Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and ...boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
Background We showed previously that nasal mucociliary clearance was decreased in critically ill elderly subjects, most of whom had diabetes mellitus (DM) and/or hypertension (HTN). To determine if ...these changes were due to the effects of aging, disease, or critical illness, we studied nasal mucociliary clearance and mucus properties in an ambulatory population consisting of young, elderly, and healthy subjects and those with DM, HTN, or both. Methods Of 440 subjects contacted, 252 entered the study. The subjects were divided into the following groups: (1) healthy (n = 79, 18–94 years, 50 men) and (2) DM and/or HTN, of which 37 had DM (14–90 years, 12 men), 52 had HTN (23–90 years, 12 men), and 84 had both DM and HTN (25–82 years, 33 men). Subjects were also grouped by age: < 40 years, 40 to 59 years, and ≥ 60 years. We assessed demographic and clinical data, quality of life using the 36-Item Short Form Health Survey (SF-36) questionnaire, nasal mucociliary clearance using the saccharine transit test (STT), and in vitro mucus properties by examining the sneeze (high airflow) clearability and contact angle. A logistic regression analysis for prolonged STT > 12 min was used, and we controlled for age, sex, and diseases. Results Subjects aged > 60 years reported a decreased SF-36 physical component relative to other age groups. Sex, BMI, BP, heart rate, pulse oximetry, blood glucose level, and mucus properties were not associated with prolonged STT. Aging and DM and/or HTN independently increased the risk of prolonged STT. Conclusions Aging and DM, HTN, or both diseases are independently associated with decreased nasal mucociliary clearance. This may predispose toward respiratory infections.
Background Little is known about the effects of long-term nasal low-flow oxygen (NLFO) on mucus and symptoms and how this variable is affected by dry or cold humidified gas. The aim of this study was ...to investigate the effects of dry-NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation, and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy. Methods Eighteen subjects (mean age, 68 years; 7 male; 66% with COPD) initiating NLFO were randomized to receive dry-NLFO (n = 10) or humidified-NLFO (n = 8). Subjects were assessed at baseline, 12 h, 7 days, 30 days, 12 months, and 24 months by measuring nasal MCC using the saccharin transit test, mucus contact angle (surface tension), inflammation (cells and cytokine concentration in nasal lavage), and symptoms according to the Sino-Nasal Outcome Test–20. Results Nasal MCC decreased significantly (40% longer saccharin transit times) and similarly in both groups over the study period. There was a significant association between impaired nasal MCC and decline in lung function. Nasal lavage revealed an increased proportion of macrophages, interleukin-8, and epidermal growth factor concentrations with decreased interleukin-10 during the study. No changes in the proportion of ciliated cells or contact angle were observed. Coughing and sleep symptoms decreased similarly in both groups. There were no outcome differences comparing dry vs cold bubble humidified NLFO. Conclusions In subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification. Trial Registry ClinicalTrials.gov; No.: NCT02515786 ; URL: www.clinicaltrials.gov.
Background Smoking is responsible for most COPD. Although people with COPD often have concomitant nasal disease, there are few studies that report physiologic or inflammatory changes in the upper ...airways in young asymptomatic smokers. We investigated physiologic and inflammatory changes in the nasal and lower airways of young smokers and if these changes were related to smoking history. Methods Seventy-two subjects aged between 18 and 35 years (32 healthy nonsmokers and 40 young smokers) participated in this study. We measured nasal mucociliary clearance (MCC), nasal mucus surface contact angle, cell counts, myeloperoxidase and cytokine concentrations in nasal lavage fluid, exhaled breath condensate (EBC) pH, and lung function. Results Smokers had faster MCC, an increased number of cells (macrophages, ciliated cells, and goblet cells), increased lavage myeloperoxidase concentration, and decreased EBC pH compared with nonsmokers. There was a significant inverse relationship between pack-year smoking history and EBC pH. There were no differences in lung function or mucus surface properties comparing smokers to nonsmokers. Conclusions Young adult smokers have functional and inflammatory changes in the nasal and lower airways and these correlate with smoking history. However, in these young smokers, smoking history was not associated with pulmonary function decline, probably because it is unlikely that spirometry detects early physiologic changes in the airways. Trial registry ClinicalTrials.gov ; No.: NCT01877291; URL: www.clinicaltrials.gov
Intestinal lymphangiectasia (IL) is a common complication in dogs. This study analyzed intestinal microbiota using 16S rRNA amplicon analysis as candidate factors that strongly influence the small ...intestinal lymphatic vessels in dogs with and without IL. Twelve dogs were included, of which six were diagnosed with lymphoplasmacytic enteritis, four with small-cell lymphoma, and two with large-cell lymphoma. Seven of these dogs had IL, whereas five did not. First, the microbial diversity analyzed by Faith pd index was significantly decreased in dogs with IL compared to dogs without IL. Then, the relative amounts of each bacterial taxa were compared between dogs with and without IL using Linear discriminant analysis effect size analysis. At the genus level, the Ruminococcus gnavus groupsignificantly increased in dogs with IL compared to dogs without IL. A total of four genera, including Ruminococcus torques group and Faecalibacterium, which produce butyrate, significantly decreased in dogs with IL. This study showed decreased intestinal bacterial diversity and several alterations of intestinal microbiota, including a decrease in butyrate-producing bacteria in dogs with IL, compared to dogs without IL.
: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory ...diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes.
To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative.
NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants.
A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses.
We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that ...neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogenesis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore, acetylome analysis of Hmgcs2 KO cells revealed enhanced acetylation of mitochondrial proteins. These findings suggest that neonatal ketogenesis protects the energy-producing capacity of mitochondria by preventing the hyperacetylation of mitochondrial proteins.
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