleic acid, and lipid metabolism. Furthermore, we discuss the possible causes and consequences of dysregulated mTOR signaling activity, and summarize relevant applications, such as inhibition of mTOR activity to treat these diseases. This review will advance our comprehensive knowledge of the association between mTOR and metabolic homeostasis, which has significant ramifications for human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)