IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115966/1/eji3410.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115966/2/eji3410-sup-0002-PRC.pd

Stage-Specific Immune Dysregulation in Multiple Sclerosis

A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4+ T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to disease-modifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140109/1/jir.2014.0025.pd

IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition

The interleukin (IL)-12p40 family of cytokines plays a critical role in the development of experimental autoimmune encephalomyelitis (EAE). However, the relative contributions of IL-12 and IL-23 to the pathogenic process remain to be elucidated. Here, we show that activation of uncommitted myelin-reactive T cells in the presence of either IL-12p70 or IL-23 confers encephalogenicity. Adoptive transfer of either IL-12p70– or IL-23–polarized T cells into naive syngeneic hosts resulted in an ascending paralysis that was clinically indistinguishable between the two groups. However, histological and reverse transcription–polymerase chain reaction analysis of central nervous system (CNS) tissues revealed distinct histopathological features and immune profiles. IL-12p70–driven disease was characterized by macrophage-rich infiltrates and prominent NOS2 up-regulation, whereas neutrophils and granulocyte–colony-stimulating factor (CSF) were prominent in IL-23–driven lesions. The monocyte-attracting chemokines CXCL9, 10, and 11 were preferentially expressed in the CNS of mice injected with IL-12p70–modulated T cells, whereas the neutrophil-attracting chemokines CXCL1 and CXCL2 were up-regulated in the CNS of mice given IL-23–modulated T cells. Treatment with anti–IL-17 or anti–granulocyte/macrophage-CSF inhibited EAE induced by transfer of IL-23–polarized, but not IL-12p70–polarized, cells. These findings indicate that autoimmunity can be mediated by distinct effector populations that use disparate immunological pathways to achieve a similar clinical outcome

Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain.

Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood-brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders

Uniaxial Tensile Properties of AS4 3D Woven Composites with Four Different Resin Systems: Experimental Results and Analysis: Property Computations

As a part of the NASA Composite Technology for Exploration project, eight different AS4 3D orthogonal woven composite panels were manufactured and were subjected to mechanical testing including uniaxial tension along the weaves' warp direction. Each set, with four different resin systems (KCR-IR6070, EP2400, RTM6, and RS-50), included weave architectures designed using 12K and 6K AS4 carbon fiber yarns. For the tension testing conducted at Room Temperature Ambient (RTA) conditions, the elastic modulus and strength of these eight panels (as-processed and thermally-cycled) were measured and compared while the potential evolution of micro-cracking before and after thermal cycling were monitored via optical microscopy and X-Ray Computed Tomography. The data set also included test results of the as-processed materials at Elevated Temperature Wet (ETW) conditions. In the second part of this study, efforts were made to compute elastic constants for AS4 6K/RTM6 and AS4 12K/RTM6 materials by implementing a finite element approach and the Multiscale Generalized Method of Cells (MSGMC) technique developed at NASA Glenn Research Center. Digimat-FE was used to model the weave architectures, assign properties, calculate yarn properties, create the finite element mesh, and compute the elastic properties by applying periodic boundary conditions to finite element models of each repeating unit cell. The required input data for MSGMC was generated using Matlab from Digimat exported weave information. Experimental and computational results were compared, and the differences and limitations in correlating to the test data were briefly discussed

Speaking out about gender imbalance in invited speakers improves diversity.

Omissions of qualified women scientists from major meeting programs continue to occur despite a surge in articles indicating persistent gender-discriminatory practices in hiring and promotion, and calls for gender balance in conference organizing committees

Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation

BACKGROUND: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils. RESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotype(SCT). Smoking had no effect on pneumotype allocation, α, or β diversity. Pneumotype(SCT) was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022). CONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation