Homeostatic Regulation Research Articles

Investigating the alterations of endocannabinoidome signaling in the human small intestine in the context of obesity and type 2 diabetes

BackgroundHuman studies have linked obesity-related diseases, such as type-2 diabetes (T2D), to the modulation of endocannabinoid signaling. Cannabinoid CB1 and CB2 receptor activation by the endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), both derived from arachidonic acid, play a role in homeostatic regulation. Other long chain fatty acid-derived endocannabinoid-like molecules have extended the metabolic role of this signaling system through other receptors. In this study, we aimed to assess in depth the interactions between the circulating and intestinal tone of this extended eCB system, or endocannabinoidome (eCBome), and their involvement in the pathogenesis of diabetes. MethodsPlasma and ileum samples were collected from subjects with obesity and harboring diverse degrees of insulin resistance or T2D, who underwent bariatric surgery. The levels of eCBome mediators and their congeners were then assessed by liquid chromatography coupled to tandem mass spectrometry, while gene expression was screened with qPCR arrays. FindingsIntestinal and circulating levels of eCBome mediators were higher in subjects with T2D. We found an inverse correlation between the intestinal and circulating levels of monoacylglycerols (MAGs). Additionally, we identified genes known to be implicated in both lipid metabolism and intestinal function that are altered by the context of obesity and glucose homeostasis. InterpretationAlthough the impact of glucose metabolism on the eCBome remains poorly understood in subjects with advanced obesity state, our results suggest a strong causative link between altered glucose homeostasis and eCBome signaling in the intestine and the circulation.

Abstract 1621 Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis

Abstract 1621 Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis

Keeping Your Brain in Balance: Homeostatic Regulation of Network Function.

To perform computations with the efficiency necessary for animal survival, neocortical microcircuits must be capable of reconfiguring in response to experience, while carefully regulating excitatory and inhibitory connectivity to maintain stable function. This dynamic fine-tuning is accomplished through a rich array of cellular homeostatic plasticity mechanisms that stabilize important cellular and network features such as firing rates, information flow, and sensory tuning properties. Further, these functional network properties can be stabilized by different forms of homeostatic plasticity, including mechanisms that target excitatory or inhibitory synapses, or that regulate intrinsic neuronal excitability. Here we discuss which aspects of neocortical circuit function are under homeostatic control, how this homeostasis is realized on the cellular and molecular levels, and the pathological consequences when circuit homeostasis is impaired. A remaining challenge is to elucidate how these diverse homeostatic mechanisms cooperate within complex circuits to enable them to be both flexible and stable.

Endogenous feline leukemia virus long terminal repeat integration site diversity is highly variable in related and unrelated domestic cats

Endogenous retroviruses (ERV) are indicators of vertebrate evolutionary history and play important roles as homeostatic regulators. ERV long terminal repeat (LTR) elements may act as cis-activating promoters or trans-activating enhancer elements modifying gene transcription distant from LTR insertion sites. We previously documented that endogenous feline leukemia virus (FeLV)-LTR copy number variation in individual cats tracks inversely with susceptibility to virulent FeLV disease. To evaluate FeLV-LTR insertion characteristics, we assessed enFeLV-LTR integration site diversity in 20 cats from three genetically distinct populations using a baited linker-mediated PCR approach. We documented 765 individual integration sites unequally represented among individuals. Only three LTR integration sites were shared among all individuals, while 412 sites were unique to a single individual. When primary fibroblast cultures were challenged with exogenous FeLV, we found significantly increased expression of both exogenous and endogenous FeLV orthologs, supporting previous findings of potential exFeLV-enFeLV interactions; however, viral challenge did not elicit transcriptional changes in genes associated with the vast majority of integration sites. This study assesses FeLV-LTR integration sites in individual animals, providing unique transposome genotypes. Further, we document substantial individual variation in LTR integration site locations, even in a highly inbred population, and provide a framework for understanding potential endogenous retroviral element position influence on host gene transcription.

Brain-IT: Targeting the brain using information technology for secondary prevention of mild neurocognitive disorder

Brain-IT: Targeting the brain using information technology for secondary prevention of mild neurocognitive disorder

Atrial fibrillation initiation and organization in a mechanistic model of atrial remodeling and calcium homeostatic regulation

Atrial fibrillation initiation and organization in a mechanistic model of atrial remodeling and calcium homeostatic regulation

Na+/K+-ATPase: ion pump, signal transducer, or cytoprotective protein, and novel biological functions.

Na+/K+-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na+ out of and two K+ into cells. Additionally, Na+/K+-ATPase participates in Ca2+-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane. Na+/K+-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells. Therefore, it is not surprising that Na+/K+-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases. However, published studies have so far only elucidated the important roles of Na+/K+-ATPase dysfunction in disease development, and we are lacking detailed mechanisms to clarify how Na+/K+-ATPase affects cell function. Our recent studies revealed that membrane loss of Na+/K+-ATPase is a key mechanism in many neurological disorders, particularly stroke and Parkinson's disease. Stabilization of plasma membrane Na+/K+-ATPase with an antibody is a novel strategy to treat these diseases. For this reason, Na+/K+-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein, participating in signal transduction such as neuronal autophagy and apoptosis, and glial cell migration. Thus, the present review attempts to summarize the novel biological functions of Na+/K+-ATPase and Na+/K+-ATPase-related pathogenesis. The potential for novel strategies to treat Na+/K+-ATPase-related brain diseases will also be discussed.

RcMYB8 enhances salt and drought tolerance in rose (Rosa chinensis) by modulating RcPR5/1 and RcP5CS1

Plant Myeloblastosis (MYB) proteins function crucially roles upon variegated abiotic stresses. Nonetheless, their effects and mechanisms in rose (Rosa chinensis) are not fully clarified. In this study, we characterized the effects of rose RcMYB8 under salt and drought tolerances. For induction of the RcMYB8 expression, NaCl and drought stress treatment were adopted. Rose plants overexpressing RcMYB8 displayed enhanced tolerance to salinity and drought stress, while silencing RcMYB8 resulted in decreased tolerance, as evidenced by lowered intra-leaf electrolyte leakage and callose deposition, as well as photosynthetic sustainment under stressed conditions. Here, we further show that RcMYB8 binds similarly to the promoters of RcPR5/1 and RcP5C51 in vivo and in vitro. Inhibiting RcP5CS1 by virus-induced gene silencing led to decreased drought tolerance through the reactive oxygen species (ROS) homeostatic regulation. RcP5CS1-silenced plants showed an increase in ion leakage and reduce of proline content, together with the content of malondialdehyde (MDA) increased, lowered activities of Catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). Our study highlights the transcriptional modulator role of RcMYB8 in drought and salinity tolerances, which bridges RcPR5/1 and RcP5CS1 by promoting ROS scavenging. Besides, it is probably applicable to the rose plant engineering for enhancing their abiotic stress tolerances.Graphical

An integrated single-cell RNA-seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types.

The hypothalamic paraventricular nucleus (PVN) is a highly complex brain region that is crucial for homeostatic regulation through neuroendocrine signaling, outflow of the autonomic nervous system, and projections to other brain areas. In the past years, single-cell datasets of the hypothalamus have contributed immensely to the current understanding of the diverse hypothalamic cellular composition. While the PVN has been adequately classified functionally, its molecular classification is currently still insufficient. To address this, we created a detailed atlas of PVN transcriptomic cell types by integrating various PVN single-cell datasets into a recently published hypothalamus single-cell transcriptome atlas. Furthermore, we functionally profiled transcriptomic cell types, based on relevant literature, existing retrograde tracing data, and existing single-cell data of a PVN-projection target region. Finally, we validated our findings with immunofluorescent stainings. In our PVN atlas dataset, we identify the well-known different neuropeptide types, each composed of multiple novel subtypes. We identify Avp-Tac1, Avp-Th, Oxt-Foxp1, Crh-Nr3c1, and Trh-Nfib as the most important neuroendocrine subtypes based on markers described in literature. To characterize the preautonomic functional population, we integrated a single-cell retrograde tracing study of spinally projecting preautonomic neurons into our PVN atlas. We identify these (presympathetic) neurons to cocluster with the Adarb2+ clusters in our dataset. Further, we identify the expression of receptors for Crh, Oxt, Penk, Sst, and Trh in the dorsal motor nucleus of the vagus, a key region that the pre-parasympathetic PVN neurons project to. Finally, we identify Trh-Ucn3 and Brs3-Adarb2 as some centrally projecting populations. In conclusion, our study presents a detailed overview of the transcriptomic cell types of the murine PVN and provides a first attempt to resolve functionality for the identified populations.

IKKβ deletion from CNS macrophages increases neuronal excitability and accelerates the onset of EAE, while from peripheral macrophages reduces disease severity

BackgroundMultiple sclerosis (MS) is a neuroinflammatory demyelinating disease characterized by motor deficits and cognitive decline. Many immune aspects of the disease are understood through studies in the experimental autoimmune encephalomyelitis (EAE) model, including the contribution of the NF-κB transcription factor to neuroinflammation. However, the cell-specific roles of NF-κB to EAE and its cognitive comorbidities still needs further investigation. We have previously shown that the myeloid cell NF-κB plays a role in the healthy brain by exerting homeostatic regulation of neuronal excitability and synaptic plasticity and here we investigated its role in EAE.MethodsWe used constitutive MφIKKβΚΟ mice, in which depletion of IKKβ, the main activating kinase of NF-κB, was global to CNS and peripheral macrophages, and ΜgΙΚΚβKO mice, in which depletion was inducible and specific to CNS macrophages by 28 days after tamoxifen administration. We subjected these mice to MOG35-55 induced EAE and cuprizone-induced demyelination. We measured pathology by immunohistochemistry, investigated molecular mechanisms by RNA sequencing analysis and studied neuronal functions by in vivo electrophysiology in awake animals.ResultsGlobal depletion of IKKβ from myeloid cells in MφIKKβΚΟ mice accelerated the onset and significantly supressed chronic EAE. Knocking out IKKβ only from CNS resident macrophages accelerated the onset and exacerbated chronic EAE, accompanied by earlier demyelination and immune cell infiltration but had no effect in cuprizone-induced demyelination. Peripheral T cell effector functions were not affected by myeloid cell deletion of IKKβ, but CNS resident mechanisms, such as microglial activation and neuronal hyperexcitability were altered from early in EAE. Lastly, depletion of myeloid cell IKKβ resulted in enhanced late long-term potentiation in EAE.ConclusionsIKKβ-mediated activation of NF-κΒ in myeloid cells has opposing roles in EAE depending on the cell type and the disease stage. In CNS macrophages it is protective while in peripheral macrophages it is disease-promoting and acts mainly during chronic disease. Although clinically protective, CNS myeloid cell IKKβ deletion dysregulates neuronal excitability and synaptic plasticity in EAE. These effects of IKKβ on brain cognitive abilities deserve special consideration when therapeutic interventions that inhibit NF-κB are used in MS.

Noninvasive EEG measurement of sleep in the family cat and comparison with the dog

Abstract We have successfully measured the sleep electroencephalogram (EEG) of 12 family cats during an afternoon nap using a completely noninvasive methodology originally developed and validated for family dogs. Extracting both macrostructural and spectral sleep variables from the acquired data, we: (1) provided a descriptive analysis of sleep structure in cats and the power spectral density (PSD) distribution considering 3 sleep stages—drowsiness, non-rapid eye movement (NREM), and rapid eye movement (REM) sleep; and (2) compared the results to those obtained in family dogs measured under the same conditions and using the same methodology. Importantly, our description of sleep structure and PSD distribution in cats proved to be comparable to those of earlier invasive studies, highlighting that appropriate noninvasive methodologies may provide a viable alternative to those that are invasive in some cases. While no macrostructural differences were found between the sleep of cats and dogs, and the characteristic PSDs were mostly similar across sleep stages within the 2 species, the high-frequency resolution comparison of PSD distributions revealed differences between the 2 species in all sleep stages (concerning the delta, theta, alpha, sigma, and beta bands in drowsiness and NREM sleep; and the delta, alpha, and sigma bands in REM sleep). Potential factors underlying these differences are discussed, including differences in circadian rhythms, sleep homeostatic regulation, experienced stress, or even differential attitudes toward owners—highlighting important links between sleep characteristics and often more complex neural and behavioral features.

Maintenance of an Acidic Skin Surface with a Novel Zinc Lactobionate Emollient Preparation Improves Skin Barrier Function in Patients with Atopic Dermatitis.

The skin of patients with atopic dermatitis (AD) is characterised by elevated pH. As a central homeostatic regulator, an increasedpH accelerates desquamation and suppresses lipid processing, resulting in diminished skin barrier function. The aim of this study was to determine whether a novel zinc lactobionate emollient cream can strengthen the skin barrier by lowering skin surface pH. A double-blind, forearm-controlled cohort study was undertaken in patients with AD. Participants applied the test cream to one forearm and a vehicle cream to the other (randomised allocation) twice daily for 56days. Skin surface pH and barrier function (primary outcomes) were assessed at baseline and after 28days and 56days of treatment, amongst other tests. A total of 23 adults with AD completed the study. During and after treatment, a sustained difference in skin surface pH was observed between areas treated with the test cream and vehicle (4.50 ± 0.38 versus 5.25 ± 0.54, respectively, p < 0.0001). This was associated with significantly reduced transepidermal water loss (TEWL) on the test cream treated areas compared with control (9.71 ± 2.47 versus 11.20 ± 3.62g/m2/h, p = 0.0005). Improvements in skin barrier integrity, skin sensitivity to sodium lauryl sulphate, skin hydration, and chymotrypsin-like protease activity were all observed at sites treated with the test cream compared with the control. Maintenance of an acidic skin surface pH and delivery of physiologic lipids are beneficial for skin health and may help improve AD control by reducing sensitivity to irritants and allergens.

Homeostasis and self-regulation

ABSTRACT Homeostasis, a self-regulating process that aims for stability, is presented to be the most fundamental regulatory principle of the psyche. Stability, or avoiding the extremes, is crucial for survival. The mind operates on different layers of homeostasis. Freud’s three phylogenetic layers and regulating principles, namely nirvana, constancy, and psychic structure, are reviewed here. The self-image and its identity of perception form the core of the structure. In a clinical context, a cure that deviates too much from the self-image is perceived as threatening stability. The therapeutic relationship is an ideal setting for fostering the ego’s mentalization capacity and the development of psychic structure. This paper demonstrates how mentalization and autonomous self-regulation challenge pathologic homeostatic regulation through clinical examples. The defensive resistance to cure, with its intriguing deep unconscious phylogenetic roots in homeostatic regulation, underscores the practical implications of these theoretical viewpoints in a clinical setting.

The contribution of granger causality analysis to our understanding of cardiovascular homeostasis: from cardiovascular and respiratory interactions to central autonomic network control.

Homeostatic regulation plays a fundamental role in maintenance of multicellular life. At different scales and in different biological systems, this principle allows a better understanding of biological organization. Consequently, a growing interest in studying cause-effect relations between physiological systems has emerged, such as in the fields of cardiovascular and cardiorespiratory regulations. For this, mathematical approaches such as Granger causality (GC) were applied to the field of cardiovascular physiology in the last 20years, overcoming the limitations of previous approaches and offering new perspectives in understanding cardiac, vascular and respiratory homeostatic interactions. In clinical practice, continuous recording of clinical data of hospitalized patients or by telemetry has opened new applicability for these approaches with potential early diagnostic and prognostic information. In this review, we describe a theoretical background of approaches based on linear GC in time and frequency domains applied to detect couplings between time series of RR intervals, blood pressure and respiration. Interestingly, these tools help in understanding the contribution of homeostatic negative feedback and the anticipatory feedforward mechanisms in homeostatic cardiovascular and cardiorespiratory controls. We also describe experimental and clinical results based on these mathematical tools, consolidating previous experimental and clinical evidence on the coupling in cardiovascular and cardiorespiratory studies. Finally, we propose perspectives allowing to complete the understanding of these interactions between cardiovascular and cardiorespiratory systems, as well as the interplay between brain and cardiac, and vascular and respiratory systems, offering a high integrative view of cardiovascular and cardiorespiratory homeostatic regulation.

Homeostatic Synaptic Plasticity may be Targeted for the Prevention of Post-Stroke Epilepsy

Stroke is the most common cause of acquired epilepsy, with up to 30 percent of stroke survivors developing epilepsy over time. However, the mechanisms leading to neuronal hyperexcitability and epilepsy in stroke survivors are not fully understood. In a recently published work, we demonstrate that ischemic stroke induces homeostatic plasticity regulation in the surviving neurons in the peri-stroke area. Furthermore, activity enhancement through optogenetic stimulation of excitatory pyramidal neurons in the peri-stroke area or systemic administration of D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, reduces seizure susceptibility in mice. Here, we briefly review current understanding on the role of homeostatic plasticity in post-stroke epileptogenesis and discuss how homeostatic plasticity could be targeted to prevent post-stroke epilepsy. We comment on our activity enhancement findings and close by discussing implications for clinical treatment.

Meta-learning modeling and the role of affective-homeostatic states in human cognition

Abstract The meta-learning framework proposed by Binz et al. would gain significantly from the inclusion of affective and homeostatic elements, currently neglected in their work. These components are crucial as cognition as we know it is profoundly influenced by affective states, which arise as intricate forms of homeostatic regulation in living bodies.

Whole-brain inputs and outputs of Phox2b and GABAergic neurons in the nucleus tractus solitarii.

The nucleus tractus solitarii (NTS) plays a critical role in the homeostatic regulation of respiration, blood pressure, sodium consumption and metabolic processes. Despite their significance, the circuitry mechanisms facilitating these diverse physiological functions remain incompletely understood. In this study, we present a whole-brain mapping of both the afferent and efferent connections of Phox2b-expressing and GABAergic neurons within the NTS. Our findings reveal that these neuronal populations not only receive monosynaptic inputs primarily from the medulla oblongata, pons, midbrain, supra-midbrain and cortical areas, but also mutually project their axons to these same locales. Moreover, intense monosynaptic inputs are received from the central amygdala, the paraventricular nucleus of the hypothalamus, the parasubthalamic nucleus and the intermediate reticular nucleus, along with brainstem nuclei explicitly engaged in respiratory regulation. In contrast, both neuronal groups extensively innervate brainstem nuclei associated with respiratory functions, although their projections to regions above the midbrain are comparatively limited. These anatomical findings provide a foundational platform for delineating an anatomical framework essential for dissecting the specific functional mechanisms of these circuits.

Association of Meal Irregularity and Chronotypes with Dietary and Sleep Patterns: A Cross-sectional Study

Introduction: The circadian clock is a homeostatic regulation system comprising clock genes in the body that regulate various physiological and behavioural processes. Diet determines our health and the timing and periodicity of feeding, in addition to nutritional quality, influence circadian rhythms and metabolism significantly. Aim: To assess the association of meal irregularity and chronotypes with dietary and sleep patterns. Materials and Methods: This cross-sectional study was conducted on 375 female adults using the convenience sampling method. Information on socio-demographic characteristics, dietary patterns, sleep patterns, chronotypes, and physical activity was collected through a self-administered questionnaire consisting of 26 questions. Participants aged 18-40 years and who completed the study questionnaire were enrolled. Pregnant or lactating mothers and users of tranquilisers and psychotropic drugs were excluded. T-tests and one-way Analysis of Variance (ANOVA) were used for continuous variables, and the Chisquare test was used for categorical variables. Results: A total of 197 (52.5%) participants reported consuming their meals at a regular time every day, while 178 (47.5%) did not. Concerning eating meals at a regular time every day, a significant association was found between eating meals at a regular time every day and the number of meals per day (Chi-squared, p-value&lt;0.001). The data indicated that most participants were of the intermediate type (190, 50.7%), followed by the morning type (111, 29.6%), and then the evening type (74, 19.7%). Regarding the Morning-Evening Questionnaire (MEQ), there were significant associations between MEQ and the time of the last meal (Chi-squared, p-value=0.001), eating a meal after 9 pm (Chi-squared, p-value&lt;0.001), and the need for a nap in the middle of the day (Chi-squared, p-value&lt;0.001). Conclusion: The present study suggests that the regular timing of eating is associated with the number of meals per day. Dietary and sleep patterns, including the time of the last meal, eating a meal after 9 pm, and the need for a nap in the middle of the day, were also associated with chronotype.

Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates.

Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.

The adhesion G-protein-coupled receptor mayo/CG11318 controls midgut development in Drosophila

Adhesion G-protein-coupled receptors (aGPCRs) form a large family of cell surface molecules with versatile tasks in organ development. Many aGPCRs still await their functional and pharmacological deorphanization. Here, we characterized the orphan aGPCR CG11318/mayo of Drosophila melanogaster and found it expressed in specific regions of the gastrointestinal canal and anal plates, epithelial specializations that control ion homeostasis. Genetic removal of mayo results in tachycardia, which is caused by hyperkalemia of the larval hemolymph. The hyperkalemic effect can be mimicked by a raise in ambient potassium concentration, while normal potassium levels in mayoKO mutants can be restored by pharmacological inhibition of potassium channels. Intriguingly, hyperkalemia and tachycardia are caused non-cell autonomously through mayo-dependent control of enterocyte proliferation in the larval midgut, which is the primary function of this aGPCR. These findings characterize the ancestral aGPCR Mayo as a homeostatic regulator of gut development.