State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis.

Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis. Glucagon-like peptide-1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within the nucleus tractus solitarius (NTS), suppresses feeding through projections to multiple brain targets1-3. Although GLP-1 analogs are proven clinically effective in treating type 2 diabetes and obesity4, the mechanisms of GLP-1 action within the brain remain unclear. Here, we investigate the involvement of GLP-1 receptor (GLP-1R) mediated signaling in a descending circuit formed by GLP-1R neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) that project to dorsal vagal complex (DVC) neurons of the brain stem in mice. PVNGLP- 1R→DVC synapses release glutamate that is augmented by GLP-1 via a presynaptic mechanism. Chemogenetic activation of PVNGLP-1R→DVC neurons suppresses feeding. The PVNGLP-1R→DVC synaptic transmission is dynamically regulated by energy states. In a state of energy deficit, synaptic strength is weaker but is more profoundly augmented by GLP-1R signaling compared to an energy-replete state. In an obese state, the dynamic synaptic strength changes in the PVNGLP-1R→DVC descending circuit are disrupted. Blocking PVNGLP-1R→DVC synaptic release or ablation of GLP-1R in the presynaptic compartment increases food intake and causes obesity, elevated blood glucose, and impaired insulin sensitivity. These findings suggest that the state-dependent synaptic plasticity in this PVNGLP-1R→DVC descending circuit mediated by GLP-1R signaling is an essential regulator of energy homeostasis.

ß-Cell Insulin Resistance Plays a Causal Role in Fat-Induced ß-Cell Dysfunction In Vitro and In Vivo.

In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in ß-cells where they play a role in ß-cell function. Therefore, inhibition of the insulin/insulin-like growth factor 1 pathway may be involved in fat-induced ß-cell dysfunction. To address the role of ß-cell insulin resistance in FFA-induced ß-cell dysfunction we co-infused bisperoxovanadate (BPV) with oleate or olive oil for 48 hours in rats. BPV, a tyrosine phosphatase inhibitor, acts as an insulin mimetic and is devoid of any antioxidant effect that could prevent ß-cell dysfunction, unlike most insulin sensitizers. Following fat infusion, rats either underwent hyperglycemic clamps for assessment of ß-cell function in vivo or islets were isolated for ex vivo assessment of glucose-stimulated insulin secretion (GSIS). We also incubated islets with oleate or palmitate and BPV for in vitro assessment of GSIS and Akt (protein kinase B) phosphorylation. Next, mice with ß-cell specific deletion of PTEN (phosphatase and tensin homolog; negative regulator of insulin signaling) and littermate controls were infused with oleate for 48 hours, followed by hyperglycemic clamps or ex vivo evaluation of GSIS. In rat experiments, BPV protected against fat-induced impairment of ß-cell function in vivo, ex vivo, and in vitro. In mice, ß-cell specific deletion of PTEN protected against oleate-induced ß-cell dysfunction in vivo and ex vivo. These data support the hypothesis that ß-cell insulin resistance plays a causal role in FFA-induced ß-cell dysfunction.

Sedentary behavior and lifespan brain health.

Higher levels of physical activity are known to benefit aspects of brain health across the lifespan. However, the role of sedentary behavior (SB) is less well understood. In this review we summarize and discuss evidence on the role of SB on brain health (including cognitive performance, structural or functional brain measures, and dementia risk) for different age groups, critically compare assessment approaches to capture SB, and offer insights into emerging opportunities to assess SB via digital technologies. Across the lifespan, specific characteristics of SB (particularly whether they are cognitively active or cognitively passive) potentially act as moderators influencing the associations between SB and specific brain health outcomes. We outline challenges and opportunities for future research aiming to provide more robust empirical evidence on these observations.

Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1-8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology.

Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.

In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution.

Introduction: The endocannabinoid (eCB) system is named after the discovery that endogenous cannabinoids bind to the same receptors as the phytochemical compounds found in Cannabis. While endogenous cannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), exogenous phytocannabinoids include Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds finely tune neurotransmission following synapse activation, via retrograde signaling that activates cannabinoid receptor 1 (CB1R) and/or transient receptor potential cation channel subfamily V member 1 (TRPV1). Recently, the eCB system has been linked to several neurological diseases, such as neuro-ocular abnormalities, pain insensitivity, migraine, epilepsy, addiction and neurodevelopmental disorders. In the current study, we aim to: (i) highlight a potential link between the eCB system and neurological disorders, (ii) assess if THC exposure alters the expression of eCB-related genes, and (iii) identify evolutionary-conserved residues in CB1R or TRPV1 in light of their function. Methods: To address this, we used several bioinformatic approaches, such as transcriptomic (Gene Expression Omnibus), protein-protein (STRING), phylogenic (BLASTP, MEGA) and structural (Phyre2, AutoDock, Vina, PyMol) analyzes. Results: Using RNA sequencing datasets, we did not observe any dysregulation of eCB-related transcripts in major depressive disorders, bipolar disorder or schizophrenia in the anterior cingulate cortex, nucleus accumbens or dorsolateral striatum. Following in vivo THC exposure in adolescent mice, GPR55 was significantly upregulated in neurons from the ventral tegmental area, while other transcripts involved in the eCB system were not affected by THC exposure. Our results also suggest that THC likely induces neuroinflammation following in vitro application on mice microglia. Significant downregulation of TPRV1 occurred in the hippocampi of mice in which a model of temporal lobe epilepsy was induced, confirming previous observations. In addition, several transcriptomic dysregulations were observed in neurons of both epileptic mice and humans, which included transcripts involved in neuronal death. When scanning known interactions for transcripts involved in the eCB system (n = 12), we observed branching between the eCB system and neurophysiology, including proteins involved in the dopaminergic system. Our protein phylogenic analyzes revealed that CB1R forms a clade with CB2R, which is distinct from related paralogues such as sphingosine-1-phosphate, receptors, lysophosphatidic acid receptors and melanocortin receptors. As expected, several conserved residues were identified, which are crucial for CB1R receptor function. The anandamide-binding pocket seems to have appeared later in evolution. Similar results were observed for TRPV1, with conserved residues involved in receptor activation. Conclusion: The current study found that GPR55 is upregulated in neurons following THC exposure, while TRPV1 is downregulated in temporal lobe epilepsy. Caution is advised when interpreting the present results, as we have employed secondary analyzes. Common ancestors for CB1R and TRPV1 diverged from jawless vertebrates during the late Ordovician, 450 million years ago. Conserved residues are identified, which mediate crucial receptor functions.

Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE) 1-8 . However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific in vivo CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY + p300 + memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY + p300 + astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes in vitro ; scRNA-seq and immunohistochemistry studies detected increased ACLY + p300 + astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.

Crosstalk between GABAA receptors in astrocytes and neurons triggered by general anesthetic drugs.

General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABAA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABAA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABAA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABAA receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1ß and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1ß and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABAA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary BACKGROUND: Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABAA receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. TRANSLATIONAL SIGNIFICANCE: We discovered that commonly used general anesthetic drugs stimulate GABAA receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABAA receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery.

Immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells survive long term in allogeneic hosts.

The immunogenicity of transplanted allogeneic cells and tissues is a major hurdle to the advancement of cell therapies. Here we show that the overexpression of eight immunomodulatory transgenes (Pdl1, Cd200, Cd47, H2-M3, Fasl, Serpinb9, Ccl21 and Mfge8) in mouse embryonic stem cells (mESCs) is sufficient to immunologically 'cloak' the cells as well as tissues derived from them, allowing their survival for months in outbred and allogeneic inbred recipients. Overexpression of the human orthologues of these genes in human ESCs abolished the activation of allogeneic human peripheral blood mononuclear cells and their inflammatory responses. Moreover, by using the previously reported FailSafe transgene system, which transcriptionally links a gene essential for cell division with an inducible and cell-proliferation-dependent kill switch, we generated cloaked tissues from mESCs that served as immune-privileged subcutaneous sites that protected uncloaked allogeneic and xenogeneic cells from rejection in immune-competent hosts. The combination of cloaking and FailSafe technologies may allow for the generation of safe and allogeneically accepted cell lines and off-the-shelf cell products.

Postpartum defects in inflammatory response after gestational diabetes precede progression to type 2 diabetes: a nested case-control study within the SWIFT study.

BACKGROUND: Gestational diabetes (GDM) is a distinctive form of diabetes that first presents in pregnancy. While most women return to normoglycemia after delivery, they are nearly ten times more likely to develop type 2 diabetes than women with uncomplicated pregnancies. Current prevention strategies remain limited due to our incomplete understanding of the early underpinnings of progression. AIM: To comprehensively characterize the postpartum profiles of women shortly after a GDM pregnancy and identify key mechanisms responsible for the progression to overt type 2 diabetes using multi-dimensional approaches. METHODS: We conducted a nested case-control study of 200 women from the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy (SWIFT) to examine biochemical, proteomic, metabolomic, and lipidomic profiles at 6-9 weeks postpartum (baseline) after a GDM pregnancy. At baseline and annually up to two years, SWIFT administered research 2-hour 75-gram oral glucose tolerance tests. Women who developed incident type 2 diabetes within four years of delivery (incident case group, n = 100) were pair-matched by age, race, and pre-pregnancy body mass index to those who remained free of diabetes for at least 8 years (control group, n = 100). Correlation analyses were used to assess and integrate relationships across profiling platforms. RESULTS: At baseline, all 200 women were free of diabetes. The case group was more likely to present with dysglycemia (e.g., impaired fasting glucose levels, glucose tolerance, or both). We also detected differences between groups across all omic platforms. Notably, protein profiles revealed an underlying inflammatory response with perturbations in protease inhibitors, coagulation components, extracellular matrix components, and lipoproteins, whereas metabolite and lipid profiles implicated disturbances in amino acids and triglycerides at individual and class levels with future progression. We identified significant correlations between profile features and fasting plasma insulin levels, but not with fasting glucose levels. Additionally, specific cross-omic relationships, particularly among proteins and lipids, were accentuated or activated in the case group but not the control group. CONCLUSIONS: Overall, we applied orthogonal, complementary profiling techniques to uncover an inflammatory response linked to elevated triglyceride levels shortly after a GDM pregnancy, which is more pronounced in women who progress to overt diabetes.

Type 2 Diabetes Mellitus and Sarcopenia as Comorbid Chronic Diseases in Older Adults: Established and Emerging Treatments and Therapies.

Type 2 diabetes mellitus (T2DM) and sarcopenia (low skeletal muscle mass and function) share a bidirectional relationship. The prevalence of these diseases increases with age and they share common risk factors. Skeletal muscle fat infiltration, commonly referred to as myosteatosis, may be a major contributor to both T2DM and sarcopenia in older adults via independent effects on insulin resistance and muscle health. Many strategies to manage T2DM result in energy restriction and subsequent weight loss, and this can lead to significant declines in muscle mass in the absence of resistance exercise, which is also a first-line treatment for sarcopenia. In this review, we highlight recent evidence on established treatments and emerging therapies targeting weight loss and muscle mass and function improvements in older adults with, or at risk of, T2DM and/or sarcopenia. This includes dietary, physical activity and exercise interventions, new generation incretin-based agonists and myostatin-based antagonists, and endoscopic bariatric therapies. We also highlight how digital health technologies and health literacy interventions can increase uptake of, and adherence to, established and emerging treatments and therapies in older adults with T2DM and/or sarcopenia.

Astrocytes on steroids binge on synapses to cope with stress.

Many mechanisms by which stress mediates its effects within the central nervous system still remain unknown. Byun, Kim, Kim et al. find that early-life stress triggers corticosterone release to drive astrocyte-dependent synapse elimination and altered behavior. Thus, this work defines a steroid-sensitive astrocyte transcriptional circuit controlling behavior, highlighting how the study of CNS immunoregulation may shed light on behavior.

metGWAS 1.0: an R workflow for network-driven over-representation analysis between independent metabolomic and meta-genome-wide association studies.

MOTIVATION: The method of genome-wide association studies (GWAS) and metabolomics combined provide an quantitative approach to pinpoint metabolic pathways and genes linked to specific diseases; however, such analyses require both genomics and metabolomics datasets from the same individuals/samples. In most cases, this approach is not feasible due to high costs, lack of technical infrastructure, unavailability of samples, and other factors. Therefore, an unmet need exists for a bioinformatics tool that can identify gene loci-associated polymorphic variants for metabolite alterations seen in disease states using standalone metabolomics. RESULTS: Here, we developed a bioinformatics tool, metGWAS 1.0, that integrates independent GWAS data from the GWAS database and standalone metabolomics data using a network-based systems biology approach to identify novel disease/trait-specific metabolite-gene associations. The tool was evaluated using standalone metabolomics datasets extracted from two metabolomics-GWAS case studies. It discovered both the observed and novel gene loci with known single nucleotide polymorphisms when compared to the original studies. AVAILABILITY AND IMPLEMENTATION: The developed metGWAS 1.0 framework is implemented in an R pipeline and available at: https://github.com/saifurbd28/metGWAS-1.0.

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

Heterogeneity in Early Postpartum Metabolic Profiles Among Women with GDM Who Progressed to Type 2 Diabetes During 10-Year Follow-Up: The SWIFT Study.

GDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum profiles of women with recent GDM who later developed incident T2D using a soft clustering method, followed by the integration of both clinical phenotypic variables and metabolomics to characterize these heterogeneous clusters/groups clinically and their molecular mechanisms. We identified three clusters based on two indices of glucose homeostasis at 6-9 weeks postpartum - HOMA-IR and HOMA-B among women who developed incident T2D during the 12-year follow-up. The clusters were classified as follows: pancreatic beta-cell dysfunction group (cluster-1), insulin resistant group (cluster-3), and a combination of both phenomena (cluster-2) comprising the majority of T2D. We also identified postnatal blood test parameters to distinguish the three clusters for clinical testing. Moreover, we compared these three clusters in their metabolomics profiles at the early stage of the disease to identify the mechanistic insights. A significantly higher concentration of a metabolite at the early stage of a T2D cluster than other clusters indicates its essentiality for the particular disease character. As such, the early-stage characters of T2D cluster-1 pathology include a higher concentration of sphingolipids, acyl-alkyl phosphatidylcholines, lysophosphatidylcholines, and glycine, indicating their essentiality for pancreatic beta-cell function. In contrast, the early-stage characteristics of T2D cluster-3 pathology include a higher concentration of diacyl phosphatidylcholines, acyl-carnitines, isoleucine, and glutamate, indicating their essentiality for insulin actions. Notably, all these biomolecules are found in the T2D cluster-2 with mediocre concentrations, indicating a true nature of a mixed group. In conclusion, we have deconstructed incident T2D heterogeneity and identified three clusters with their clinical testing procedures and molecular mechanisms. This information will aid in adopting proper interventions using a precision medicine approach.

Aircraft and satellite observations reveal historical gap between top-down and bottom-up CO2 emissions from Canadian oil sands.

Measurement-based estimates of greenhouse gas (GHG) emissions from complex industrial operations are challenging to obtain, but serve as an important, independent check on inventory-reported emissions. Such top-down estimates, while important for oil and gas (O&G) emissions globally, are particularly relevant for Canadian oil sands (OS) operations, which represent the largest O&G contributor to national GHG emissions. We present a multifaceted top-down approach for estimating CO2 emissions that combines aircraft-measured CO2/NOx emission ratios (ERs) with inventory and satellite-derived NOx emissions from Ozone Monitoring Instrument (OMI) and TROPOspheric Ozone Monitoring Instrument (TROPOMI) and apply it to the Athabasca Oil Sands Region (AOSR) in Alberta, Canada. Historical CO2 emissions were reconstructed for the surface mining region, and average top-down estimates were found to be >65% higher than facility-reported, bottom-up estimates from 2005 to 2020. Higher top-down vs. bottom-up emissions estimates were also consistently obtained for individual surface mining and in situ extraction facilities, which represent a growing category of energy-intensive OS operations. Although the magnitudes of the measured discrepancies vary between facilities, they combine such that the observed reporting gap for total AOSR emissions is ≥(31 ± 8) Mt for each of the last 3 years (2018-2020). This potential underestimation is large and broadly highlights the importance of continued review and refinement of bottom-up estimation methodologies and inventories. The ER method herein offers a powerful approach for upscaling measured facility-level or regional fossil fuel CO2 emissions by taking advantage of satellite remote sensing observations.

A newly developed Lagrangian chemical transport scheme: Part 1. Simulation of a boreal forest fire plume.

Forest fire research over the last several decades has improved the understanding of fire emissions and impacts. Nevertheless, the evolution of forest fire plumes remains poorly quantified and understood. Here, a Lagrangian chemical transport model, the Forward Atmospheric Stochastic Transport model coupled with the Master Chemical Mechanism (FAST-MCM), has been developed to simulate the transport and chemical transformations of plumes from a boreal forest fire over several hours since their emission. The model results for NOx (NO and NO2), O3, HONO, HNO3, pNO3 and 70 VOC species are compared with airborne in-situ measurements within plume centers and their surrounding portions during the transport. Comparisons between simulation results and measurements show that the FAST-MCM model can properly reproduce the physical and chemical evolution of forest fire plumes. The results indicate that the model can be an important tool used to aid the understanding of the downwind impacts of forest fire plumes.

Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets.