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Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease- contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway., Introduction Complex diseases of aging provide unique challenges for the identification of specific disease-causing genetic variants and associated cellular dysfunctions using traditional genetic approaches. Disease modeling using iPSCs is a [...]

Purpose: Reflex cough is an essential airway protective mechanism that often occurs in the context of divided attention. The effect of divided attention on measures of reflexive cough airflow and sensitivity remains unknown. We present findings from a study testing the effects of divided attention (via a dual-task paradigm) on measures of reflex cough in healthy young adults. Method: Volunteers (N = 20, age = 20-40 years) underwent 4 blocks of capsaicin-induced cough challenges. Within each block, capsaicin ranging from 0 to 200 [micro]M was presented in a randomized order. Two blocks consisted of cough testing only (single task). During the other 2 blocks, participants counted tones while simultaneously undergoing cough testing (dual task). Measures of cough motor response, self-reported urge-to-cough, cough frequency, and cough airflow were collected. Results: Participants coughed more in the single-task condition compared to the dual-task condition (p [less than or equal to] .001). Participants' urge-to-cough ratings were lower in the dual-task condition ([bar.x] = 2, 'slight') compared to the single-task condition ([bar.x] = 3, 'moderate'; p = .007). Participants' cough reflex sensitivity thresholds were significantly increased in the dual-task condition (p = .002). Cough peak expiratory flow rates did not change between the 2 conditions (p = .34). Conclusions: Somatosensation of tussive stimuli changes during dual tasking. Abnormal cortical resource allocation may be a mechanism involved in silent aspiration., Reflex cough is an essential airway protective mechanism that occurs in response to penetration and aspiration of foods and liquids. Airway protection and coughing must often take place in the [...]

The release of reactive oxygen species (ROS) and cytokines by alveolar macrophages has been demonstrated in asbestos-induced pulmonary fibrosis, but the mechanism linking alveolar macrophages to the pathogenesis is not known. The GTPase Rac1 is a second messenger that plays an important role in host defense. In this study, we demonstrate that Rac1 null mice are protected from asbestos-induced pulmonary fibrosis, as determined by histological and biochemical analysis. We hypothesized that Rac1 induced pulmonary fibrosis via generation of ROS. Asbestos increased TNF-[alpha] and ROS in a Rac1-dependent manner. TNF-[alpha] was elevated only 1 day after exposure, whereas ROS generation progressively increased in bronchoalveolar lavage cells obtained from wild-type (WT) mice. To determine whether ROS generation contributed to pulmonary fibrosis, we overexpressed catalase in WT monocytes and observed a decrease in ROS generation in vitro. More importantly, administration of catalase to WT mice attenuated the development of fibrosis in vivo. For the first time, these results demonstrate that Rac1 plays a crucial role in asbestos-induced pulmonary fibrosis. Moreover, it suggests that a simple intervention may be useful to prevent progression of the disease. macrophages doi: 10.1152/ajplung.90590.2008.

The kinetic Limulus amebocyte lysate (LAL) assay and the recombinant factor C (rFC) assay are used for comparing airborne endotoxin concentrations in laboratory- and field-collected parallel air samples. Mixed-model analysis of variance (ANOVA) for the field studies has showed major interactions of facility-sampler and facility-assay and the studies have shown that the LAL assay and rFC assay have returned similar estimates of exposure in livestock facilities.

In Kurzban and Descioli's article 'Why Religions Turn Oppressive' (Vo. 15, No. z), I think there is a missing connection between kin selection and 'moralistic rules [which] pertain to doing [...]