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INTRODUCTION:Eosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal inflammation and fibrosis with a higher disease prevalence in males than females (3:1). The underlying mechanisms behind this sexual dimorphism remain unclear.METHODS:Primary human fibroblasts from males and females with active EoE were isolated from esophageal biopsies. Normal fibroblasts were isolated from donor esophageal explants. Fibroblasts were treated with recombinant IL-4, IL-13, or TGFβ1 and analyzed for inflammatory and fibrotic gene expression by qPCR. Esophageal biopsy specimens from active disease patients were scored using a standardized histology score.RESULTS:IL-4 or IL-13 induced significantly more eotaxin-3/ccl26 mRNA expression in esophageal fibroblasts from males as compared with females (P < 0.001). This trend was observed in fibroblasts derived from adults or children, consistent with increased EoE onset in males of all ages. TGFβ1 induced significantly higher levels of collagen-1, α-smooth muscle actin, fibronectin, and serpinE1 (P < 0.03) mRNA in male (n = 5) EoE esophageal fibroblasts as compared with females (n = 3). Hematoxylin and eosin staining of EoE esophageal biopsies (n = 153, 125 males and 28 females) revealed that while overall eosinophil count correlated with epithelial remodeling score (r = 0.3550, P < 0.0001) within the distal esophagus, this correlation was distinctly stronger in the male patients (r = 0.4062, P < 0.0001) than within the female patients (r = 0.1546, P = 0.4323). The same pattern was found in the middle (male r = 0.6080, P < 0.0001; female r = 0.4723, P = 0.013) and proximal esophageal levels (male r = 0.8504, P < 0.0001; female r = 0.5235, P = 0.006). Immunohistochemical staining of EoE esophageal biopsies showed significantly more TGFβ1-positive cells in female than male patients (P < 0.001) but no differences in Smad2/3 phosphorylation.CONCLUSION:Male esophageal fibroblasts have a more robust response to Th2 interleukins and TGFβ1 as compared with female fibroblasts in adults and children and during the normal and active disease states, suggesting an intrinsic sexual dimorphism in esophageal cells. Epithelial histologic disease severity in males also correlates more strongly with elevated eosinophil counts than in females, suggesting that the male esophagus may have more profound responses to cytokines or antigens as compared to females. These data support a potential mechanism for the sex biased disease expression of EoE.

There is renewed interest in extracellular vesicles over the past decade or 2 after initially being thought of as simple cellular garbage cans to rid cells of unwanted components. Although there has been intense research into the role of extracellular vesicles in the fields of tumour and stem cell biology, the possible role of extracellular vesicles in nerve regeneration is just in its infancy. When a peripheral nerve is damaged, the communication between spinal cord motor neurons and their target muscles is disrupted and the result can be the loss of coordinated muscle movement. Despite state-of-the-art surgical procedures only approximately 10% of adults will recover full function after peripheral nerve repair. To improve upon such results will require a better understanding of the basic mechanisms that influence axon outgrowth and the interplay between the parent motor neuron and the distal end organ of muscle. It has previously been shown that extracellular vesicles are immunologically tolerated, display targeting ligands on their surface, and can be delivered in vivo to selected cell populations. All of these characteristics suggest that extracellular vesicles could play a significant role in nerve regeneration. We have carried out studies using 2 very well characterized cell lines, the C2C12 muscle cell line and the motor neuron cell line NSC-34 to ask the question: Do extracellular vesicles from muscle influence cell survival and/or neurite outgrowth of motor neurons? Our results show striking effects of extracellular vesicles derived from the muscle cell line on the motor neuron cell line in terms of neurite outgrowth and survival.

Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE. Genotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype. The TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGFβ1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling. Our data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE.

Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGF[beta]1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGF[beta]1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE. Genotype at TGF[beta]1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype. The TGF[beta]1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGF[beta]1 (CC subjects = 1300 per mm.sup.2 ; TT = 2250 per mm.sup.2) (p<0.05) and tryptase (CC subjects = 145 per mm.sup.2 : TT = 307 per mm.sup.2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGF[beta]1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling. Our data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system. It is more common in women than men. Current evidence indicates that there is a decrease in the MS relapse rates during the third trimester of pregnancy, and an increase in MS exacerbation rates in the post-partum period. Using the Oxford Centre of Evidence-Based Medicine Levels of Evidence, a systematic review was completed. The researchers hypothesized that hormonal therapy interventions could decrease exacerbations of the clinical manifestations of relapse-remitting multiple sclerosis (RRMS). The results show that different forms and levels of estrogen and progesterone may decrease MS disease activity, and could provide beneficial effects for women diagnosed with RRMS. The authors conclude that estrogen replacement therapy would significantly reduce the exacerbations of MS in women with RRMS, leading to an increased quality of life. Keywords: multiple sclerosis, pregnancy, hormones, estrogen, progesterone, relapse rates, post-partum, and experimental autoimmune encephalomyelitis.

Background Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGF[Beta]1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGF[Beta]1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE. Methods Genotype at TGF[Beta]1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype. Results The TGF[Beta]1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGF[Beta]1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGF[Beta]1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling. Conclusions Our data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.

Targeted protein degradation (TPD) is an emerging therapeutic modality in which small molecules are used to recruit targets to the natural protein degradation machinery of the cell. Molecular glue degraders (MGD) are monovalent small molecules that accomplish this by redirecting E3 ubiquitin ligases to target proteins, offering the potential to degrade previously unliganded and ″undruggable″ proteins in cancer, neurodegenerative, and other diseases. While attractive due to their drug-like properties, MGDs are exceptionally hard to discover and have largely been identified serendipitously. The Von Hippel-Lindau (VHL) E3 ligase is the second most widely used effector for TPD, though current VHL-based degraders are primarily large heterobifunctional PROTACs (proteolysis-targeting chimeras) designed using target-based ligands. Here, we have instead pursued target-agnostic discovery of VHL MGDs leveraging proprietary ultra-miniaturized microfluidics devices (Picowells) to facilitate unbiased RNA-seq screening of a biased E3-focused library. This resulted in dGEM3, a novel VHL molecular glue that targets the survival of motor neuron (SMN) complex member GEMIN3 for degradation. Through a combination of cellular, biochemical, and biophysical assays, we have characterized the GEMIN3 degron within its helicase ATP-binding domain, and how the kinetics of ternary complex formation impact degradation. These findings provide insights on the re-programmability of VHL for novel targets using drug-like molecular glues.

Poaching can contribute to the failure of biodiversity conservation efforts and inflict diverse harms on human livelihoods. We applied crime script analysis to the case of snare poaching—an illegal hunting activity—in three Vietnamese protected areas. Our goal was to enhance the understanding about the opportunity structure underlying snare poaching to advance the suite of community-based crime prevention activities. We analyzed crime scripts for three types of poachers across nine stages of the poaching process using expert-based elicitation with 13 workshop participants in Vinh, Vietnam, 2018. Five stages were similar, clustered toward the early stages, and two were different, clustered around middle crime stages. Analysis produced systematic crime-specific insight about the procedural aspects and requirements for poaching from preparation to hunt to selling one’s catch. Stages identify multiple entry points to apply prevention techniques and match techniques with different types of snare poaching or poachers. Although this research focused on protected areas, the interdisciplinary approach applied herein may be adapted to other conservation contexts.

Aviation turbine fuel and diesel fuel were blended with synthetic paraffins produced via two pathways and the combustion properties measured. Both aviation and diesel fuel containing synthetics produced from the fermentation of sugars, had a linear response to blending with decreasing ignition delay times from 5.05 - 3.52 ms for F-34 and 3.84 - 3.52 ms for F-76. For the same fuels blended with synthetics produced from the fermentation of alcohols, ignition delay times were increased out to 18.66 ms. The derived cetane number of the blends followed an inversely similar trend. Additionally, simulated distillation using ASTM D2887 at high synthetic paraffinic kerosene blend ratios resulted in the recovery temperatures being incorrectly reported. In this case, higher recovery volumes were at lower temperatures than earlier recovery points i.e. T90< T50, for SIP-SPK.