Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

Association of insulin resistance with polycystic ovary syndrome phenotypes and patients' characteristics: a cross-sectional study in Iran.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. This disorder affects 6-15% of women of childbearing age worldwide. It is diagnosed with hyperandrogenism, polycystic ovaries, and chronic anovulation with insulin resistance. This study aimed to assess the prevalence of insulin resistance (IR) in 4 phenotypes of PCOS, and its relationship with demographic, clinical, and paraclinical individual characteristics in a sample of Iranian PCOS patients. METHODS: This particular cross-sectional investigation involved 160 female participants, aged between 18 and 45 years, who were receiving care at gynecology clinics in Urmia, northwestern Iran. All the participants had been diagnosed with PCOS and were categorized into one of four phenotypes. All the participants underwent clinical evaluations, paraclinical assessments, and ultrasound scans. IR was defined as HOMA-IR > 2.5. The statistical significance level was 0.05. RESULTS: Among the 160 participants, the prevalences of the 4 phenotypes were: A: 83 (51.9%), B: 37 (23.1%), C: 21 (13.1%), and D: 19 (11.9%). IR was detected in 119 participants (74.4%); its rate was significantly different between the 4 phenotypes (p-value: 0.008) as A: 62 (74.7%), B: 34 (91.9%), C: 12 (57.1%), D: 11 (57.9%). Linear and logistic regression analyses were performed to control confounding factors. In linear regression, PCOS phenotype, classic phenotype (A&B), economic status, and Hb levels were significantly related to HOMA-IR; in logistic regression Hb levels, exercise, economic status, and PCOS phenotypes were significantly associated with insulin resistance. CONCLUSIONS: The most prevalent PCOS phenotype in this study was A. PCOS phenotypes were significantly related to insulin resistance and HOMA-IR, with the highest levels of insulin resistance and HOMA-IR observed in phenotype B. Determining the phenotype of PCOS may be helpful for better management of PCOS and its associated complications. However, further investigations are recommended in this regard.

IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R-/- mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R-/- mice correlates with increased numbers of GM-CSF+ CD4+ T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R-/- mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4+ T cells through the modulation of DCs.

Predictors of retirement satisfaction in the older adults of Urmia: a cross-sectional study.

BACKGROUND: Retirement is a challenge that, as a process, influences the individual's role, status, life patterns, expectations, and available resources. Therefore, the present study aims at determining the predictors of retirement satisfaction among men in the city of Urmia. METHODS: In this descriptive-analytical study, 140 retired men living in Urmia were selected by multi-stage sampling method. The instruments used are the Retirement Satisfaction Scale, life satisfaction, and quality of life questionnaires. Data were analyzed in SPSS v.21 using descriptive statistics, one-way ANOVA, and regression at a significance level of p ≤ 0.05. RESULTS: Based on the results of this study, the mean score of retirement satisfaction was 115.37 + 10.13 and there was no significant difference (p = .068) in retirement satisfaction of the retired men based on level of education. Also, the retrospective multiple linear regression model indicated that 44.4% of the variance of retirement satisfaction score is predicted by two subscales of life satisfaction and quality of life. CONCLUSION: According to the results, it seems that life satisfaction and quality of life are inseparable, effective factors in retirement satisfaction, so, to promote retirement satisfaction in all of its scales and subscales, it is recommended to improve these two factors.

Efficacy of triamcinolone acetonide-impregnated Gelfoam nasal pack in management of chronic sinusitis with nasal polyps following endoscopic sinus surgery: a perfectly matched, placebo-controlled trial study.

PURPOSE: This perfectly matched, double-blinded, placebo-controlled trial study was performed to investigate the efficacy of triamcinolone acetonide (TAA)-impregnated Gelfoam nasal pack in management of different endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) following endoscopic sinus surgery (ESS). METHODS: One hundred and four patients with bilateral CRSwNP undergoing ESS were selected and randomized to receive TAA-soaked nasal packing in one nostril and saline-impregnated dressing contra-laterally. Validated Perioperative Sinus Endoscopy (POSE) scoring system was used to assess the participants' condition at postoperative months 1, 3, 6, 12, and 18. RESULTS: The treatment side of eosinophilic CRSwNP (EosCRSwNP) group had significantly better endoscopic scores than the contralateral control side in all follow-up visits (P < 0.05 for all comparisons) except for the first postoperative month. No significant difference was detected between the TAA- and saline-treated nostrils in the non-eosinophilic CRSwNP (nonEosCRSwNP) subgroup during the follow-up period. Intergroup comparisons revealed a borderline better POSE score for the treatment side of the EosCRSwNP group compared with the treatment nostril of the nonEosCRSwNP group at months 12 (P = 0.041) and 18 (P = 0.044). At the end of the study period, the treatment side of the EosCRSwNP group demonstrated better clinical response than the saline-treated side in terms of the total POSE scores (P = 0.019), middle turbinate synechia (P = 0.008), middle meatal narrowing (P = 0.010), ethmoid polypoid changes (P = 0.039), ethmoid polyposis (P = 0.027), ethmoid cavity secretions (P = 0.042), and sphenoid severity (P = 0.018). CONCLUSION: TAA-soaked Gelfoam dressing following bilateral ESS was found to be an effective method for treating CRSwNP particularly for the eosinophilic endotype of the disease.

Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model.

Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4+ T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.

Chloroquine-treated dendritic cells require STAT1 signaling for their tolerogenic activity.

MS and EAE are T cell-driven autoimmune diseases of the CNS where IL-17-producing Th17 cells promote damage and are pathogenic. Conversely, tolerogenic DCs induce Treg cells and suppress Th17 cells. Chloroquine (CQ) suppresses EAE through the modulation of DCs by unknown mechanisms. Here, we show that STAT 1 is necessary for CQ-induced tolerogenic DCs (tolDCs) to efficiently suppress EAE. We observed that CQ induces phosphorylation of STAT1 in DCs in vivo and in vitro. Genetic blockage of STAT1 abrogated the suppressive activity of CQ-treated DCs. Opposed to its WT counterparts, CQ-treated STAT1-/- BMDCs were unable to suppress Th17 cells and increased EAE severity. Our findings show that STAT1 is a major signaling pathway in CQ-induced tolDCs and may shed light on new therapeutic avenues for the induction of tolDCs in autoimmune diseases such as MS.

miR-23b Suppresses Leukocyte Migration and Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting CCL7.

MicroRNAs (miRNAs) are small, non-coding RNAs involved in immune response regulation. Specific miRNAs have been linked to the development of various autoimmune diseases; however, their contribution to the modulation of CNS-directed cellular infiltration remains unclear. In this study, we found that miR-23b, in addition to its reported functions in the suppression of IL-17-associated autoimmune inflammation, halted the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by directly inhibiting the migration of pathogenic leukocytes to the CNS. We demonstrated that miR-23b was specifically decreased during the acute phase of EAE and that overexpression of miR-23b resulted in a defect in leukocyte migration and strong resistance to EAE. Furthermore, we found that miR-23b suppressed leukocyte migration of EAE by targeting CCL7, a chemokine that attracts monocytes during inflammation and metastasis. Finally, in the adoptive transfer model, miR-23b reduced the severity of EAE by inhibiting the migration of pathogenic T cells to the CNS rather than diminishing the encephalitogenesis of T cells. Taken together, our results characterize a novel aspect of miR-23b function in leukocyte migration, and they identify miR-23b as a potential therapeutic target in the amelioration of MS and likely other autoimmune diseases.

Galectin-1 is essential for the induction of MOG35-55 -based intravenous tolerance in experimental autoimmune encephalomyelitis.

In experimental autoimmune encephalomyelitis (EAE), intravenous (i.v.) injection of the antigen, myelin oligodendrocyte glycoprotein-derived peptide, MOG35-55 , suppresses disease development, a phenomenon called i.v. tolerance. Galectin-1, an endogenous glycan-binding protein, is upregulated during autoimmune neuroinflammation and plays immunoregulatory roles by inducing tolerogenic dendritic cells (DCs) and IL-10 producing regulatory type 1 T (Tr1) cells. To examine the role of galectin-1 in i.v. tolerance, we administered MOG35-55 -i.v. to wild-type (WT) and galectin-1 deficient (Lgals1(-/-) ) mice with ongoing EAE. MOG35-55 suppressed disease in the WT, but not in the Lgals1(-/-) mice. The numbers of Tr1 cells and Treg cells were increased in the CNS and periphery of tolerized WT mice. In contrast, Lgals1(-/-) MOG-i.v. mice had reduced numbers of Tr1 cells and Treg cells in the CNS and periphery, and reduced IL-27, IL-10, and TGF-ß1 expression in DCs in the periphery. DCs derived from i.v.-tolerized WT mice suppressed disease when adoptively transferred into mice with ongoing EAE, whereas DCs from Lgals1(-/-) MOG-i.v. mice were not suppressive. These findings demonstrate that galectin-1 is required for i.v. tolerance induction, likely via induction of tolerogenic DCs leading to enhanced development of Tr1 cells, Treg cells, and downregulation of proinflammatory responses.

1,25-Dihydroxyvitamin D3 suppressed experimental autoimmune encephalomyelitis through both immunomodulation and oligodendrocyte maturation.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has recently been found to have the anti-inflammatory potential to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, its direct effect on neural cells is not clear. In the current study we show that 1,25(OH)2D3 treatment effectively suppressed clinical signs of ongoing EAE and reduced inflammation and demyelination scores in the central nervous system (CNS). The treatment significantly decreased production/expression of pro-inflammatory cytokines IFN-γ, GM-CSF and IL-17A, while it increased anti-inflammatory cytokines IL-4 and IL-10. Further, 1,25(OH)2D3 treatment effectively elevated the numbers of neural stem cells, oligodendrocyte precursor cells, as well as oligodendrocytes in disease lesions in the CNS. These results, together with its in vitro effect of inducing oligodendrocyte differentiation as shown in our previous findings, demonstrate that 1,25(OH)2D3 suppressed EAE not only by its immunomodulatory capacity, but also by its effect on oligodendrocyte differentiation and maturation, and thus has potential for remyelination and neural repair.

Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-ß Therapy.

Multiple sclerosis (MS) is an autoimmune disease of the CNS. Studies in animal models of MS have shown that GM-CSF produced by T cells is necessary for the development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients and to determine the effect of IFN-ß therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-ß were characterized in samples of untreated and IFN-ß-treated MS patients versus healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF(+)CD4(+) and CD8(+) T cells in PB compared with healthy controls and IFN-ß-treated MS patients. IFN-ß significantly suppressed GM-CSF production by T cells in vitro. A number of CD4(+) and CD8(+) T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-ß therapy, namely suppression of GM-CSF production.

1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has recently been found to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although its effect was attributed to an anti-inflammatory mechanism, it is not clear whether this treatment can also directly act on neural cells to promote CNS recovery. The present study investigates the effect of various concentrations of 1,25(OH)2D3 on neural stem cell (NSC) proliferation and their differentiation to oligodendrocytes, the myelinating cells. We have, for the first time, shown that NSCs constitutively express vitamin D receptor (VDR), which can be upregulated by 1,25(OH)2D3. This vitamin significantly enhanced proliferation of NSCs, and enhanced their differentiation into neurons and oligodendrocytes, but not astrocytes. NSCs treated with 1,25(OH)2D3 showed increased expression of NT-3, BDNF, GDNF and CNTF, important neurotrophic factors for neural cell survival and differentiation. Overall, we demonstrated that 1,25(OH)2D3 has a direct effect on NSC proliferation, survival, and neuron/oligodendrocyte differentiation, thus representing a novel mechanism underlying its remyelinating and neuroprotective effect in MS/EAE therapy.

Energy and macronutrient intakes in older urban and rural Iranian adults.

Adequacy of energy and macronutrient intakes is important for disease prevention, health maintenance and nutrition program development in older adults. The present study was designed to evaluate and compare the adequacy of energy and macronutrient intakes of elderly living in rural and urban areas in the north-west of Iran. A total of 432 older adults (332 urban and 100 rural) were selected through stratified, multistage probability cluster sampling. Dietetic information was obtained through three-day 24-hour dietary recall interviews. A small proportion of the subjects (4% rural and 0.6% urban) were underweight while approximately half was either overweight or obese. Aged subjects from the urban had a significantly higher mean body mass index (BMI) (t=3.46, p<0.05) than their rural counterparts. There was also significant greater proportion of elderly subjects who were overweight or obese (X2=14.42, p<0.05). Older adults from the rural had significant more daily energy (t=3.49, p<0.05), carbohydrates (t=2.96, p<0.05) and fat intakes (t=3.15, p<0.05) than their urban counterparts. Generally, average daily intake of energy was lower than the Recommended Dietary Allowance (RDA) in developing countries. High contribution of carbohydrates and low contribution of proteins to total calory intake were observed in the daily diet of the elderly. There is a need to offer health and nutrition awareness programs for the elderly and their families by health care providers.

The impact of teach-back training method (TBTM) on treatment adherence in hemodialysis patients: a randomized controlled trial.

Introduction: Ensuring adherence to treatment is vital for individuals undergoing haemodialysis. The demanding treatment frequency and duration often present challenges for patients in maintaining a consistent routine. Non-adherence can result in adverse health effects and an increased risk of hospitalization. This study aimed to evaluate the impact of teach-back training on treatment adherence among haemodialysis patients. Method: A randomized controlled trial involved 60 end-stage kidney disease patients undergoing haemodialysis. Participants were randomly assigned to either the control or intervention group. Data were collected using the End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ), assessing adherence in four dimensions: HD incidence, medication use, fluid restriction, and diet recommendations. The intervention group received feedback-based training on diet and fluid restriction during four 45-60-min sessions, while the control group received regular indoor training. Result: Following the intervention, significant differences in mean scores for HD frequency, medication use, and fluid restriction were observed between the two groups (P<0.001). However, there was no significant difference in the mean score for food recommendations (P=0.108). Conclusion: The teach-back training method (TBTM) is an effective communication strategy that enhances treatment adherence in haemodialysis patients. This intervention has the potential to improve patient outcomes and overall quality of life by simplifying medical information and encouraging patient engagement.

Comparing Geant4 physics models for proton-induced dose deposition and radiolysis enhancement from a gold nanoparticle.

Gold nanoparticles (GNPs) are materials that make the tumor cells more radiosensitive when irradiated with ionizing radiation. The present study aimed to evaluate the impact of different physical interaction models on the dose calculations and radiochemical results around the GNP. By applying the Geant4 Monte Carlo (MC) toolkit, a single 50-nm GNP was simulated, which was immersed in a water phantom and irradiated with 5, 50, and 150 MeV proton beams. The present work assessed various parameters including the secondary electron spectra, secondary photon spectra, radial dose distribution (RDD), dose enhancement factor (DEF), and radiochemical yields around the GNP. The results with an acceptable statistical uncertainty of less than 1% indicated that low-energy electrons deriving from the ionization process formed a significant part of the total number of secondary particles generated in the presence of GNP; the Penelope model produced a larger number of these electrons by a factor of about 30%. Discrepancies of the secondary electron spectrum between Livermore and Penelope were more obvious at energies of less than 1 keV and reached the factor of about 30% at energies between 250 eV and 1 keV. The RDDs for Livermore and Penelope models were very similar with small variations within the first 6 nm from NP surface by a factor of 10%. In addition, neither the G-value nor the REF was affected by the choice of physical interaction models with the same energy cut-off. This work illustrated the similarity of the Livermore and Penelope models (within 15%) available in Geant4 for future simulation studies of GNP enhanced proton therapy with physical, physicochemical, and chemical mechanisms.

The Effect of Couple's Motivational Interviewing on Exposure to Secondhand Smoke Among Pregnant Women at Home.

Objective: Secondhand smoke (SHS) during pregnancy is associated with many maternal-fetal complications. Iran has a high male smoking prevalence rate. This study aimed to determine the effect of motivational interviewing with couples on exposure to SHS at home in pregnant women referring to health centers in Urmia in 2019. Materials and methods : A randomized control trial was performed on 112 non-smoking pregnant women with smoking husbands, randomly allocated into two groups (each with 56 members). The participants were asked to specify the daily average times and duration of exposure during the last week. Five motivational interviewing sessions were held for the members of the intervention group. Each session lasted90 minutes and two sessions were held per week. The data were collected before and four weeks after the intervention. The data were analyzed using the repeated-measures analysis of variance (ANOVA) by SPSS-20 at a significance level of 0.05. Results: Of 112 couples who were randomized, 102 (91.07%) completed the trial. There was a significant reduction in terms of the daily frequency and duration of SHS exposure of the husband one week and one month after the intervention in the intervention group. The daily frequency and duration of SHS exposure of people other than the spouse at home did not decrease over time. Conclusion: Following the results of the study, the couple-based motivational interviewing approach can be used to reduce SHS exposure in women at home.

The effect of evidence-based nursing education on nurses' clinical decision making: A randomized controlled trial.

Introduction: Nurses are the largest group of health-care providers and their clinical decisions have an essential role in patients' clinical condition. Evidence-based nursing has been proposed as a health-care method based on the latest findings and evidence. Therefore, we aimed to determine the effect of evidence-based nursing education on dialysis nurses' clinical decision-making. Material and Methods: This single-blind experimental study conducted in 2021 at dialysis wards of teaching hospitals affiliated to Urmia University of Medical Sciences. In this study, a total of 60 dialysis nurses were recruited using convenience sampling and allocated to two groups of intervention (n = 30) and control (n = 30). Data were collected at three time points of before, 1 week after, and 1 month after the intervention using a demographic questionnaire and the Lauri and Salantera Clinical Decision-Making Questionnaire (LSCD-MQ). Nurses in the intervention group received 12 sessions of evidence-based nursing education, while nurses in the control group received no intervention. Results: The results showed the mean score of clinical decision-making had a significant decreasing trend over time (p < 0.001) so that it decreased significantly 1 week after the intervention (72.83 ± 4.90) compared with before the intervention (69.5 ± 67.34) in the intervention group. Moreover, participants' decision-making moved toward analytical decision-making. The results also indicated there was a significant difference between the baseline mean score of clinical decision-making and the postintervention mean scores obtained 1 week (p = 0.025) and 1 month (p = 0.001) after the intervention. However, this difference was not found to be significant in the control group (p = 1.000). Conclusions: The study results indicate the positive effect of evidence-based education on nurses' clinical decision-making. Therefore, nurses are recommended to apply evidence-based education methods to improve their level of clinical decision-making. Health officials are also recommended to hold in-service evidence-based workshops to update nurses' knowledge.

Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype.

GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that in addition to T-bet, TF RUNX3 also contributes to the Th1 switch of ThGM cells. T-bet-deficient ThGM cells in the CNS of mice with EAE had low expression of RUNX3, and knockdown of RUNX3 expression in ThGM cells abrogated the Th1-inducing effect of IL-12. Comparison of ThGM and Th1 cell transcriptomes showed that ThGM cells expressed a set of TFs known to inhibit the development of other Th lineages. Lack of expression of lineage-specific cytokines and TFs by ThGM cells, together with expression of TFs that inhibit the development of other Th lineages, suggests that ThGM cells are a non-polarized subset of Th cells with lineage characteristics.

Response of Astrocyte Subpopulations Following Spinal Cord Injury.

There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly enhanced synaptogenic properties in vitro, as compared with other astrocyte subpopulations of adult cortex and spinal cord. Following spinal cord injury (SCI), damaged neurons lose synaptic connections with neuronal partners, resulting in persistent functional loss. We determined whether SCI induces an enhanced synaptomodulatory astrocyte phenotype by shifting toward a greater proportion of Population C cells and/or increasing expression of relevant synapse formation-associated genes within one or more astrocyte subpopulations. Using flow cytometry and RNAscope in situ hybridization, we found that astrocyte subpopulation distribution in the spinal cord did not change to a selectively synaptogenic phenotype following mouse cervical hemisection-type SCI. We also found that spinal cord astrocytes expressed synapse formation-associated genes to a similar degree across subpopulations, as well as in an unchanged manner between uninjured and SCI conditions. Finally, we confirmed these astrocyte subpopulations are also present in the human spinal cord in a similar distribution as mouse, suggesting possible conservation of spinal cord astrocyte heterogeneity across species.

Engineered extracellular vesicles encapsulated Bryostatin-1 as therapy for neuroinflammation.

Targeted and effective drug delivery to central nervous system (CNS) lesions is a major challenge in the treatment of multiple sclerosis (MS). Extracellular vesicles (EVs) have great promise as a drug delivery nanosystem given their unique characteristics, including a strong cargo-loading capacity, low immunogenicity, high biocompatibility, inherent stability, high delivery efficiency, ease of manipulation, and blood-brain barrier (BBB) penetration. Clinical applications are, however, limited by their insufficient targeting capability and "dilution effects" upon systemic administration. Neural stem cells (NSCs) provide an abundant source of EVs because of their remarkable capacity for self-renewal. Here, we developed a novel therapeutic strategy for local delivery and treatment using EVPs, which are derived from NSCs with the expression of the CNS lesion targeting ligand-PDGFRα. Furthermore, we used EVPs as a targeting carrier for encapsulating Bryostatin-1 (Bryo-1), a natural compound with remarkable anti-inflammation ability. Our data showed that Bryo-1 delivered by EVPs was more stable and concentrated in the CNS than native Bryo-1. Systemic injection of a low dosage (1 × 108 particles) of EVPs + Bryo-1, versus only EVPs or Bryo-1 administration, significantly ameliorated clinical disease development, decreased the infiltration of pro-inflammatory cells, blocked myelin loss and astrogliosis, protected BBB integrity, and altered microglia pro-inflammatory phenotype in the CNS of EAE mice. Taken as a whole, our study showed that engineered EVs have a CNS targeting capacity, and it provides potentially powerful therapeutic effects for the treatment of various neuroinflammatory diseases.