The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS

Different Slopes for Different Folks: Socioeconomic and Racial/Ethnic Disparities in Asthma and Hay Fever among 173,859 U.S. Men and Women.

Although allergic diseases such as asthma and hay fever are a major cause of morbidity in industrialized countries, most studies have focused on patterns of prevalence among children and adolescents, with relatively few studies on variations in prevalence by race/ethnicity and socioeconomic position among adults. Our study examined racial/ethnic and socioeconomic patterns in the prevalence of asthma overall, asthma with hay fever, asthma without hay fever, and hay fever overall, in a population of 173,859 women and men in a large prepaid health plan in northern California. Using education as a measure of socioeconomic position, we found evidence of a positive gradient for asthma with hay fever with increasing level of education but an inverse gradient for asthma without hay fever. Hay fever was also strongly associated with education. Compared with their White counterparts, Black women and men were more likely to report asthma without hay fever, and Black women were less likely to have asthma with hay fever. Asian men were also more likely to report asthma with hay fever, and Asian women and men were much more likely to have hay fever. Racial/ethnic disparities in prevalence of allergic diseases were largely independent of education. We discuss implications for understanding these social inequalities in allergic disease risk in relation to possible differences in exposure to allergens and determinants of immunologic susceptibility and suggest directions for future research

Myelosuppressive Conditioning Using Busulfan Enables Bone Marrow Cell Accumulation in the Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis

Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning

Drosophila adducin regulates Dlg phosphorylation and targeting of Dlg to the synapse and epithelial membrane

AbstractAdducin is a cytoskeletal protein having regulatory roles that involve actin filaments, functions that are inhibited by phosphorylation of adducin by protein kinase C. Adducin is hyperphosphorylated in nervous system tissue in patients with the neurodegenerative disease amyotrophic lateral sclerosis, and mice lacking β-adducin have impaired synaptic plasticity and learning. We have found that Drosophila adducin, encoded by hu-li tai shao (hts), is localized to the post-synaptic larval neuromuscular junction (NMJ) in a complex with the scaffolding protein Discs large (Dlg), a regulator of synaptic plasticity during growth of the NMJ. hts mutant NMJs are underdeveloped, whereas over-expression of Hts promotes Dlg phosphorylation, delocalizes Dlg away from the NMJ, and causes NMJ overgrowth. Dlg is a component of septate junctions at the lateral membrane of epithelial cells, and we show that Hts regulates Dlg localization in the amnioserosa, an embryonic epithelium, and that embryos doubly mutant for hts and dlg exhibit defects in epithelial morphogenesis. The phosphorylation of Dlg by the kinases PAR-1 and CaMKII has been shown to disrupt Dlg targeting to the NMJ and we present evidence that Hts regulates Dlg targeting to the NMJ in muscle and the lateral membrane of epithelial cells by controlling the protein levels of PAR-1 and CaMKII, and consequently the extent of Dlg phosphorylation

The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation

We thank Cowen lab members for helpful discussions. We also thank David Rogers (University of Tennessee) for sharing microarray analysis of the CAS5 homozygous mutant, and Li Ang (University of Macau) for assistance in optimizing the ChIP-Seq experiments. J.L.X. is supported by a Canadian Institutes of Health Research Doctoral award and M.D.L. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072). B.T.G. holds an Ontario Graduate Scholarship. C.B. and B.J.A. are supported by the Canadian Institutes of Health Research Foundation Grants (FDN-143264 and -143265). D.J.K. is supported by a National Institute of Allergy and Infectious Diseases grant (1R01AI098450) and J.D.L.C.D. is supported by the University of Rochester School of Dentistry and Medicine PREP program (R25 GM064133). A.S. is supported by the Creighton University and the Nebraska Department of Health and Human Services (LB506-2017-55). K.H.W. is supported by the Science and Technology Development Fund of Macau S.A.R. (FDCT; 085/2014/A2). L.E.C. is supported by the Canadian Institutes of Health Research Operating Grants (MOP-86452 and MOP-119520), the Natural Sciences and Engineering Council (NSERC) of Canada Discovery Grants (06261 and 462167), and an NSERC E.W.R. Steacie Memorial Fellowship (477598).Peer reviewedPublisher PD

Venous endothelial dysfunction in Chagas' disease patients without heart failure

OBJECTIVE: To analyze the venous endothelial function in Chagas' disease patients without heart failure. METHODS: The Chagas' disease Group (G1) was composed by 14 women and 2 men aged 46 ± 2,7 and the Control Group (G0) by 7 women and 1 man matched by age, weight and height. Dorsal Hand Vein Compliance Technique was used to evaluate the venous endothelial function. Crescent doses of phenylephrine were infused to get a 70% pre-constriction of the vein; after that, acetylcholine and sodium nitroprusside were respectively administrated to analyze the endothelium-dependent and -independent venodilation. RESULTS: No significant systemic hemodynamic changes were observed in both groups during the experiment. The necessary phenylephrine dose to reach 70% pre-constriction of the vein was significantly higher in the G1 (1116 ± 668,2 ng/ml) compared to G0 (103 ± 28 ng/ml) p = 0,05. The endothelium-dependent venous dilation was significantly lower in G1 (65,5 ± 8%) compared to G0 (137 ± 20 %) p = 0,009. No difference was observed in the endothelium-independent venous dilatation between groups. CONCLUSION: Patients with Chagas' disease without heart failure presented venous endothelial dysfunction.OBJETIVO: Analisar a função endotelial venosa em pacientes chagásicos sem insuficiência cardíaca. MÉTODOS: O grupo Chagas (G1) foi composto por quatorze mulheres e dois homens com idade de 46 ± 2,7 anos, e o grupo controle (G0), por sete mulheres e um homem, pareados em idade, peso, altura. A Técnica de Complacência da Veia Dorsal da Mão foi utilizada para avaliação da função endotelial venosa. Foram infundidas doses crescentes de fenilefrina para se obter pré-constrição de 70% do basal; a seguir, foram administradas acetilcolina e nitroprussiato de sódio para avaliar as respostas de venodilatação, respectivamente, dependentes e independentes do endotélio. RESULTADOS: Não houve variação entre os valores hemodinâmicos nos grupos durante o experimento. A dose média de fenilefrina necessária para pré-constrição da veia foi significativamente maior no G1 (1116 ± 668,2 ng/ml), comparada à do G0 (103 ± 28 ng/ml) p = 0,05. A resposta de venodilatação máxima dependente do endotélio foi significativamente menor no grupo G1 (65,5 ± 8%), comparada à do G0 (137 ± 20 %) p = 0,009. Não houve diferença nas respostas de venodilatação independente do endotélio entre os grupos. CONCLUSÃO: Pacientes com doença de Chagas sem insuficiência cardíaca apresentam disfunção endotelial venosa.Universidade Federal de São Paulo (UNIFESP)FMUSP Hospital das Clínicas IIInstituto do CoraçãoUniversidade Estadual de CampinasUniversidade de Cruz AltaUNIFESPSciEL