suppression-pro-fibrotic-signaling-potentiates-factor-mediated

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Trans-differentiation of one somatic cell type into another has enormous potential to model and treat human diseases. Previous studies have shown that ...

augusta university

Obesity management guidelines specify initial goals for participation and weight reduction for the first 6 months of a weight-reduction intervention, but guidelines do not specify when to assess early response and make adjustments. We aimed to determine whether very early or early weight reduction in the weight-reduction program MOVE! predicted later participation or achievement of weight-reduction goals.

Initial Response to Program, Program Participation, and Weight Reduction Among 375 MOVE! Participants, Augusta, Georgia, 2008-2010.

The aim of the present study was to determine the best anthropometric discriminators of type 2 diabetes mellitus (T2DM) among White and Black males and females in a large US sample.

Anthropometric discriminators of type 2 diabetes among White and Black American adults.

Mouse resources such as Collaborative Cross (CC), Outbred Stocks (OS), Hybrid Mouse Diversity Panel (HMDP), and Chromosome Substitution Strains (CSSs) have been instrumental to many progresses in the studies of complex traits genetics. We have established a population of chromosome 1 (Chr 1) substitution lines (C1SLs) in which donor chromosomes were derived from Chinese wild mice. Genome sequencing of 18 lines of this population showed that Chr 1 had been replaced by donor chromosome. About 4.5 million unique single nucleotide polymorphisms (SNPs) and indels were discovered on Chr 1, of which, 1.3 million were novel. Compared with sequenced classical inbred (CI) strains, Chr 1 of each C1SL had five fold more variants, and more loss of function and potentially regulatory variants. Further haplotype analysis showed that donor chromosome accumulated more historical recombination events with the largest haplotype block being only 100kb and about 57% of the blocks were less than 1kb. Subspecies origin analysis showed that these chromosomes had mosaic genome structure which dominantly originated from M. m. musculus and M. m. canstanes subspecies except for C57BL/6J-Chr 1 (KM) line from M. m. domesticus In addition, phenotyping four of these lines on blood biochemistry suggested that there were substantial phenotypic variations among our lines, especially line C57BL/6J-Chr 1 (HZ) and donor strain C57BL/6J (B6). Further GO enrichment revealed that the differentially expressed genes among liver expressed genes between B6 and HZ were enriched in lipid metabolism biological processes. All these characteristics enabled C1SLs to be a unique resource for identifying and fine mapping quantitative trait loci (QTLs) on mouse Chr 1, and carrying out systems genetics studies of complex traits.

Genome Sequencing of Chromosome 1 Substitution Lines Derived from Chinese Wild Mice Revealed a Unique Resource for Genetic Studies of Complex Traits.

Impaired pulmonary endothelial barrier function in sickle cell mice.

Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.

To determine which anthropometric measures are the strongest discriminators of incident type 2 diabetes (T2DM) among White and Black males and females in a large U.S. cohort.

Best anthropometric discriminators of incident type 2 diabetes among white and black adults: A longitudinal ARIC study.

The Chinese Kunming (KM) mouse is a widely used outbred mouse stock in China. However, its genetic structure remains unclear. In this study, we sequenced the genome of the C57BL/6J-Chr1 (B6-Chr1) strain, the chromosome 1 (Chr 1) of which was derived from one KM mouse. With 36.6× average coverage of the entire genome, 0.48 million single nucleotide polymorphisms (SNPs) and 96,679 indels were detected on Chr 1 through comparison with reference strain C57BL/6J. Moreover, 46,590 of them were classified as novel mutations. Further functional annotation identified 155 genes harboring potentially functional variants, among which 27 genes have been associated with human diseases. We then performed sequence similarity and Bayesian concordance analysis using the SNPs identified on Chr 1 and their counterparts in three subspecies, , , and  Both analyses suggested that the Chr 1 sequence of B6-Chr1 was predominantly derived from  while 9.7% of the sequence was found to be from . In conclusion, our analysis provided a detailed description of the genetic variations on Chr 1 of B6-Chr1 and a new perspective on the subspecies origin of KM mouse which can be used to guide further genetic studies with this mouse strain.

Chromosome 1 Sequence Analysis of C57BL/6J-Chr1 Mouse Strain.

Both natural and artificial selection play a critical role in animals' adaptation to the environment. Detection of the signature of selection in genomic regions can provide insights for understanding the function of specific phenotypes. It is generally assumed that laboratory mice may experience intense artificial selection while wild mice more natural selection. However, the differences of selection signature in the mouse genome and underlying genes between wild and laboratory mice remain unclear. In this study, we used two mouse populations: chromosome 1 (Chr 1) substitution lines (C1SLs) derived from Chinese wild mice and mouse genome project (MGP) sequenced inbred strains and two selection detection statistics: Fst and Tajima's D to identify the signature of selection footprint on Chr 1. For the differentiation between the C1SLs and MGP, 110 candidate selection regions containing 47 protein coding genes were detected. A total of 149 selection regions which encompass 7.215 Mb were identified in the C1SLs by Tajima's D approach. While for the MGP, we identified nearly twice selection regions (243) compared with the C1SLs which accounted for 13.27 Mb Chr 1 sequence. Through functional annotation, we identified several biological processes with significant enrichment including seven genes in the olfactory transduction pathway. In addition, we searched the phenotypes associated with the 47 candidate selection genes identified by Fst. These genes were involved in behavior, growth or body weight, mortality or aging, and immune systems which align well with the phenotypic differences between wild and laboratory mice. Therefore, the findings would be helpful for our understanding of the phenotypic differences between wild and laboratory mice and applications for using this new mouse resource (C1SLs) for further genetics studies.

Sequence analysis of chromosome 1 revealed different selection patterns between Chinese wild mice and laboratory strains.

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34 cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.

Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness.

Indoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients. IDO-1 protein expression was assessed in 40 cases via immunohistochemistry and quantified by a novel 'composite IDO-1 score'. In a univariate analysis, higher age (p = 0.0018), male gender (p = 0.019), high risk cytogenetics (p = 0.002), higher IDO-1 mRNA (p = 0.005), higher composite IDO-1 score (p < 0.0001) and not undergoing allogeneic stem cell transplant (SCT, p = 0.0005) predicted poor overall survival. In a multivariate model that included the aforementioned variables, higher composite IDO-1 score (p = 0.007) and not undergoing allogeneic SCT (p = 0.007) was found to significantly predict poor outcomes. Further, patients who failed induction had higher composite IDO-1 score (p = 0.01). In conclusion, 'composite IDO-1 score' is a prognostic tool that can help identify a certain subset of AML patients with 'early mortality'. This unique subset of patients can potentially benefit from specific IDO-1 inhibitor therapy, currently in clinical trials.

A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression.

CD103 dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c monocytic precursors. These Ly6cCD103 cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6cCD103 phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6cCD103 population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6cCD103 cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6cCD103 monocytic cells represents a potent and previously unrecognized target for immunotherapy.

Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6cCD103 Monocytic Antigen-Presenting Cells in Tumors.

Optic nerve sheath diameter (ONSD) measured by transocular ultrasound is a marker of real-time intracranial pressure (ICP). The objective of this study was to evaluate the association between optic nerve sheath (ONS) dilation after a Valsalva maneuver and a prior history of mild to moderate traumatic brain injury (mTBI) in a heterogeneous sample of participants. Participants were excluded if they had had a recent brain injury, were symptomatic from a prior brain injury, had a history consistent with severe TBI and/or had undergone intracranial surgery. Ninety-five participants with and without a history of mTBI were included in the study. Transocular ultrasound of the ONS was performed before and after a Valsalva maneuver. Differences in the ONSD before and after a Valsalva maneuver were analyzed and correlated to the participants' history of mTBI. Baseline ONSD measurements between groups were not statistically significant. Following Valsalva, participants with a history of mTBI had a statistically significant increase in the ONSD compared with participants with no history of mTBI. This significant difference persisted after controlling for age, race, and sex. This study demonstrated an association between a prior history of mTBI and dilation of the ONS after Valsalva maneuver in a sample of asymptomatic participants, which was not seen in participants without a history of mTBI.

Hongyan Xu

Department of Population Health Sciences,
Medical College of Georgia,
Department of Population Health Sciences, Medical College of Georgia

augusta university

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Hongyan Xu

Department of Population Health Sciences,Medical College of Georgia,Department of Population Health Sciences, Medical College of Georgia

augusta university

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Department of Population Health Sciences,
Medical College of Georgia,
Department of Population Health Sciences, Medical College of Georgia