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The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI.
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Nephrogenic adenoma (NA) is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with antecedent inflammation, instrumentation, or an operative history. Its histopathologic diversity can create diagnostic dilemmas and pathologists use morphologic evaluation along with available immunohistochemical (IHC) markers to navigate these challenges. IHC assays currently do not designate or specify NA's potential putative cell of origin. Leveraging single-cell RNA-sequencing technology, we nominated a principal (P) cell-collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for NA. IHC characterization revealed L1CAM to be positive in all 35 (100%) patient samples of NA; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma (UCA) in situ, prostatic adenocarcinoma, majority of high-grade UCA, and metastatic UCA. In the study, we also used single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for the proximal tubule, loop of Henle, and distal tubule (DT) (including P and intercalated cells), which can be used to perform nephronal mapping using RNA in situ hybridization and IHC technology. Employing this technique on NA we found enrichment of both the P-cell marker L1CAM and, the proximal tubule type-A and -B cell markers, PDZKI1P1 and PIGR, respectively. The cell-type markers for the intercalated cell of DTs (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in NA. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between DT P cells and NA. L1CAM expression will be of potential value in assisting surgical pathologists toward a diagnosis of NA in challenging patient samples.
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BACKGROUND: Same-day discharge after mastectomy has potential patient- and hospital-level benefits; however, few data are available regarding factors affecting the likelihood of same-day discharge in order to address barriers. We sought to evaluate factors contributing to same-day discharge, focusing on the timing of mastectomy during the operative day. METHODS: We conducted a single-institution retrospective review of patients who underwent mastectomies for malignancy over a 3-y time frame. Clinicopathologic variables were collected along with a binary variable for mastectomy start time (morning versus afternoon). Our primary endpoint was rate of same-day discharge. A multivariable logistic regression model was constructed from significant univariate variables to determine independent predictors of same-day discharge. A secondary endpoint was a cost-utility analysis for morning versus afternoon start time, using hospital cost data. RESULTS: There were 451 patients included in the analysis. Factors associated with same-day discharge rate included the American Society of Anesthesiologists score, use of a preoperative regional anesthesia block, type of mastectomy performed, individual surgeon variation, and a morning start for the mastectomy. On multivariable analysis, morning start was a strong independent predictor of same-day discharge (odd ratio = 2.83; 95% CI, 1.75-4.60). The cost-utility analysis favored a morning start, with average cost savings of $550 per patient. CONCLUSION: Despite patient- and surgeon-specific variations, simple scheduling policies can improve same-day discharge rates after mastectomy, leading to improved hospital bed use and cost reduction.
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Neoplasias de la Mama , Mastectomía , Humanos , Femenino , Neoplasias de la Mama/cirugía , Ahorro de Costo , Procedimientos Quirúrgicos Ambulatorios , Alta del Paciente , Estudios RetrospectivosRESUMEN
BACKGROUND: Studies have shown that patients with abdominal pain and biliary dyskinesia (low ejection fraction <35 â%) have significant improvement of symptoms following laparoscopic cholecystectomy, but there is lack of evidence that demonstrates whether patients with biliary symptoms and a normal ejection fraction (>35 â%) will have similar results. METHODS: Retrospective, single center study of patients with biliary pain and negative workup, including HIDA with EF>35 â%, who were treated with laparoscopic cholecystectomy from 2017 to 2022. RESULTS: There were 117 total patients. The mean age was 45.49 â± â15.5 years and 101 (86 â%) were female. 101 (86 â%) of patients underwent a right upper quadrant ultrasound, 91 had normal findings, 9 difficult to visualize anatomy and 1 had adenomyomatosis. All patients had a normal HIDA scan and ejection fraction 104 (89 â%) of patients followed up in clinic within 30 days of surgical intervention. 87 (84 â%) reported resolution of pre-operative symptomatology after surgical intervention. There was no statistically significant correlation between pain with CCK administration during HIDA (p â= â0.803) scan or ejection fraction (p â= â0.0977) with resolution of symptoms. CONCLUSIONS: Laparoscopic cholecystectomy appears to be a beneficial intervention for patients with abdominal pain and normokinetic biliary disease. Offering surgical intervention early on can potentially save patients from exhaustive diagnostic investigations and possibly misdiagnosis.
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Discinesia Biliar , Colecistectomía Laparoscópica , Enfermedades de la Vesícula Biliar , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Colecistectomía Laparoscópica/efectos adversos , Colecistectomía Laparoscópica/métodos , Estudios Retrospectivos , Iminoácidos , Discinesia Biliar/diagnóstico , Discinesia Biliar/cirugía , Enfermedades de la Vesícula Biliar/cirugía , Dolor Abdominal/etiología , Resultado del TratamientoRESUMEN
Cardiometabolic disorders (CMD) are a growing public health problem across the world. Among the known cardiometabolic risk factors are compounds that induce endocrine and metabolic dysfunctions, such as endocrine disrupting chemicals (EDCs). To date, how EDCs influence molecular programs and cardiometabolic risks has yet to be fully elucidated, especially considering the complexity contributed by species-, chemical-, and dose-specific effects. Moreover, different experimental and analytical methodologies employed by different studies pose challenges when comparing findings across studies. To explore the molecular mechanisms of EDCs in a systematic manner, we established a data-driven computational approach to meta-analyze 30 human, mouse, and rat liver transcriptomic datasets for 4 EDCs, namely bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), tributyltin (TBT), and perfluorooctanoic acid (PFOA). Our computational pipeline uniformly re-analyzed pre-processed quality-controlled microarray data and raw RNAseq data, derived differentially expressed genes (DEGs) and biological pathways, modeled gene regulatory networks and regulators, and determined CMD associations based on gene overlap analysis. Our approach revealed that DEHP and PFOA shared stable transcriptomic signatures that are enriched for genes associated with CMDs, suggesting similar mechanisms of action such as perturbations of peroxisome proliferator-activated receptor gamma (PPARγ) signaling and liver gene network regulators VNN1 and ACOT2. In contrast, TBT exhibited highly divergent gene signatures, pathways, network regulators, and disease associations from the other EDCs. In addition, we found that the rat, mouse, and human BPA studies showed highly variable transcriptomic patterns, providing molecular support for the variability in BPA responses. Our work offers insights into the commonality and differences in the molecular mechanisms of various EDCs and establishes a streamlined data-driven workflow to compare molecular mechanisms of environmental substances to elucidate the underlying connections between chemical exposure and disease risks.
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Enfermedades Cardiovasculares , Dietilhexil Ftalato , Disruptores Endocrinos , Fenoles , Humanos , Ratones , Ratas , Animales , Transcriptoma , Redes Reguladoras de Genes , Disruptores Endocrinos/metabolismo , Perfilación de la Expresión Génica , Hígado/metabolismo , Compuestos de BencidriloRESUMEN
Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.
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Aterosclerosis , Enfermedad de la Arteria Coronaria , Humanos , Ratones , Animales , Enfermedad de la Arteria Coronaria/genética , Aterosclerosis/genética , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.
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Histoplasmosis is a systemic infection caused by the fungus, Histoplasma capsulatum Infection of H. capsulatum frequently occurs by inhaling the spores of the fungus, which is found in bat and bird droppings, or soil enriched with their excrement. If not detected and treated, histoplasmosis can develop late, severe complications such as mediastinal fibrosis, or even develop into a disseminated infection. However, histoplasmosis infections are often asymptomatic, making its detection more difficult. Further, only 6% of histoplasmosis cases will present with erythema nodosum, with most cases associated with female patients. This case presents a woman in her 50s with a pertinent history of fibromyalgia and hypothyroidism secondary to Hashimoto's who initially sought medical care for painful nodules on her legs and was eventually diagnosed with histoplasmosis. This report clearly demonstrates the importance of maintaining a broad differential when working up inflammatory manifestations, such as erythema nodosum.
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Eritema Nudoso , Histoplasmosis , Humanos , Femenino , Histoplasmosis/complicaciones , Histoplasmosis/diagnóstico , Histoplasmosis/tratamiento farmacológico , Histoplasma , Eritema Nudoso/etiología , Eritema Nudoso/complicacionesRESUMEN
The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta-endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain.
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Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.
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Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , NADH Deshidrogenasa/metabolismo , Material Particulado/farmacología , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/tratamiento farmacológico , Taurina/uso terapéutico , Adenina/análogos & derivados , Adenina/farmacología , Anciano , Animales , Autofagia/efectos de los fármacos , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Línea Celular , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Genes Mitocondriales/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfisema Pulmonar/metabolismoRESUMEN
The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in Met murine hepatocytes (MMH)-D3, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that the cell-autonomous clock can drive many rhythms, and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both cophasic and antiphasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase and spermidine synthase. Metabolic profiling revealed that the enzymatic product of spermidine synthase, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis.
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Poliaminas Biogénicas/biosíntesis , Ritmo Circadiano , Hepatocitos/citología , Transcripción Genética , Animales , RatonesRESUMEN
BACKGROUND: A large outbreak of diarrhea and the hemolytic-uremic syndrome caused by an unusual serotype of Shiga-toxin-producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin-producing E. coli have been reported--3167 without the hemolytic-uremic syndrome (16 deaths) and 908 with the hemolytic-uremic syndrome (34 deaths)--indicating that this strain is notably more virulent than most of the Shiga-toxin-producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS: We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS: The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS: Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin-producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens.
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Brotes de Enfermedades , Infecciones por Escherichia coli/microbiología , Genoma Bacteriano , Síndrome Hemolítico-Urémico/microbiología , Escherichia coli Shiga-Toxigénica/genética , Técnicas de Tipificación Bacteriana , Secuencia de Bases , Diarrea/epidemiología , Diarrea/microbiología , Infecciones por Escherichia coli/epidemiología , Heces/microbiología , Femenino , Alemania/epidemiología , Síndrome Hemolítico-Urémico/epidemiología , Humanos , Persona de Mediana Edad , Filogenia , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Escherichia coli Shiga-Toxigénica/clasificación , Escherichia coli Shiga-Toxigénica/aislamiento & purificaciónRESUMEN
To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.
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Mucosa Gástrica/metabolismo , Hígado/metabolismo , Obesidad Mórbida/epidemiología , Obesidad Mórbida/genética , Adiposidad/genética , Adulto , Estudios de Cohortes , Comorbilidad , Bases de Datos Genéticas , Femenino , Derivación Gástrica , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Polimorfismo de Nucleótido Simple , Pérdida de PesoRESUMEN
Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.
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Aterosclerosis/genética , Enfermedad de la Arteria Coronaria/genética , Enfermedad Coronaria/genética , Infarto del Miocardio/genética , Tejido Adiposo , Animales , Aorta , Genes , Estudio de Asociación del Genoma Completo , Humanos , Hígado , Ratones , Ratones Noqueados , Fenotipo , Polimorfismo Genético , Factores de RiesgoRESUMEN
By treating the transcript abundance as a quantitative trait, gene expression can be mapped to local or distant genomic regions relative to the gene encoding the transcript. Local expression quantitative trait loci (eQTL) generally act in cis (that is, control the expression of only the contiguous structural gene), whereas distal eQTL act in trans. Distal eQTL are more difficult to identify with certainty due to the fact that significant thresholds are very high since all regions of the genome must be tested, and confounding factors such as batch effects can produce false positives. Here, we compare findings from two large genetic crosses between mouse strains C3H/HeJ and C57BL/6J to evaluate the reliability of distal eQTL detection, including "hotspots" influencing the expression of multiple genes in trans. We found that >63% of local eQTL and >18% of distal eQTL were replicable at a threshold of LOD > 4.3 between crosses and 76% of local and >24% of distal eQTL at a threshold of LOD > 6. Additionally, at LOD > 4.3 four tissues studied (adipose, brain, liver, and muscle) exhibited >50% preservation of local eQTL and >17% preservation of distal eQTL. We observed replicated distal eQTL hotspots between the crosses on chromosomes 9 and 17. Finally, >69% of local eQTL and >10% of distal eQTL were preserved in most tissues between sexes. We conclude that most local eQTL are highly replicable between mouse crosses, tissues, and sex as compared to distal eQTL, which exhibited modest replicability.
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Replicación del ADN , Perfilación de la Expresión Génica , Genoma , Sitios de Carácter Cuantitativo , Tejido Adiposo/metabolismo , Animales , Encéfalo/metabolismo , Mapeo Cromosómico , Femenino , Hígado/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Músculos/metabolismo , Especificidad de Órganos , Fenotipo , Factores Sexuales , Distribución TisularRESUMEN
BACKGROUND: Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans. METHODS AND RESULTS: We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F(2) mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE(-/-)) null BACKGROUND: gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification. CONCLUSIONS: Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.
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Aterosclerosis/genética , Aterosclerosis/patología , Calcinosis , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Aorta/patología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Sitios de Carácter CuantitativoRESUMEN
Copy number variants (CNVs) are genomic segments which are duplicated or deleted among different individuals. CNVs have been implicated in both Mendelian and complex traits, including immune and behavioral disorders, but the study of the mechanisms by which CNVs influence gene expression and clinical phenotypes in humans is complicated by the limited access to tissues and by population heterogeneity. We now report studies of the effect of 19 CNVs on gene expression and metabolic traits in a mouse intercross between strains C57BL/6J and C3H/HeJ. We found that 83% of genes predicted to occur within CNVs were differentially expressed. The expression of most CNV genes was correlated with copy number, but we also observed evidence that gene expression was altered in genes flanking CNVs, suggesting that CNVs may contain regulatory elements for these genes. Several CNVs mapped to hotspots, genomic regions influencing expression of tens or hundreds of genes. Several metabolic traits including cholesterol, triglycerides, glucose and body weight mapped to three CNVs in the genome, in mouse chromosomes 1, 4 and 17. Predicted CNV genes, such as Itlna, Defcr-1, Trim12 and Trim34 were highly correlated with these traits. Our results suggest that CNVs have a significant impact on gene expression and that CNVs may be playing a role in the mechanisms underlying metabolic traits in mice.
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Metabolismo Basal/genética , Dosificación de Gen/genética , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Tejido Adiposo/metabolismo , Animales , Encéfalo/metabolismo , Mapeo Cromosómico , Cromosomas de los Mamíferos/genética , Hibridación Genómica Comparativa , Cruzamientos Genéticos , Femenino , Variación Genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos , Músculos/metabolismo , Sitios de Carácter Cuantitativo/genéticaRESUMEN
A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.
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Proteínas Portadoras/genética , Glutatión Peroxidasa/genética , Glicoproteínas/genética , Proteínas del Tejido Nervioso/genética , Obesidad/genética , Abdomen/anatomía & histología , Tejido Adiposo/anatomía & histología , Animales , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Variación Genética , Humanos , Hígado/fisiología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Músculo Esquelético/anatomía & histología , Fenotipo , Reproducibilidad de los Resultados , Transcripción Genética , Proteínas de Transporte VesicularRESUMEN
OBJECTIVE: We sought to determine the genetic factors contributing to atherosclerotic plaque size and cellular composition in the innominate artery, a murine model of advanced atherosclerosis. METHODS AND RESULTS: We examined genetic contributions to innominate atherosclerotic plaque size and cellular composition in an intercross between C57BL/6J.Apoe(-/-), a strain susceptible to aortic lesions, and C3H/HeJ.Apoe(-/-), a strain resistant to aortic lesions. Surprisingly, total innominate lesion size was similar in the two strains. Genetic analyses identified one novel locus on Chromosome 2 for innominate artery lesion size, a significant locus for fibrous cap thickness on Chromosome 15, and several suggestive loci for cellular composition, all distinct from loci influencing aortic lesions. The Chromosome 2 locus contains a candidate, CD44. We show that CD44 is expressed in the innominate artery and differs strikingly in expression between the parental strains. CONCLUSION: Multiple aspects of innominate lesion composition are genetically determined, but in a manner largely independent of the genetic contributions to aortic lesions.
Asunto(s)
Aterosclerosis/genética , Tronco Braquiocefálico/patología , Cromosomas de los Mamíferos , Hiperlipidemias/genética , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/patología , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Ligamiento Genético , Predisposición Genética a la Enfermedad , Receptores de Hialuranos/genética , Hiperlipidemias/complicaciones , Hiperlipidemias/patología , Lípidos/sangre , Escala de Lod , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Sitios de Carácter Cuantitativo , Factores Sexuales , Especificidad de la EspecieRESUMEN
We previously used high-density expression arrays to interrogate a genetic cross between strains C3H/HeJ and C57BL/6J and observed thousands of differences in gene expression between sexes. We now report analyses of the molecular basis of these sex differences and of the effects of sex on gene expression networks. We analyzed liver gene expression of hormone-treated gonadectomized mice as well as XX male and XY female mice. Differences in gene expression resulted in large part from acute effects of gonadal hormones acting in adulthood, and the effects of sex chromosomes, apart from hormones, were modest. We also determined whether there are sex differences in the organization of gene expression networks in adipose, liver, skeletal muscle, and brain tissue. Although coexpression networks of highly correlated genes were largely conserved between sexes, some exhibited striking sex dependence. We observed strong body fat and lipid correlations with sex-specific modules in adipose and liver as well as a sexually dimorphic network enriched for genes affected by gonadal hormones. Finally, our analyses identified chromosomal loci regulating sexually dimorphic networks. This study indicates that gonadal hormones play a strong role in sex differences in gene expression. In addition, it results in the identification of sex-specific gene coexpression networks related to genetic and metabolic traits.