Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology.

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility.

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.

Appraisal and coping predict health and well-being during the COVID-19 pandemic: An international approach.

COVID-19 has had a devastating impact on people worldwide. We conducted an international survey (n = 3646) examining the degree to which people's appraisals and coping activities around the pandemic predicted their health and well-being. We obtained subsamples from 12 countries-Bangladesh, Bulgaria, China, Colombia, India, Israel, the Netherlands, Norway, Peru, Portugal, Turkey and the United States. For each, we assessed appraisals and coping strategies as well as indicators of physical and mental health and well-being. Results indicated that, despite mean-level societal differences in outcomes, the pattern of appraisals and coping strategies predicting health and well-being was consistent across countries. Use of disengagement coping (particularly behavioural disengagement and self-isolation) was associated with relatively negative outcomes. In contrast, optimistic appraisals (particularly of high accommodation-focused coping potential and the ability to meet one's physical needs), use of problem-focused coping strategies (especially problem-solving) and accommodative coping strategies (especially positive reappraisal and self-encouragement) were associated with relatively positive outcomes. Our study highlights the critical importance of considering accommodative coping in stress and coping research. It also provides important information on how people have been dealing with the pandemic, the predictors of well-being under pandemic conditions and the generality of such relations.

Crossing boundaries: Interplay between the immune system and oligodendrocyte lineage cells.

Oligodendrocytes and their progenitors are glial cells in the central nervous system, which have been mainly implicated with the homeostatic roles of axonal myelin ensheathment but serve as targets of the peripheral immune system attack in the context of diseases like multiple sclerosis. This view of oligodendroglia as passive bystanders with no immunological properties was first challenged in the 1980s when it was reported that the cytokine interferon γ could induce the gene expression of the major histocompatibility complexes (MHC) class I and II. While the physiological role of this induction was controversial for decades to follow, recent studies suggest that oligodendroglia survey their environment, respond to a larger array of cues and can indeed exert immunomodulatory functions, which are particularly relevant in the context of neurodegeneration and demyelinating diseases. The alternative functionality of oligodendroglia not only regulates immune cell responses, but also hinders remyelination, and might thereby be key to understanding MS disease pathology and promoting regeneration after immune-mediated demyelination.

Profiles of appraisal, motivation, and coping for positive emotions.

We used a retrospective survey (N = 346) to model the patterns of appraisal, motivation, and coping that uniquely correspond with 12 positive emotions (affection/love, amusement, awe, challenge/determination, compassion, gratitude, happiness/joy, hope, interest, pride, relief, and serenity/tranquillity). Generally, we conceptually replicated previously demonstrated appraisal profiles of positive emotion while also examining how additional appraisals differentiate among positive emotions. We then uncovered the motivational goals and coping processes associated with each positive emotion. We discuss the implications of our findings for future research on positive emotion.

Quetiapine has an additive effect to triiodothyronine in inducing differentiation of oligodendrocyte precursor cells through induction of cholesterol biosynthesis.

Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors, oligodendrocyte precursor cells (OPCs), have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a mechanism for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS.

Glutamine antagonism attenuates physical and cognitive deficits in a model of MS.

OBJECTIVE: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: Splenic-derived T cells and bone marrow-derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test. RESULTS: JHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment. CONCLUSIONS: JHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS.

Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination.

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.

Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning.

Efficient oligodendrogenesis is the therapeutic goal of a number of areas of research including spinal cord injury, neonatal hypoxia, and demyelinating diseases such as multiple sclerosis and transverse myelitis. Myelination is required to not only facilitate rapid impulse propagation within the central nervous system, but also to provide trophic support to underlying axons. Oligodendrocyte progenitor cells (OPCs) can be studied in vitro to help identify factors that may promote or inhibit oligodendrocyte differentiation. To date, many of the methods available to evaluate this process have either required large numbers of cells, thus limiting the number of conditions that can be investigated at any one time, or labor-intensive methods of quantification. Herein, we describe a protocol for the isolation of large numbers of highly pure OPCs together with a fast and reliable method to determine oligodendrogenesis from multiple conditions simultaneously. OPCs are isolated from P5-P7 neonatal rat cortices and grown in vitro for three days prior to differentiation. Four days after differentiation, oligodendrogenesis is evaluated using a dual-infrared fluorescence-scanning assay to determine expression of the myelin protein.

Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination.

Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1) and IL-17A-producing (TH17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice.

Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4(+) T cells. Characterization of this model reveals both Th1 and Th17 CD4(+) T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.

A selective thyroid hormone ß receptor agonist enhances human and rodent oligodendrocyte differentiation.

Nerve conduction within the mammalian central nervous system is made efficient by oligodendrocyte-derived myelin. Historically, thyroid hormones have a well described role in regulating oligodendrocyte differentiation and myelination during development; however, it remains unclear which thyroid hormone receptors are required to drive these effects. This is a question with clinical relevance since nonspecific thyroid receptor stimulation can produce deleterious side-effects. Here we report that GC-1, a thyromimetic with selective thyroid receptor ß action and a potentially limited side-effect profile, promotes in vitro oligodendrogenesis from both rodent and human oligodendrocyte progenitor cells. In addition, we used in vivo genetic fate tracing of oligodendrocyte progenitor cells via PDGFαR-CreER;Rosa26-eYFP double-transgenic mice to examine the effect of GC-1 on cellular fate and find that treatment with GC-1 during developmental myelination promotes oligodendrogenesis within the corpus callosum, occipital cortex and optic nerve. GC-1 was also observed to enhance the expression of the myelin proteins MBP, CNP and MAG within the same regions. These results indicate that a ß receptor selective thyromimetic can enhance oligodendrocyte differentiation in vitro and during developmental myelination in vivo and warrants further study as a therapeutic agent for demyelinating models.

IFN-γ-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling.

Engraftment of human embryonic stem cell (hESC)-derived OPCs in animal models of demyelination results in remyelination and clinical recovery, supporting the feasibility of cell replacement therapies in promoting repair of damaged neural tissue. A critical gap in our understanding of the mechanisms associated with repair revolves around the effects of the local microenvironment on transplanted cell survival. We have determined that treatment of human ESC-derived OPCs with the pleiotropic cytokine IFN-γ promotes apoptosis that is associated with mitochondrial cytochrome c released into the cytosol with subsequent caspase 3 activation. IFN-γ-induced apoptosis is mediated, in part, by secretion of the CXC chemokine ligand 10 (CXCL10) from IFN-γ-treated cells. Signaling through the chemokine receptor CXCR2 by the ligand CXCL1 functions in a tonic manner by muting apoptosis and this is associated with reduced levels of cytosolic cytochrome c and impaired cleavage of caspase 3. These findings support a role for both IFN-γ and CXCL10 in contributing to neuropathology by promoting OPC apoptosis. In addition, these data suggest that hOPCs used for therapeutic treatment for human neurologic disease/damage are susceptible to death through exposure to local inflammatory cytokines present within the inflammatory milieu.

Glycogen synthase kinase 3 (GSK3) inhibitor, SB-216763, promotes pluripotency in mouse embryonic stem cells.

Canonical Wnt/ß-catenin signaling has been suggested to promote self-renewal of pluripotent mouse and human embryonic stem cells. Here, we show that SB-216763, a glycogen synthase kinase-3 (GSK3) inhibitor, can maintain mouse embryonic stem cells (mESCs) in a pluripotent state in the absence of exogenous leukemia inhibitory factor (LIF) when cultured on mouse embryonic fibroblasts (MEFs). MESCs maintained with SB-216763 for one month were morphologically indistinguishable from LIF-treated mESCs and expressed pluripotent-specific genes Oct4, Sox2, and Nanog. Furthermore, Nanog immunostaining was more homogenous in SB-216763-treated colonies compared to LIF. Embryoid bodies (EBs) prepared from these mESCs expressed early-stage markers for all three germ layers, and could efficiently differentiate into cardiac-like cells and MAP2-immunoreactive neurons. To our knowledge, SB-216763 is the first GSK3 inhibitor that can promote self-renewal of mESC co-cultured with MEFs for more than two months.

Racial disparities in the treatment of depression in low-income persons with diabetes.

OBJECTIVE: Individuals with diabetes are at higher risk for depression than the general population. Although depression can be treated with antidepressant medications, patients with diabetes and comorbid depression often go untreated. The goal of this study was to examine racial disparities in the treatment of depression with antidepressant medication in the southeastern U.S. RESEARCH DESIGN AND METHODS: Cross-sectional data were collected at baseline from 69,068 participants (71% African American, 60% female, and 82% with incomes <$25,000) recruited from community health centers and enrolled in the Southern Cohort Community Study (SCCS). The SCCS is a prospective epidemiological cohort study designed to explore causes of health disparities in adults aged 40-79 years. Binary logistic regression was used to identify factors associated with antidepressant use among those with diabetes (n = 14,279). RESULTS: Individuals with diagnosed diabetes (14,279) were classified with no depressive symptoms (54.7%), or with mild (24.2%), moderate (12.8%), or severe depressive symptoms (8.3%). After controlling for sex, age, insurance, income, education, BMI, smoking status, alcohol consumption, and level of depression, African Americans with diabetes were much less likely to report taking antidepressant medication than whites (adjusted odds ratio 0.32 [95% CI 0.29-0.35], P < 0.0001). CONCLUSIONS: Antidepressant use is much less common among African Americans than among whites with diabetes. Reasons for racial disparities in treatment of depressive symptoms are unclear but may include a combination of differential diagnosis and treatment by health professionals as well as cultural differences in seeking help for emotional distress.

Registered nurses' perceptions of nursing.

In Part II of this six part series on the state of the registered nurse (RN) workforce in the United States, the focus is on RNs' perceptions of nursing including RNs' satisfaction with their jobs in general and on specific elements of their work experiences, such as the quality of professional relationships. Satisfaction with a nursing career and whether RNs would recommend nursing to others are also examined. The improvements in nursing found in this analysis of two national surveys in 2002 and 2004 should be broadly communicated not only to energize individuals and organizations to continue their efforts to improve the workplace environment, but to challenge the many individuals in the nursing profession who hold onto a sense that nothing will ever improve in their organizations.

Appraisal as a pervasive determinant of anger.

L. Berkowitz and E. Harmon-Jones (2004) challenge appraisal theories of emotion by describing 2 sets of conditions (physical discomfort and anger-related muscle actions) in which anger appears to be elicited in the absence of theoretically predicted appraisals. In response, the authors discuss the ability of the specific appraisal model they have developed (e.g., C. A. Smith & L. D. Kirby, 2000, 2001; C. A. Smith & R. S. Lazarus, 1990) to account for such instances of anger. First, a number of issues are clarified relevant to the authors' model, including the nature of both the cognitive operations underlying appraisal and the specific appraisals hypothesized to evoke anger. The authors then describe how their model can account for the instances of anger described by L. Berkowitz and E. Harmon-Jones and how both accounts might be tested.

Cardiovascular correlates of challenge and threat appraisals: a critical examination of the biopsychosocial analysis.

In this article we examine critically the biopsychosocial (BPS) challenge versus threat analysis proposed by Blascovich and his coworkers. We conclude that the BPS analysis should be viewed with considerable caution. We conclude this in part because the analysis is associated with notable problems, including (a) its conception of demand, (b) its definitions of goal-relevant and evaluative situations, (c) its assertion regarding primary and secondary appraisal determinants of challenge and threat, and (d) its cardiovascular (CV) predictions. We conclude this as well because BPS analysis studies have not made a compelling empirical case. BPS analysis studies are unpersuasive because (a) their CV results are only partially consistent with BPS analysis predictions, (b) they have compared CV responses of groups bearing an uncertain relationship to the primary and secondary appraisal criteria specified for the production of challenge and threat effects, (c) they have not compared challenge and threat appraisals between challenge and threat groups, and (d) they provided data that are incomplete. Theoretical modifications and additional research could make a better case for the BPS view.