Altered extracellular matrix dynamics is associated with insulin resistance in adolescent children with obesity.

Objective: The objective of this study was to examine the hypothesis that abdominal and gluteal adipocyte turnover, lipid dynamics, and fibrogenesis are dysregulated among insulin-resistant (IR) compared with insulin-sensitive (IS) adolescents with obesity.

Methods: Seven IS and seven IR adolescents with obesity participated in a 3-h oral glucose tolerance test and a multi-section magnetic resonance imaging scan of the abdominal region to examine body fat distribution patterns and liver fat content. An 8-week 70% deuterated water ( H O) labeling protocol examined adipocyte turnover, lipid dynamics, and fibrogenesis in vivo from biopsied abdominal and gluteal fat.

Stem cell migration drives lung repair in living mice.

Tissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 cells (AT2s) act as stem cells to replenish both themselves and alveolar type 1 cells (AT1s); however, the complex orchestration of stem cell activity after injury is poorly understood. Here, we establish longitudinal imaging of AT2s in murine intact tissues ex vivo and in vivo in order to track their dynamic behavior over time.

Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity.

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of adipose tissue of youth with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of adolescents with obesity but without diabetes, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both oral glucose tolerance test and euglycemic-hyperinsulinemic clamp.

Untargeted metabolomics analysis of esophageal squamous cell cancer progression.

90% of esophageal cancer are esophageal squamous cell carcinoma (ESCC) and ESCC has a very poor prognosis and high mortality. Nevertheless, the key metabolic pathways associated with ESCC progression haven't been revealed yet. Metabolomics has become a new platform for biomarker discovery over recent years.

Characterization of the COPD alveolar niche using single-cell RNA sequencing.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD.

MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model.

Excessive inflammation drives the progression from sepsis to septic shock. Macrophage migration inhibitory factor (MIF) is of interest because MIF promoter polymorphisms predict mortality in different infections, and anti-MIF antibody improves survival in experimental models when administered 8 hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrome tautomerase (D-DT/MIF-2), prompted closer investigation of MIF-dependent responses.

CIDEA expression in SAT from adolescent girls with obesity and unfavorable patterns of abdominal fat distribution.

Objective: This study investigated whether variations in cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) mRNA expression and protein levels are modulated by the pattern of abdominal fat distribution in adolescent girls with obesity.

Methods: This study recruited 35 adolescent girls with obesity and characterized their abdominal fat distribution by magnetic resonance imaging. Participants had only a periumbilical/abdominal (n = 14) or a paired abdominal and gluteal subcutaneous adipose tissue (SAT) biopsy (n = 21).

MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease.

The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD.

The omentum of obese girls harbors small adipocytes and browning transcripts.

Severe obesity (SO) affects about 6% of youth in the United States, augmenting the risks for cardiovascular disease and type 2 diabetes. Herein, we obtained paired omental adipose tissue (omVAT) and abdominal subcutaneous adipose tissue (SAT) biopsies from girls with SO undergoing sleeve gastrectomy (SG), to test whether differences in cellular and transcriptomic profiles between omVAT and SAT depots affect insulin sensitivity differently. Following weight loss, these analyses were repeated in a subgroup of subjects having a second SAT biopsy.

Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls.

Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (high VAT/[VAT + SAT]) is a major determinant of fatty liver and metabolic impairment over time, with these effects being more pronounced in girls than in boys.

A low visceral fat proportion, independent of total body fat mass, protects obese adolescent girls against fatty liver and glucose dysregulation: a longitudinal study.

Background: The relative proportion of visceral fat (VAT) to subcutaneous fat (SAT) has been described as a major determinant of insulin resistance (IR). Our study sought to evaluate the effect of body fat distribution on glucose metabolism and intrahepatic fat content over time in a multiethnic cohort of obese adolescents.

Subjects/methods: We examined markers of glucose metabolism by oral glucose tolerance test, and body fat distribution by abdominal MRI at baseline and after 19.

Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort.

Unlabelled: We conducted a prospective study in a large, multiethnic cohort of obese adolescents to characterize clinical and genetic features associated with pediatric nonalcoholic fatty liver (NAFL), the most common cause of chronic liver disease in youth. A total of 503 obese adolescents were enrolled, including 191 (38.0%) whites, 134 (26.

A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents.

The innate immune cell sensor leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning.

Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import.

To translate the 13 mtDNA-encoded mRNAs involved in oxidative phosphorylation (OXPHOS), mammalian mitochondria contain a dedicated set of ribosomes comprising rRNAs encoded by the mitochondrial genome and mitochondrial ribosomal proteins (MRPs) that are encoded by nuclear genes and imported into the matrix. In addition to their role in the ribosome, several MRPs have auxiliary functions or have been implicated in other cellular processes like cell cycle regulation and apoptosis. For example, we have shown that human MRPL12 binds and activates mitochondrial RNA polymerase (POLRMT), and hence has distinct functions in the ribosome and mtDNA transcription.

Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness.

The A1555G mutation in the 12S rRNA gene of human mitochondrial DNA causes maternally inherited, nonsyndromic deafness, an extreme case of tissue-specific mitochondrial pathology. A transgenic mouse strain that robustly overexpresses the mitochondrial 12S ribosomal RNA methyltransferase TFB1M (Tg-mtTFB1 mice) exhibits progressive hearing loss that we proposed models aspects of A1555G-related pathology in humans. Although our previous studies of Tg-mtTFB1 mice implicated apoptosis in the spiral ganglion and stria vascularis because of mitochondrial reactive oxygen species-mediated activation of AMP kinase (AMPK) and the nuclear transcription factor E2F1, detailed auditory pathology was not delineated.

microManaging mitochondrial translation.

Regulation of gene expression in mammalian mitochondria by microRNAs is reported by Zhang et al. During muscle cell differentiation, localization of a miRNA is increased within mitochondria, where it interacts with Ago2 to selectively activate translation of mtDNA-encoded mRNAs. The findings represent a new mitochondrial regulatory pathway and a potentially powerful means to purposefully manipulate mtDNA expression.

ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies.

Oxidative phosphorylation and fatty acid oxidation are two major metabolic pathways in mitochondria. Acyl-CoA dehydrogenase 9 (ACAD9), an enzyme assumed to play a role in fatty acid oxidation, was recently identified as a factor involved in complex I biogenesis. Here we further investigated the role of ACAD9's enzymatic activity in fatty acid oxidation and complex I biogenesis.

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment.

Here we report a patient with a new pathogenic mutation in ACAD9. Shortly after birth she presented with respiratory insufficiency and a high lactate level. At age 7 weeks, she was diagnosed with severe hypertrophic cardiomyopathy and she suffered from muscle weakness and hypotonia.

3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients.

Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator.

Assembly factors as a new class of disease genes for mitochondrial complex I deficiency: cause, pathology and treatment options.

Complex I deficiency is the most frequent cause of oxidative phosphorylation disorders. The disease features a large diversity of clinical symptoms often leading to progressive encephalomyopathies with a fatal outcome. There is currently no cure, and although disease-causing mutations have been found in the genes encoding complex I subunits, half of the cases remain unexplained.

NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I.

Complex I (NADH:ubiquinone oxidoreductase) is the first and largest protein complex of the oxidative phosphorylation. Crystal structures have elucidated the positions of most subunits of bacterial evolutionary origin in the complex, but the positions of the eukaryotic subunits are unknown. Based on the analysis of sequence conservation we propose intra-molecular disulfide bridges and the inter-membrane space localization of three Cx(9)C-containing subunits in human: NDUFS5, NDUFB7 and NDUFA8.

Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I.

Acyl-CoA dehydrogenase 9 (ACAD9) is a recently identified member of the acyl-CoA dehydrogenase family. It closely resembles very long-chain acyl-CoA dehydrogenase (VLCAD), involved in mitochondrial beta oxidation of long-chain fatty acids. Contrary to its previously proposed involvement in fatty acid oxidation, we describe a role for ACAD9 in oxidative phosphorylation.

Immunochemical detection of aminoglycosides in milk and kidney.

In 1996, the European Union established provisional maximum residue limits (MRL) for gentamicin, neomycin, streptomycin and dihydrostreptomycin in milk and tissue (0.1-5 mg kg-1). For the detection of these four aminoglycosides, three enzyme linked immunosorbent assays (ELISA) for applications in milk and kidney were developed.

Suitability of the Charm HVS and a microbiological multiplate system for detection of residues in raw milk at EU maximum residue levels.

In this paper we assessed the suitability of the Charm HVS and a newly developed microbiological multiplate system as post-screening tests to confirm the presence of residues in raw milk at or near the maximum permissible residue level (MRL). The multiplate system is composed of Bacillus stearothermophilus var. calidolactis plate at pH 8.

Testing of raw milk for tetracycline residues.

A newly improved Bacillus calidolactis tube diffusion test and two postscreening test systems--a receptor assay (Charm HVS; Charm Sciences, Inc., Malden, MA) and a newly developed Bacillus cereus ATCC 11778 mycoides test system--were evaluated for the detection and identification of tetracycline residues using 973 samples of bulk milk taken at random in The Netherlands. All milk samples were assayed with the B.