ABSTRACT
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , SOXD Transcription Factors/metabolism , Animals , Calcium/metabolism , Calcium Channels/metabolism , Chromatin/metabolism , Exocytosis , Female , Gene Expression Regulation , Humans , Insulin/metabolism , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis , Phenotype , Phlorhizin/chemistry , RNA, Small Interfering/metabolism , Rats , Valproic Acid/chemistryABSTRACT
The abnormal deposition of amyloid-ß protein in the brain plays an important role in Alzheimer's disease (AD), being considered a potential clinical biomarker. To investigate genetic associations with amyloid-ß we used biomarker data and genome-wide variants from individuals with AD and mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We used a standard linear model and retested the associations with a mixed linear model to correct the residual sample structure. Both methods' results showed two identical significant SNPs associated with the A ß-42 levels in CSF (rs2075650 at intron region TOMM40 with p-value ≥ 1 × 10-16 and rs439401 in the intergenic region of LOC100129500 and APOC1 with p-value ≥ 1 × 10-9) and highlighted APOC1 and TOMM40, which are well-known genes previously associated with AD. Extending our analysis, we considered possible candidate genes mapped to SNPs with p-value ≥ 1 × 10-6 to explore gene-set enrichment e gene-gene network analysis, which reveals genes related to synaptic transmission, transmission of nerve impulses, cell-cell signaling and neurological processes. These genes require fine mapping and replication studies to allow more detailed understanding of how they may contribute to the genetic architecture of AD.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein C-I/genetics , Membrane Transport Proteins/genetics , Peptide Fragments/cerebrospinal fluid , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/genetics , Case-Control Studies , Female , Gene Regulatory Networks , Humans , Male , Mitochondrial Precursor Protein Import Complex Proteins , Peptide Fragments/geneticsABSTRACT
Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.
Subject(s)
Cell Movement , Cell Proliferation , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Microfilament Proteins/metabolism , Neoplasm Proteins/metabolism , Animals , Apoptosis , Blotting, Western , Chromatin Immunoprecipitation , Gene Expression Regulation, Leukemic , Humans , Mice , Mice, Inbred C3H , Mice, Transgenic , Microfilament Proteins/genetics , Neoplasm Proteins/genetics , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
This paper makes a reflection on the knowledge and ideologies present in the nursing practice within a hospital context, based on theoretical references used by the sociologist Noemia da Glória Mendes Lopes in her MS dissertation in Lisbon, Portugal, in 1994. In this dissertation she analyzes the work of nurses within hospital contexts. The author observed that within the professional context of nursing there are many social practices of work indicating different strategies of valuing and revaluating the profession. It was concluded from this reflection that there are better possibilities of performing such strategies in specialized services than in medical clinic services.
Subject(s)
Health Knowledge, Attitudes, Practice , Nursing Evaluation Research , Nursing TheoryABSTRACT
We examined the effects of a combined education and token system intervention to improve adherence to inhaled corticosteroids for an 8-year-old girl and a 10-year-old boy with asthma. Adherence was measured by an electronic chronolog monitor, and disease outcome was assessed by repeated pulmonary function testing. A withdrawal design demonstrated improved adherence and, for 1 child, an associated improvement in pulmonary function occurred. Methodological and clinical implications are discussed, including variables other than adherence that may affect disease outcome.