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Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

Recent experimental evidence indicates a role for the intermediate filament vimentin in regulating cellular mechanical homeostasis, but its precise contribution remains to be discovered. Mechanical homeostasis requires a balanced bi-directional interplay between the cell's microenvironment and the cellular morphological and mechanical state-this balance being regulated via processes of mechanotransduction and mechanoresponse, commonly referred to as mechanoreciprocity. Here, we systematically analyze vimentin-expressing and vimentin-depleted cells in a swatch of in vitro cellular microenvironments varying in stiffness and/or ECM density. We find that vimentin-expressing cells maintain mechanical homeostasis by adapting cellular morphology and mechanics to micromechanical changes in the microenvironment. However, vimentin-depleted cells lose this mechanoresponse ability on short timescales, only to reacquire it on longer time scales. Indeed, we find that the morphology and mechanics of vimentin-depleted cell in stiffened microenvironmental conditions can get restored to the homeostatic levels of vimentin-expressing cells. Additionally, we observed vimentin-depleted cells increasing collagen matrix synthesis and its crosslinking, a phenomenon which is known to increase matrix stiffness, and which we now hypothesize to be a cellular compensation mechanism for the loss of vimentin. Taken together, our findings provide further insight in the regulating role of intermediate filament vimentin in mediating mechanoreciprocity and mechanical homeostasis.

Antibacterial properties of the stem cells and human- and plant- derived microvesicles are attracting increasing attention of the research community. Awareness of publications pointing out to the pronounced anti-bacterial properties of microvesicles isolated from the supernatants of different human origin prompted us to test corresponding properties of supernatant isolated using simplified protocol. Extensive research with more than 100 laboratory strains and hospital isolates of Gram-positive and Gram- negative bacteria point out to a pronounced anti-bacterial activity of the supernatant isolated from the cultures of actively dividing human cells. Simultaneous support of cell proliferation homeostasis and anti-bacterial activity led us to the hypotheses suggesting that there exists some archaic (possibly relict) mechanism with bivalent activity, which is provided by certain entities present in the supernatant. Taking into account that dried supernatant does not lose its potency for relatively long time, we would like to attract activity of wide research community to the opening application possibilities, and to the critical discussions over the formulated hypothesis.

The aim of this study was to investigate the comparative effects of mindful meditation and cyclic hyperventilation with retention upon interoceptive ability and heart rate variability (HRV). Further studies comparing meditation and breathwork contribute to a greater understanding of their potential benefits and have the potential to enhance overall well-being in the general population. A pre-post randomized controlled trial design was employed. Interoceptive accuracy was assessed through heartbeat detection task. Interoceptive sensibility was measured through confidence judgments, and interoceptive awareness by the correlation between accuracy and sensibility. Participants were randomly assigned to perform mindful meditation or cyclic hyperventilation with retention once per day for 21 consecutive days. No differences in interoceptive capacity and HRV was observed between the groups, but a tendency towards improved accuracy and increased confidence for both groups. However, the mindful meditation group exhibited a stronger positive association between HRV and interoceptive accuracy after the intervention, while the opposite was true for the cyclic hyperventilation group. Additionally, interoceptive awareness remained stable throughout the study. Mindful meditation demonstrated an enhancement in parasympathetic activity, as evidenced by higher RMSSD values. In contrast, cyclic hyperventilation with retention resulted in a substantial reduction in parasympathetic activity. This study highlights the complexity of interoception and emphasizes the need for further investigation in the context of mindfulness-based and breathwork interventions., Syftet med denna studie var att undersöka de jämförande effekterna av medveten meditation och cyklisk hyperventilation med bibehållande på interoceptiv förmåga och hjärtfrekvensvariabilitet (HRV). Fler studier som jämför meditation och andningsövningar leder till en ökad förståelse av dess potentiella fördelar och står att gynna det övergripande välbefinnandet i den breda befolkningen. En pre-post randomiserad försöksdesign användes. Interoceptiv noggrannhet bedömdes genom en uppgift för att känna hjärtslag. Interoceptiv känslighet mättes genom konfidenskattningar och interoceptiv medvetenhet genom korrelationen mellan noggrannhet och känslighet. Deltagarna tilldelades slumpmässigt medveten meditation eller cyklisk hyperventilation en gång om dagen i 21 dagar. Inga skillnader i interoceptiv förmåga och HRV observerades mellan grupperna, men det fanns en tendens till förbättrad noggrannhet och ökad sensibilitet för båda grupperna. Likväl visade medveten meditation en starkare positiv association mellan HRV och interoceptiv noggrannhet efter interventionen, medan det motsatta var sant för cyklisk hyperventilation. Dessutom förblev interoceptiv medvetenhet stabil under hela studien. Medveten meditation visade en förbättring av parasympatisk aktivitet, vilket bevisades av högre RMSSD-värden. Å andra sidan resulterade cyklisk hyperventilation med bibehållande en betydande minskning av parasympatisk aktivitet. Denna studie belyser interoceptionens komplexitet och betonar behovet av ytterligare undersökning inom ramen för interventioner baserade på mindfulness och andningsarbete.

Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity.

In cell models, changes in the 'accessible' pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.

Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles in ex vivo cortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations.SIGNIFICANCE STATEMENT The connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used an ex vivo approach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms

Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10+CD33-), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR-CD33+CD11b-). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DRhi classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.

Drug transporters and drug-metabolizing enzymes are primarily known for their role in the absorption, distribution, metabolism, and excretion (ADME) of small molecule drugs, but they also play a key role in handling endogenous metabolites. Recent cross-tissue co-expression network analyses have revealed a "Remote Sensing and Signaling Network" of multispecific, oligo-specific, and monospecific transporters and enzymes involved in endogenous metabolism. This includes many proteins from families involved in ADME (e.g., SLC22, SLCO, ABCC, CYP, UGT). Focusing on the gut-liver-kidney axis, we identified the endogenous metabolites potentially regulated by this network of ~1000 proteins by associating SNPs in these genes with the circulating levels of thousands of small, polar, bioactive metabolites, including free fatty acids, eicosanoids, bile acids, and other signaling metabolites that act in part via G-protein coupled receptors (GPCRs), nuclear receptors, and kinases. We identified 77 genomic loci associated with 7236 unique metabolites. This included metabolites that were associated with multiple, distinct loci, indicating coordinated regulation between multiple genes (including drug transporters and drug-metabolizing enzymes) of specific metabolites. We analyzed existing pharmacogenomic data and noted SNPs implicated in endogenous metabolite handling (e.g., rs4149056 in SLCO1B1) also affecting drug ADME. The overall results support the existence of close relationships, via interactions with signaling metabolites, between drug transporters and drug-metabolizing enzymes that are part of the Remote Sensing and Signaling Network, and with GPCRs and nuclear receptors. These analyses highlight the potential for drug-metabolite interactions at the interfaces of the Remote Sensing and Signaling Network and the ADME protein network.

Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.

ObjectiveMitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.MethodsIn this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based oxygen consumption rate measurement, and Mitoplate S-1 mitochondrial substrate utilization analysis.ResultsTranscriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR KO liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy.ConclusionsAhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.

IntroductionAfrican Americans are at increased risk for type 2 diabetes.ObjectivesThis work aimed to examine metabolomic signature of glucose homeostasis in African Americans.MethodsWe used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans.ResultsWe confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans.ConclusionWe extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.

Considerable evidence confirms the importance of Cyp26a1 to all-trans-retinoic acid (RA) homeostasis during embryogenesis. In contrast, despite its presence in postnatal liver as a potential major RA catabolizing enzyme and its acute sensitivity to induction by RA, some data suggested that Cyp26a1 contributes only marginally to endogenous RA homeostasis postnatally. We report reevaluation of a conditional Cyp26a1 knockdown in the postnatal mouse. The current results show that Cyp26a1 mRNA in WT mouse liver increases 16-fold upon refeeding after a fast, accompanied by an increased rate of RA elimination and a 41% decrease in the RA concentration. In contrast, Cyp26a1 mRNA in the refed homozygotic knockdown reached only 2% of its extent in WT during refeeding, accompanied by a slower rate of RA catabolism and no decrease in liver RA, relative to fasting. Refed homozygous knockdown mice also had decreased Akt1 and 2 phosphorylation and pyruvate dehydrogenase kinase 4 (Pdk4) mRNA and increased glucokinase (Gck) mRNA, glycogen phosphorylase (Pygl) phosphorylation, and serum glucose, relative to WT. Fasted homozygous knockdown mice had increased glucagon/insulin relative to WT. These data indicate that Cyp26a1 participates prominently in moderating the postnatal liver concentration of endogenous RA and contributes essentially to glucoregulatory control.

Metabolism constitutes the core chemistry of life. How it began on the early Earth and whether it had a cellular origin are still uncertain. A leading hypothesis for life's origins postulates that metabolism arose from geochemical CO2-fixing pathways, driven by inorganic catalysts and energy sources, long before enzymes or genes existed. The acetyl-CoA pathway and the reductive tricarboxylic acid cycle are considered ancient reaction networks that hold relics of early carbon-fixing pathways. Although transition metals can promote many steps of these pathways, whether they form a functional metabolic network in abiotic cells has not been demonstrated. Here, we formulate a nonenzymatic carbon-fixing network from these pathways and determine its functional feasibility in abiotic cells by imposing fundamental physicochemical constraints. Using first principles, we show that abiotic cells can sustain a steady carbon-fixing cycle that performs a systemic function over a relatively narrow range of conditions. Furthermore, we find that in all feasible steady states, the operation of the cycle elevates the osmotic pressure, leading to volume expansion. These results suggest that achieving homeostatic metabolic states under prebiotic conditions was possible, but challenging, and volume growth was a fundamental property of early metabolism.

SUV3 is a nuclear-encoded helicase that is highly conserved and localizes to the mitochondrial matrix. In yeast, loss of SUV3 function leads to the accumulation of group 1 intron transcripts, ultimately resulting in the loss of mitochondrial DNA, causing a petite phenotype. However, the mechanism leading to the loss of mitochondrial DNA remains unknown. SUV3 is essential for survival in higher eukaryotes, and its knockout in mice results in early embryonic lethality. Heterozygous mice exhibit a range of phenotypes, including premature aging and an increased cancer incidence. Furthermore, cells derived from SUV3 heterozygotes or knockdown cultural cells show a reduction in mtDNA. Transient downregulation of SUV3 leads to the formation of R-loops and the accumulation of double-stranded RNA in mitochondria. This review aims to provide an overview of the current knowledge regarding the SUV3-containing complex and discuss its potential mechanism for tumor suppression activity.

Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation1 to study the proteomes of striatal astrocytes and neurons in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive-compulsive disorder (OCD) and repetitive behaviours2-8, was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined with behavioural analyses and molecular assessments in a mouse model of OCD4 lacking SAPAP3 revealed distinct contributions of astrocytic and neuronal SAPAP3 to repetitive and anxiety-related OCD-like phenotypes. Our data define how astrocytes and neurons differ at the protein level and in their major signalling pathways. Moreover, they reveal how astrocyte subproteomes vary between physiological subcompartments and how both astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Our data indicate that therapeutic strategies that target both astrocytes and neurons may be useful to explore in OCD and potentially other brain disorders.

Oxido-reductive (redox) chemistry is well established to support the high ATP demands of neural activity but the full scope of redox biology operating in the brain, including the relevance of reversible oxidations of protein thiols, which can function as metabolic regulatory switches, remains to be fully and systematically investigated. Using redox phenylarsine oxide-affinity chromatography to capture proteins from rat brain forming reducible (i.e., potential regulatory) disulfide bonds, we report that creatine kinase B and ?-enolase contained thiols that were selectively oxidized compared to other metabolic enzymes of interest, including neuron-specific (gamma) enolase, under experimental conditions designed to trap in vivo protein thiol redox states. In addition, short-term delays to tissue freezing, to allow perturbations in metabolism triggered by decapitation-induced global ischemia, exposed an early reductive shift marked by transient decreases in the extents of oxidizations of protein thiols. The results reported here advance fundamental tenets of brain redox biology by (i) identifying preferred targets of protein thiol oxidations in the healthy brain, (ii) supporting the unrecognized notion that neurons and astrocytes may operate at distinct redox potentials, in vivo, and (iii) demonstrating that reversals of thiol oxidations on metabolic enzymes may occur as early adaptations to ischemic insults.

Tuft cells are found in tissues with distinct stem cell compartments, tissue architecture, and luminal exposures but converge on a shared transcriptional program, including expression of taste transduction signaling pathways. Here, we summarize seminal and recent findings on tuft cells, focusing on major categories of function-instigation of type 2 cytokine responses, orchestration of antimicrobial responses, and emerging roles in tissue repair-and describe tuft cell-derived molecules used to affect these functional programs. We review what is known about the development of tuft cells from epithelial progenitors under homeostatic conditions and during disease. Finally, we discuss evidence that immature, or nascent, tuft cells with potential for diverse functions are driven toward dominant effector programs by tissue- or perturbation-specific contextual cues, which may result in heterogeneous mature tuft cell phenotypes both within and between tissues.

Insufficient sleep impairs glucose regulation, increasing the risk of diabetes. However, what it is about the human sleeping brain that regulates blood sugar remains unknown. In an examination of over 600 humans, we demonstrate that the coupling of non-rapid eye movement (NREM) sleep spindles and slow oscillations the night before is associated with improved next-day peripheral glucose control. We further show that this sleep-associated glucose pathway may influence glycemic status through altered insulin sensitivity, rather than through altered pancreatic beta cell function. Moreover, we replicate these associations in an independent dataset of over 1,900 adults. Of therapeutic significance, the coupling between slow oscillations and spindles was the most significant sleep predictor of next-day fasting glucose, even more so than traditional sleep markers, relevant to the possibility of an electroencephalogram (EEG) index of hyperglycemia. Taken together, these findings describe a sleeping-brain-body framework of optimal human glucose homeostasis, offering a potential prognostic sleep signature of glycemic control.

Mechanosensitive mechanisms are often used to sense damage to tissue structure, stimulating matrix synthesis and repair. While this kind of mechanoregulatory process is well recognized in eukaryotic systems, it is not known whether such a process occurs in bacteria. In Vibrio cholerae, antibiotic-induced damage to the load-bearing cell wall promotes increased signaling by the two-component system VxrAB, which stimulates cell wall synthesis. Here we show that changes in mechanical stress within the cell envelope are sufficient to stimulate VxrAB signaling in the absence of antibiotics. We applied mechanical forces to individual bacteria using three distinct loading modalities: extrusion loading within a microfluidic device, direct compression and hydrostatic pressure. In all cases, VxrAB signaling, as indicated by a fluorescent protein reporter, was increased in cells submitted to greater magnitudes of mechanical loading, hence diverse forms of mechanical stimuli activate VxrAB signaling. Reduction in cell envelope stiffness following removal of the endopeptidase ShyA led to large increases in cell envelope deformation and substantially increased VxrAB response, further supporting the responsiveness of VxrAB. Our findings demonstrate a mechanosensitive gene regulatory system in bacteria and suggest that mechanical signals may contribute to the regulation of cell wall homeostasis.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.

Consumption of food and water is tightly regulated by the nervous system to maintain internal nutrient homeostasis. Although generally considered independently, interactions between hunger and thirst drives are important to coordinate competing needs. In chapter 1, I provide a review of hunger regulation and thirst regulation in mammals and Drosophila melanogaster. I then discuss the neural and hormonal coordination of hunger and thirst in both mammals and D. melanogaster.In Drosophila, four neurons called the Interoceptive Subesophageal zone Neurons (ISNs) respond to intrinsic hunger and thirst signals to oppositely regulate sucrose and water ingestion. In chapter 2, I characterize the neural circuit downstream of the ISNs. This work is presented in the form of a preprint first author manuscript. Using the fly brain connectome, genetic tools, behavioral assays, and functional imaging, I show, together with co-authors Gina Pontes, Nicholas Jourjine and Alexander Del Toro, that the ISNs modulate a peptidergic network of neurons. These include a novel cell type Bilateral T shaped neuron (BiT), insulin producing cells (IPC), crustacean cardioactive peptide (CCAP) neurons, and CCHamide-2 receptor isoform RA (CCHa2R-RA) neurons. These neurons contribute differentially to ingestion of sugar and water, with BiT, IPCs and CCAP neurons oppositely regulating sugar and water ingestion, and CCHa2R-RA neurons modulating only water ingestion. Thus, the decision to consume sugar or water occurs via regulation of a broad peptidergic network that integrates internal signals of nutritional state to generate nutrient-specific ingestion.In chapter 3, I characterize other neurons that are involved in sugar and/or water ingestion. Using a computational approach to identify neurons in close proximity, genetic manipulation, behavioral assays, and in vivo functional imaging, I characterized several neurons involved in sugar and/or water ingestion regulation. Aster, bidirectionally regulates

Ghrelina es una hormona orexigénica ejerce sus acciones a través del receptor GHSR1a. El descubrimiento de LEAP-2 como ligando endógeno de este receptor, mostrando efectos opuestos a ghrelina en ingesta ha abierto un nuevo campo de estudio como una posible diana terapéutica antiobesidad. En la presente tesis doctoral se intentan dilucidar las acciones de LEAP-2 en la regulación de la homeostasis energética y sus efectos antagonizando ghrelina, determinando los mecanismos fisiológicos responsables de estos efectos. Utilizando modelos preclínicos de ratón se analizó el efecto de LEAP-2 central sobre la termogénesis y metabolismo hepático en diferentes condiciones fisiopatológicas. Con el objetivo de discernir acciones centrales y acciones periféricas de LEAP-2 se realizaron experimentos in vitro con cultivos primarios de tejido adiposo y líneas celulares de hepatocitos humanos. Nuestros resultados indican que LEAP-2 es regulado por el estado nutricional de forma inversa a ghrelina, y que su administración central ejerce importantes acciones en la homeostasis energética del organismo actuando sobre la termogénesis y el metabolismo de ácidos grasos en hígado. Por otra parte, a nivel periférico actúa de manera directa sobre hígado y tejido adiposo. En conclusión, LEAP-2 se posiciona como una hormona contrarreguladora, jugando un papel fundamental en el sistema de ghrelina y podría ser considerada como una nueva diana terapéutica en el tratamiento de la obesidad, MAFLD y otras enfermedades metabólicas.

Societal safety is often centred on handling or managing a single risk from the perspective of a particular at-risk group or individual, in a specific time and place. However, such linear and single-facetted processes are rare and the current approaches in societal risk management fail to comprehensively include and discuss the full range of outcomes and its inherent uncertainty and complexity. By combining different examples of known and unknown outcomes of societal risk management in the scientific literature, this paper aim to contribute to the risk and safety research field by presenting a conceptual model of risk transfer. The conceptual model shows how traditional societal risk management strategies often aim at reducing a targeted risk, considering the original actors affected by this risk, in a defined geographical area and for a decided time frame despite risk management also altering the landscape of risks for other actors, in other places, and at other times, as well as for the original actors, in the original place, and during the original time. Combining these aspects in a conceptual model that accepts and incorporates complexity, the underlying intention is to initiate a discussion regarding the current approaches and understandings of societal risk management and societal safety.

Societal safety is often centred on handling or managing a single risk from the perspective of a particular at-risk group or individual, in a specific time and place. However, such linear and single-facetted processes are rare and the current approaches in societal risk management fail to comprehensively include and discuss the full range of outcomes and its inherent uncertainty and complexity. By combining different examples of known and unknown outcomes of societal risk management in the scientific literature, this paper aim to contribute to the risk and safety research field by presenting a conceptual model of risk transfer. The conceptual model shows how traditional societal risk management strategies often aim at reducing a targeted risk, considering the original actors affected by this risk, in a defined geographical area and for a decided time frame despite risk management also altering the landscape of risks for other actors, in other places, and at other times, as well as for the original actors, in the original place, and during the original time. Combining these aspects in a conceptual model that accepts and incorporates complexity, the underlying intention is to initiate a discussion regarding the current approaches and understandings of societal risk management and societal safety.

Societal safety is often centred on handling or managing a single risk from the perspective of a particular at-risk group or individual, in a specific time and place. However, such linear and single-facetted processes are rare and the current approaches in societal risk management fail to comprehensively include and discuss the full range of outcomes and its inherent uncertainty and complexity. By combining different examples of known and unknown outcomes of societal risk management in the scientific literature, this paper aim to contribute to the risk and safety research field by presenting a conceptual model of risk transfer. The conceptual model shows how traditional societal risk management strategies often aim at reducing a targeted risk, considering the original actors affected by this risk, in a defined geographical area and for a decided time frame despite risk management also altering the landscape of risks for other actors, in other places, and at other times, as well as for the original actors, in the original place, and during the original time. Combining these aspects in a conceptual model that accepts and incorporates complexity, the underlying intention is to initiate a discussion regarding the current approaches and understandings of societal risk management and societal safety.

The aim of this study was to investigate the comparative effects of mindful meditation and cyclic hyperventilation with retention upon interoceptive ability and heart rate variability (HRV). Further studies comparing meditation and breathwork contribute to a greater understanding of their potential benefits and have the potential to enhance overall well-being in the general population. A pre-post randomized controlled trial design was employed. Interoceptive accuracy was assessed through heartbeat detection task. Interoceptive sensibility was measured through confidence judgments, and interoceptive awareness by the correlation between accuracy and sensibility. Participants were randomly assigned to perform mindful meditation or cyclic hyperventilation with retention once per day for 21 consecutive days. No differences in interoceptive capacity and HRV was observed between the groups, but a tendency towards improved accuracy and increased confidence for both groups. However, the mindful meditation group exhibited a stronger positive association between HRV and interoceptive accuracy after the intervention, while the opposite was true for the cyclic hyperventilation group. Additionally, interoceptive awareness remained stable throughout the study. Mindful meditation demonstrated an enhancement in parasympathetic activity, as evidenced by higher RMSSD values. In contrast, cyclic hyperventilation with retention resulted in a substantial reduction in parasympathetic activity. This study highlights the complexity of interoception and emphasizes the need for further investigation in the context of mindfulness-based and breathwork interventions., Syftet med denna studie var att undersöka de jämförande effekterna av medveten meditation och cyklisk hyperventilation med bibehållande på interoceptiv förmåga och hjärtfrekvensvariabilitet (HRV). Fler studier som jämför meditation och andningsövningar leder till en ökad förståelse av dess potentiella fördelar och står att gynna det övergripande välbefinnandet i den breda befolkningen. En pre-post randomiserad försöksdesign användes. Interoceptiv noggrannhet bedömdes genom en uppgift för att känna hjärtslag. Interoceptiv känslighet mättes genom konfidenskattningar och interoceptiv medvetenhet genom korrelationen mellan noggrannhet och känslighet. Deltagarna tilldelades slumpmässigt medveten meditation eller cyklisk hyperventilation en gång om dagen i 21 dagar. Inga skillnader i interoceptiv förmåga och HRV observerades mellan grupperna, men det fanns en tendens till förbättrad noggrannhet och ökad sensibilitet för båda grupperna. Likväl visade medveten meditation en starkare positiv association mellan HRV och interoceptiv noggrannhet efter interventionen, medan det motsatta var sant för cyklisk hyperventilation. Dessutom förblev interoceptiv medvetenhet stabil under hela studien. Medveten meditation visade en förbättring av parasympatisk aktivitet, vilket bevisades av högre RMSSD-värden. Å andra sidan resulterade cyklisk hyperventilation med bibehållande en betydande minskning av parasympatisk aktivitet. Denna studie belyser interoceptionens komplexitet och betonar behovet av ytterligare undersökning inom ramen för interventioner baserade på mindfulness och andningsarbete.

Societal safety is often centred on handling or managing a single risk from the perspective of a particular at-risk group or individual, in a specific time and place. However, such linear and single-facetted processes are rare and the current approaches in societal risk management fail to comprehensively include and discuss the full range of outcomes and its inherent uncertainty and complexity. By combining different examples of known and unknown outcomes of societal risk management in the scientific literature, this paper aim to contribute to the risk and safety research field by presenting a conceptual model of risk transfer. The conceptual model shows how traditional societal risk management strategies often aim at reducing a targeted risk, considering the original actors affected by this risk, in a defined geographical area and for a decided time frame despite risk management also altering the landscape of risks for other actors, in other places, and at other times, as well as for the original actors, in the original place, and during the original time. Combining these aspects in a conceptual model that accepts and incorporates complexity, the underlying intention is to initiate a discussion regarding the current approaches and understandings of societal risk management and societal safety.

Societal safety is often centred on handling or managing a single risk from the perspective of a particular at-risk group or individual, in a specific time and place. However, such linear and single-facetted processes are rare and the current approaches in societal risk management fail to comprehensively include and discuss the full range of outcomes and its inherent uncertainty and complexity. By combining different examples of known and unknown outcomes of societal risk management in the scientific literature, this paper aim to contribute to the risk and safety research field by presenting a conceptual model of risk transfer. The conceptual model shows how traditional societal risk management strategies often aim at reducing a targeted risk, considering the original actors affected by this risk, in a defined geographical area and for a decided time frame despite risk management also altering the landscape of risks for other actors, in other places, and at other times, as well as for the original actors, in the original place, and during the original time. Combining these aspects in a conceptual model that accepts and incorporates complexity, the underlying intention is to initiate a discussion regarding the current approaches and understandings of societal risk management and societal safety.

Cells and their surrounding extracellular matrix (ECM) are engaged in dynamic reciprocity to maintain tissue homeostasis: cells deposit ECM, which in turn presents the signals that define cell identity. This loop of phenotype is obvious for biochemical signals, such as collagens, which are produced by and presented to cells, but the role of biomechanical signals is also increasingly recognised. In addition, cell shape goes hand in hand with cell function and tissue homeostasis. Aberrant cell shape and ECM is seen in pathological conditions, and control of cell shape in micro-fabricated platforms disclose the causal relationship between cell shape and cell function, often mediated by mechanotransduction. In this manuscript, we discuss the loop of phenotype for tendon tissue homeostasis. We describe cell shape and ECM organization in normal and diseased tissue, how ECM composition influences tenocyte shape, and how that leads to the activation of signal transduction pathways and ECM deposition. We further describe the use of technologies to control cell shape to elucidate the link between cell shape and its phenotypical markers and focus on the causal role of cell shape in the loop of phenotype. Statement of significance: The dynamic reciprocity between cells and their surrounding extracellular matrix (ECM) influences biomechanical and biochemical properties of ECM as well as cell function through activation of signal transduction pathways that regulate gene and protein expression. We refer to this reciprocity as Loop of Phenotype and it has been studied and demonstrated extensively by using micro-fabricated platforms to manipulate cell shape and cell fate. In this manuscript, we discuss this concept in tendon tissue homeostasis by giving examples in healthy and pathological tenson tissue. Furthermore, we elaborate this by showing how biomaterials are used to feed this reciprocity to manipulate cell shape and function. Finally, we elucidate the link between cell sh

Physiological homeostasis is constantly monitored and mediated by neuroregulatory mechanisms in the central nervous system (CNS). Deviation from optimal homeostatic regulation in response to the environment is a major driver of the prevalence of chronic non-communicable diseases such as hypertension, obesity and type-2 diabetes in the population. The CNS is the most complex biological system. It comprises interconnected neural networks operating a high degree a functional specificity which are regulated by diverse gene expression profiles. The particular characteristics of the CNS present unique challenges for scientific evaluation of the distinct biological processes important in health and disease. Progress made in the field of genetics, for example the identification of functionally distinct gene expression profiles or the identification of robust genetic associations with disease enriched in the CNS represent major milestones in how molecular genetic data can improve our fundamental understanding of the brain. The goal of this thesis is to explore how genetic analyses in different contexts contribute to our understanding of neural processes in health and disease. First, molecular genetic and Next-generation sequencing technologies are implemented to characterize a transcriptional network underlying the homeostatic regulation of fluid balance in the brain using a rat animal model. Secondly, the use of statistical genetics to harness human genetic datasets is explored in order to investigate relationships between the KRAB-zinc finger family of transcriptional regulators (which are enriched in the brain) and complex health outcomes. Lastly, this thesis demonstrates how published population level genetic datasets may be harnessed to isolate neural mediated effects contributing to complex traits. A demonstration is provided of how such tissue-specific effects may be integrated into genetic epidemiological analyses to estimate their effect on disease risk. Overall

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.

Seeking and consuming nutrients is essential to survival and the maintenance of life. Dynamic and volatile environments require that animals learn complex behavioral strategies to obtain the necessary nutritive substances. While this has been classically viewed in terms of homeostatic regulation, recent theoretical work proposed that such strategies result from reinforcement learning processes. This theory proposed that phasic dopamine (DA) signals play a key role in signaling potentially need-fulfilling outcomes. To examine links between homeostatic and reinforcement learning processes, we focus on sodium appetite as sodium depletion triggers state- and taste-dependent changes in behavior and DA signaling evoked by sodium-related stimuli. We find that both the behavior and the dynamics of DA signaling underlying sodium appetite can be accounted for by a homeostatically regulated reinforcement learning framework (HRRL). We first optimized HRRL-based agents to sodium-seeking behavior measured in rodents. Agents successfully reproduced the state and the taste dependence of behavioral responding for sodium as well as for lithium and potassium salts. We then showed that these same agents account for the regulation of DA signals evoked by sodium tastants in a taste- and state-dependent manner. Our models quantitatively describe how DA signals evoked by sodium decrease with satiety and increase with deprivation. Lastly, our HRRL agents assigned equal preference for sodium versus the lithium containing salts, accounting for similar behavioral and neurophysiological observations in rodents. We propose that animals use orosensory signals as predictors of the internal impact of the consumed good and our results pose clear targets for future experiments. In sum, this work suggests that appetite-driven behavior may be driven by reinforcement learning mechanisms that are dynamically tuned by homeostatic need., NIH, ANR, Peer Reviewed

Proline is a pivotal and multifunctional amino acid that is used not only as a nitrogen source but also as a stress protectant and energy source. Therefore, proline metabolism is known to be important in maintaining cellular homeostasis. Here, we discovered that proline oxidation, catalyzed by the proline oxidase Put1, a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate, controls the chronological lifespan of the yeast Saccharomyces cerevisiae. Intriguingly, the yeast strain with PUT1 deletion showed a reduced chronological lifespan compared with the wild-type strain. The addition of proline to the culture medium significantly increased the longevity of wild-type cells but not that of PUT1-deleted cells. We next found that induction of the transcriptional factor Put3-dependent PUT1 and degradation of proline occur during the aging of yeast cells. Additionally, the lifespan of the PUT3-deleted strain, which is deficient in PUT1 induction, was shorter than that of the wild-type strain. More importantly, the oxidation of proline by Put1 helped maintain the mitochondrial membrane potential and ATP production through the aging period. These results indicate that mitochondrial energy metabolism is maintained through oxidative degradation of proline and that this process is important in regulating the longevity of yeast cells.

How does a regenerating animal "know" what's missing? How are stem cells or differentiated cells used to create new tissues during regeneration? In this class we will take a comparative approach to explore this fascinating problem by critically examining classic and modern scientific literature about the developmental and molecular biology of regeneration. We will learn about conserved developmental pathways that are necessary for regeneration, and we will discuss the relevance of these findings for regenerative medicine. This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

How does a regenerating animal "know" what's missing? How are stem cells or differentiated cells used to create new tissues during regeneration? In this class we will take a comparative approach to explore this fascinating problem by critically examining classic and modern scientific literature about the developmental and molecular biology of regeneration. We will learn about conserved developmental pathways that are necessary for regeneration, and we will discuss the relevance of these findings for regenerative medicine. This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

Continuing advances in genomics, molecular and cellular mechanobiology and immunobiology, including transcriptomics and proteomics, and biomechanics increasingly reveal the complexity underlying native tissue and organ structure and function. Identifying methods to repair, regenerate, or replace vital tissues and organs remains one of the greatest challenges of modern biomedical engineering, one that deserves our very best effort. Notwithstanding the continuing need for improving standard methods of investigation, including cell, organoid, and tissue culture, biomaterials development and fabrication, animal models, and clinical research, it is increasingly evident that modern computational methods should play increasingly greater roles in advancing the basic science, bioengineering, and clinical application of regenerative medicine. This brief review focuses on the development and application of computational models of tissue and organ mechanobiology and mechanics for purposes of designing tissue engineered constructs and understanding their development in vitro and in situ. Although the basic approaches are general, for illustrative purposes we describe two recent examples from cardiovascular medicine—tissue engineered heart valves (TEHVs) and tissue engineered vascular grafts (TEVGs)—to highlight current methods of approach as well as continuing needs.

The G protein-coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor-associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.

Blood and lymphatic vessels are regulators of physiological processes, including oxygenation and fluid transport. Both vessels are ubiquitous throughout the body and are critical for sustaining tissue homeostasis. The complexity of each vessel’s processes has limited the understanding of exactly how the vessels maintain their functions. Both vessels have been shown to be involved in the pathogenesis of many diseases, including cancer metastasis, and it is crucial to probe further specific mechanisms involved. In vitro models are developed to better understand blood and lymphatic physiological functions and their mechanisms. In this review, blood and lymphatic in vitro model systems, including 2D and 3D designs made using Transwells, microfluidic devices, organoid cultures, and various other methods, are described. Models studying endothelial cell-extracellular matrix interactions, endothelial barrier properties, transendothelial transport and cell migration, lymph/angiogenesis, vascular inflammation, and endothelial-cancer cell interactions are particularly focused. While the field has made significant progress in modeling and understanding lymphatic and blood vasculature, more models that include coculture of multiple cell types, complex extracellular matrix, and 3D morphologies, particularly for models mimicking disease states, will help further the understanding of the role of blood and lymphatic vasculature in health and disease.

Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that counteract neuronal perturbations, enabling brain resilience. Currently, we lack a complete description of the homeostatic processes that operate within the mammalian brain. Here, we demonstrate that acute, partial AMPAR-specific antagonism induces potentiation of presynaptic neurotransmitter release in adult hippocampus, a form of compensatory plasticity that is consistent with the expression of presynaptic homeostatic plasticity (PHP) documented at peripheral synapses. We show that this compensatory plasticity can be induced within minutes, requires postsynaptic NMDARs, and is expressed via correlated increases in dendritic spine volume, active zone area, and docked vesicle number. Further, simultaneous postsynaptic genetic reduction of GluA1, GluA2, and GluA3 in triple heterozygous knockouts induces potentiation of presynaptic release. Finally, induction of compensatory plasticity at excitatory synapses induces a parallel, NMDAR-dependent potentiation of inhibitory transmission, a cross-modal effect consistent with the anti-epileptic activity of AMPAR-specific antagonists used in humans.

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNts neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNts neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNts neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

Homeostasis maintains serum metabolites within physiological ranges. For glucose, this requires insulin, which suppresses glucose production while accelerating its consumption. For other circulating metabolites, a comparable master regulator has yet to be discovered. Here we show that, in mice, many circulating metabolites are cleared via the tricarboxylic acid cycle (TCA) cycle in linear proportionality to their circulating concentration. Abundant circulating metabolites (essential amino acids, serine, alanine, citrate, 3-hydroxybutyrate) were administered intravenously in perturbative amounts and their fluxes were measured using isotope labelling. The increased circulating concentrations induced by the perturbative infusions hardly altered production fluxes while linearly enhancing consumption fluxes and TCA contributions. The same mass action relationship between concentration and consumption flux largely held across feeding, fasting and high- and low-protein diets, with amino acid homeostasis during fasting further supported by enhanced endogenous protein catabolism. Thus, despite the copious regulatory machinery in mammals, circulating metabolite homeostasis is achieved substantially through mass action-driven oxidation.

Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal.

Spleen dendritic cells (DC) are critical for initiation of adaptive immune responses against blood-borne invaders. Key to DC function is their positioning at sites of pathogen entry, and their abilities to selectively capture foreign antigens and promptly engage T cells. Focusing on conventional DC2 (cDC2), we discuss the contribution of chemoattractant receptors (EBI2 or GPR183, S1PR1, and CCR7) and integrins to cDC2 positioning and function. We give particular attention to a newly identified role in cDC2 for adhesion G-protein coupled receptor E5 (Adgre5 or CD97) and its ligand CD55, detailing how this mechanosensing system contributes to splenic cDC2 positioning and homeostasis. Additional roles of CD97 in the immune system are reviewed. The ability of cDC2 to be activated by circulating missing self-CD47 cells and to integrate multiple red blood cell (RBC)-derived inputs is discussed. Finally, we describe the process of activated cDC2 migration to engage and prime helper T cells. Throughout the review, we consider the insights into cDC function in the spleen that have emerged from imaging studies.

Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also acts via the central nervous system to control feeding behavior. Here we review the current understanding of FGF21 as a hormone regulating feeding behavior in rodents, non-human primates, and humans. First, we examine the nutritional contexts that induce FGF21 secretion. Initial reports describing FGF21 as a 'starvation hormone' have now been further refined. FGF21 is now better understood as an endocrine mediator of the intracellular stress response to various nutritional manipulations, including excess sugars and alcohol, caloric deficits, a ketogenic diet, and amino acid restriction. We discuss FGF21's effects on energy intake and macronutrient choice, together with our current understanding of the underlying neural mechanisms. We argue that the behavioral effects of FGF21 function primarily to maintain systemic macronutrient homeostasis, and in particular to maintain an adequate supply of protein and amino acids for use by the cells.