Gene Expression Profiling of Murine HOXB4-Transduced HSCs Shows Multiple Counter-Regulatory Signals That May Control HSC Pool Size

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2361-2361
Author(s):  
Hui Yu ◽  
Sheng Zhou ◽  
Geoffrey A. Neale ◽  
Brian P. Sorrentino
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Expression Array ◽  
Self Renewal ◽  
Time Points ◽  
Time Point

Abstract Abstract 2361 HOXB4 is a homeobox transcription factor that can induce hematopoietic stem cell (HSC) expansion both in vivo and in vitro. An interesting feature of HOXB4-induced HSC expansion is that HSC numbers do not exceed normal levels in vivo due to an unexplained physiological capping mechanism. To gain further insight into HOXB4 regulatory signals, we transplanted mice with bone marrow cells that had been transduced with a MSCV-HOXB4-ires-YFP vector and analyzed gene expression profiles in HSC-enriched populations 20 weeks after transplant, a time point at which HSC numbers have expanded to normal levels but no longer increasing beyond physiologic levels. We used Affymetrix arrays to analyze gene expression profiles in bone marrow cells sorted for a Lin−Sca-1+c-Kit+ (LSK), YFP+ phenotype. Using ANOVA, we identified1985 probe sets with >2 fold difference in expression (FDR<, 0.1) relative to a control vector-transduced LSK cells. A cohort of genes was identified that were known positive regulators of HSC self-renewal and proliferation. Hemgn, which we identified in a previous screen as a positive regulator of expansion and a direct transcriptional target of HOXB4, was 3.5 fold up-regulated in HOXB4 transduced LSKs. Other genes known to be important for HSCs survival, self-renewal and differentiation were upregulated to significant levels including N-myc, Meis1, Hoxa9, Hoxa10 and GATA2. Microarray data for selected genes was validated by quantitative real-time PCR on HOXB4 transduced CD34low LSK cells, a highly purified HSC population, obtained from another set of transplanted mice at the 20 week time point. In contrast, other gene expression changes were noted that would potentially limit or decrease stem cell numbers. PRDM16, a set domain transcription factor critical for HSC maintenance and associated with clonal hematopoietic expansions when inadvertently activated as a result of retroviral insertion, was dramatically down-regulated on the expression array and 7.6 fold decreased in the real time PCR assay of CD34low LSK cells. TFG-beta signaling is a well defined inhibitor HSC proliferation and utilize Smad proteins as downstream effectors. Expression of Smad1 and Smad7 were significantly upregulated on the LSK expression array and 8.1 and 3.5 fold up-regulated by qPCR in CD34low LSK cells. Another potential counter-regulatory signal was down regulation of Bcl3 mRNA, a potential anti-apoptotic effector in HSCs. We hypothesize that the HOXB4 expansion program involves activation of genes that lead to increased HSC numbers with later activation of counter-regulatory signals that limit expansion to physiologic numbers of HSCs in vivo. We are now examining how this program changes at various time points after transplantation and hypothesize the capping limits are set at relatively later time points during reconstitution. We also are studying the functional effects of these gene expression changes, and in particular, whether enforced expression of HOXB4 and PRMD16 will result in uncontrolled HSC proliferation and/or leukemia. Disclosures: No relevant conflicts of interest to declare.

Xenografts of Pediatric Acute Lymphoblastic Leukemia Retain the Gene Expression Pattern From the Diagnostic Material They Originated From Over Serial Passages.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1629-1629
Author(s):  
Manon Queudeville ◽  
Elena Vendramini ◽  
Marco Giordan ◽  
Sarah M. Eckhoff ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Leukemia Cells ◽  
Diagnostic Samples ◽  
Xenotransplantation Model

Abstract Abstract 1629 Poster Board I-655 Primary childhood acute lymphoblastic leukemia (ALL) samples are very difficult to culture in vitro and the currently available cell lines only poorly reflect the heterogeneous nature of the primary disease. Many groups therefore use mouse xenotransplantation models not only for in vivo testing but also as a means to amplify the number of leukemia cells to be used for various analysis. It remains unclear as to what extent the xenografted samples recapitulate their respective primary leukemia. It has been suggested for example that transplantation may result in the selection of a specific clone present only to a small amount in the primary diagnostic sample. We used a NOD/SCID xenotransplantation model and injected leukemia cells isolated from fresh primary diagnostic material of 4 pediatric ALL patients [2 pre-B-ALL, 1 pro-B-ALL (MLL/AF4}, 1 cortical T-ALL] intravenously into the lateral tail vein of unconditioned mice. As soon as the mice presented clinical signs of leukemia, leukemia cells were isolated from bone marrow and spleen. Isolated leukemia cells were retransplanted into secondary and tertiary recipients. RNA was isolated from diagnostic material and serial xenograft passages and gene expression profiles were obtained using a human whole genome array (Affymetrix U133 2.0). Simultaneously, immunophenotypic analysis via multicolor surface and cytoplasmatic staining by flow cytometry was performed for the diagnostic samples and respective serial xenograft passages. In an unsupervised clustering analysis the diagnostic sample of each patient clustered together with the 3 derived xenograft samples, although the 3 xenograft samples clustered stronger to each other than to their respective diagnostic sample. Comparison of the 4 diagnostic samples vs. all xenograft samples resulted in a gene list of 270 genes upregulated at diagnosis and 8 genes upregulated in the xenograft passages (Wilcoxon, p< .05). The high number of genes upregulated at diagnosis is most likely due to contamination of primary patient samples with normal peripheral blood and/or bone marrow cells as 15% of genes are attributed to myeloid cells, 7% to erythroid cells, 7% to lymphoid cells, 32% to bone marrow in general as well as to innate immunity, chemokines, immunoglobulins. The remaining genes can not be attributed to a specific hematopoetic cell lineage and are not known to be related to leukemia or cancer in general. Accordingly, there are no statistically significant differences between the primary, secondary and tertiary xenograft passages. The immunophenotype analysis are also in accordance with these findings, as the diagnostic blast population retains its immunophenotypic appearance during serial transplantation, whereas the contaminating CD45-positive non- leukemic cells disappear after the first xenograft passage. The few genes upregulated in xenograft samples compared to diagnosis are mainly involved in cell cycle regulation, protein translation and apoptosis resistance. Some of the identified genes have already been described in connection with cancer subtypes, their upregulation therefore being indicative of a high proliferative state in general and could argue towards a more aggressive potential of the engrafted leukemia cells but alternatively could also simply be due to the fact that the xenograft samples are pure leukemic blasts and are not contaminated with up to 15% of non-cycling healthy bone marrow cells as in the diagnostic samples. We conclude that the gene expression profiles generated from xenografted leukemias are very similar to those of their respective primary leukemia and moreover remain stable over serial retransplantation passages as we observed no statistically significant differences between the primary, secondary and tertiary xenografts. The differentially expressed genes between diagnosis and primary xenotransplant are most likely to be due to contaminating healthy cells in the diagnostic samples. Hence, the NOD/SCID-xenotransplantation model recapitulates the primary human leukemia in the mouse and is therefore an appropriate tool for in vivo and ex vivo studies of pediatric acute leukemia. Disclosures No relevant conflicts of interest to declare.

Identification of Gene Expression Profiles in Acute Lymphoblastic Leukemia Cells That Discriminate Intracellular Thioguanine Nucleotide Accumulation in ALL Cells after In Vivo Treatment with Mercaptopurine.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 453-453
Author(s):  
Gianluigi Zaza ◽  
Meyling Cheok ◽  
Wenjian Yang ◽  
Pei Deqing ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Post Treatment ◽  
Leukemia Cells ◽  
True Positive

Abstract Thioguanine nucleotides (TGN) are considered the principal active metabolites exerting the antileukemic effects of mercaptopurine (MP). Numerous clinical studies have reported substantial inter-patient variability in intracellular TGN concentrations during continuation therapy of acute lymphoblastic leukemia (ALL). To identify genes whose expression is related to the intracellular accumulation of TGN in leukemia cells after in vivo treatment with MP alone (MP) or in combination with MTX (MP+MTX), we used oligonucleotide microarrays (Affymetrixâ HG-U95Av2) to analyze the expression of approximately 9,670 genes in bone marrow leukemic blasts obtained at diagnosis from 82 children with ALL. TGN levels were determined in bone marrow aspirates of these patients 20 hours after mercaptopurine infusion (1 g/m2 I.V). Because, as previously reported, patients treated with MP alone achieved higher levels of intracellular TGN compared to those treated with the combination, we used Spearman’s rank correlation to identify genes associated with TGN levels separately for the 33 patients treated with MP alone and the 49 with the combination (MP: median TGN: 2.46 pmol/5x106 cells, range: 0.01–19.98; and MTX+MP: median TGN: 0.55 pmol/5x106 cells, range: 0.005–3.31). Hierarchical clustering using these selected probe sets clearly separated the 33 patients treated with MP alone into two major groups according to TGN concentration (< 2.46 and > 2.46 pmol/5x106 cells; n=60 genes) and two major branches were also found for patients treated with the combination (< 0.55 and > 0.55 pmol/5x106 cells; n=75 genes). Interestingly, there was no overlap between the two sets of genes, indicating that different genes influence the accumulation of TGN when this drug is given alone or in combination with MTX. The association between gene expression profiles and TGN levels determined by leave-one-out cross-validation using support vector machine (SVM) based on Spearman correlation, was rho=0.60 (p<0.001) for MP alone and rho=0.65 (p<0.001) for MTX+MP, with false discovery rate (FDR) computed using Storey’s q-value (MP: 50% true positive, MTX+MP: 70% true positive respectively). Genes highly associated with the post-treatment TGN level in ALL patients treated with MP alone encode transporters, enzymes involved in the MP metabolic pathway and cell proliferation. Genes associated with post-treatment levels of TGN after combined therapy have been implicated in protein and ATP biosynthesis. Together, these in vivo data provide new insights into the basis of inter-patient differences in TGN accumulation in ALL cells, revealing significant differences between treatment with MP alone or in combination with MTX.

scholarly journals The heterogeneity of cell subtypes from a primary culture of human amniotic fluid

2010 ◽  
Vol 15 (3) ◽  
Author(s):  
Shengli Zhang ◽  
Hongquan Geng ◽  
Hua Xie ◽  
Qiquan Wu ◽  
Xiaorong Ma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amniotic Fluid ◽  
Primary Culture ◽  
Expression Profiles ◽  
Embryonic Stem ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Human Amniotic Fluid ◽  
Expression Array

AbstractHeterogeneous human amniotic fluid contains various cell types. Herein, we report on the possibility of simultaneously isolating three subtypes of cells from one primary culture. Using a stainless steel instrument named a colony poculum, two of the three cell subtypes could be efficiently cultured, and these were further characterized. The results indicated that these two cell subtypes had different morphologies and were characterized by different cell marker expression profiles, including the differential expression of CD105, CD117 and EBAF. Furthermore, their gene expression array data revealed their different gene expression profiles. Although both cell types expressed several embryonic stem cell-specific markers, they were non-tumorigenic in vivo. This paper not only provides new insight into the heterogeneity of human amniotic fluid, it also presents a simple yet efficient cell isolation method. These results will contribute to the thorough investigation of the properties and potential future applications of human amniotic fluid-derived cells.

Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4723-4730 ◽  
Author(s):  
Mir Farshid Alemdehy ◽  
Nicole G. J. A. van Boxtel ◽  
Hans W. J. de Looper ◽  
Iris J. van den Berge ◽  
Mathijs A. Sanders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mirna Biogenesis ◽  
Monocytic Differentiation ◽  
Rnase Iii ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract MicroRNAs (miRNAs) have the potential to regulate cellular differentiation programs; however, miRNA deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions un-answered. To address this issue, we deleted Dicer1, which encodes an essential RNase III enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein α (C/EBPA)–positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA–positive progenitor cells. Analysis of gene-expression profiles from wild-type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multipotent progenitors and erythropoiesis, indicating an altered gene-expression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating the regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages, and caused myeloid dysplasia with morphologic features of Pelger-Huët anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion toward myeloid differentiation in GMPs.

Nfi Genes Are Novel Regulators Of Murine Hematopoietic Stem- and Progenitor Cell Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 735-735
Author(s):  
Per Holmfeldt ◽  
Pardieck Jennifer ◽  
Shannon McKinney-Freeman
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Gene Family ◽  
Peripheral Blood ◽  
Fetal Liver ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Hematopoietic stem cells (HSCs) are responsible for life-long maintenance of hematopoiesis. HSC transplantation represents one of the most heavily exploited cell based therapies, routinely used to treat a myriad of life threating disorders, such as leukemia and bone marrow failure. Identifying the molecular pathways that regulate HSC engraftment is crucial to further improving outcomes in patients that rely on HSC transplantation as a curative therapy. By examining the global gene expression profiles of highly purified HSC (Lineage-Sca-1+c-Kit+CD150+CD48-), we recently identified the following members of the Nfi gene family of transcription factors as highly expressed by HSC (McKinney-Freeman et al., Cell Stem Cell, 2012): Nfix, Nfia, and Nfic. These data suggest that Nfi genes may play a novel role in regulating HSC function. To test this hypothesis, HSCs were enriched from adult bone marrow (Lineage-, c-kit+, Sca-1+ (LSK) cells) and then transduced, individually, with lentiviruses carrying shRNAs targeting each Nfi gene. Twenty-four hours post-transduction, cells were injected into lethally irradiated mice along with untransduced bone marrow LSK competitor cells congenic at the CD45 allele. The peripheral blood of recipient mice was then analyzed periodically over 16 weeks for engraftment of the Nfi-depleted cells. Although shRNA mediated knockdown of Nfi gene expression had no effect on the in vitro cell growth or viability of LSK cells, Nfi-depleted HSCs displayed a significant loss of short- and long-term in vivo hematopoietic repopulating activity. This was true for Nfia-, Nfic-, and Nfix-deficient HSC. While Nfia and Nfic are only expressed by bone marrow HSC, Nfix is highly expressed by both bone marrow and fetal liver HSC. When Nfix was depleted by shRNAs from LSK cells purified from E14.5 fetal liver, a similar loss in competitive repopulating potential was seen. Lineage analysis of peripheral blood of recipients showed no significant differences in the distribution of the major blood lineages derived from LSK cells transduced with Nfi-specific shRNAs compared to controls. When the bone marrow of recipients transplanted with Nfix- depleted cells was examined 4 and 16 weeks post-transplant, a general loss of all hematopoietic stem- and progenitor compartments examined was seen relative to control. Thus, the observed decrease in repopulating activity occurs at the level of HSCs and multipotent progenitors. To confirm an essential role for an Nfi gene family member in the regulation of HSC engraftment post-transplant, LSK cells were purified from Nfix fl/fl mice, transduced with lentiviral Cre recombinase and subsequently introduced into lethally irradiated recipients alongside congenic competitor cells. Like LSK transduced with Nfix-specific shRNAs, Nfix-/- LSK cells failed to repopulate the peripheral blood of recipient mice as efficiently as control and similar trends were detected in all stem- and progenitor cell populations examined. Time-course experiments immediately following transplantation revealed that Nfix-depleted LSK cells establish themselves in the marrow of recipient mice as efficiently as control at 5 days post-transplant, but thereafter exhausted rapidly. Examination 10 days post-transplant revealed a 5-fold increase in apoptosis specifically in the LSK compartment, but not in its differentiated progeny, in recipients transplanted with Nfix-depleted LSK cells compared to control. The increase in apoptosis was not associated with any apparent change in the cell cycle status of the LSK cells. These data suggest that Nfi genes are necessary for the survival of HSC post-transplantation. In an effort to identify the molecular pathways regulated by Nfi genes in HSC, we acquired the global gene expression profiles of Nfix-depleted HSC. In agreement with our observation that Nfix-deficient HSC displays elevated levels of apoptosis following transplantation in vivo, we observed a significant decrease in multiple genes known to be important for HSC survival, such as Erg, Mecom and Mpl, in Nfix-depleted HSC. In summary, we have for the first time established a role for the Nfi gene family in HSC biology, as evident by a decrease in bone marrow repopulating activity in Nfi-depleted HSCs. By dissecting the precise role of Nfi genes in HSC biology, we will glean insights that could improve our understanding of graft failure in clinical bone marrow transplantations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gene expression profiles of bone marrow cells from mice phenotype-selected for maximal or minimal acute inflammations: searching for genes in acute inflammation modifier loci

Immunology ◽  
2009 ◽  
Vol 128 (1pt2) ◽  
pp. e562-e571 ◽  
Author(s):  
Patrícia dos S. Carneiro ◽  
Luciana C. Peters ◽  
Francisca Vorraro ◽  
Andrea Borrego ◽  
Orlando G. Ribeiro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Inflammation ◽  
Bone Marrow Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Marrow Cells

scholarly journals Bayesian approach for predicting responses to therapy from high-dimensional time-course gene expression profiles

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Arika Fukushima ◽  
Masahiro Sugimoto ◽  
Satoru Hiwa ◽  
Tomoyuki Hiroyasu
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Response To Therapy ◽  
Hcv Infection ◽  
Entire Treatment Period ◽  
Time Points ◽  
Time Course Data ◽  
Conventional Methods

Abstract Background Historical and updated information provided by time-course data collected during an entire treatment period proves to be more useful than information provided by single-point data. Accurate predictions made using time-course data on multiple biomarkers that indicate a patient’s response to therapy contribute positively to the decision-making process associated with designing effective treatment programs for various diseases. Therefore, the development of prediction methods incorporating time-course data on multiple markers is necessary. Results We proposed new methods that may be used for prediction and gene selection via time-course gene expression profiles. Our prediction method consolidated multiple probabilities calculated using gene expression profiles collected over a series of time points to predict therapy response. Using two data sets collected from patients with hepatitis C virus (HCV) infection and multiple sclerosis (MS), we performed numerical experiments that predicted response to therapy and evaluated their accuracies. Our methods were more accurate than conventional methods and successfully selected genes, the functions of which were associated with the pathology of HCV infection and MS. Conclusions The proposed method accurately predicted response to therapy using data at multiple time points. It showed higher accuracies at early time points compared to those of conventional methods. Furthermore, this method successfully selected genes that were directly associated with diseases.

scholarly journals Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

2021 ◽  
Author(s):  
Julian Baumeister ◽  
Tiago Maié ◽  
Nicolas Chatain ◽  
Lin Gan ◽  
Barbora Weinbergerova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Late Stage ◽  
Rna Splicing ◽  
Bone Marrow Cells ◽  
Myeloproliferative Neoplasms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Primary Myelofibrosis ◽  
Estrogen Signaling ◽  
Therapeutic Modalities

AbstractMyeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. Graphical abstract

scholarly journals Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Risa Okada ◽  
Shin-ichiro Fujita ◽  
Riku Suzuki ◽  
Takuto Hayashi ◽  
Hirona Tsubouchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Transcriptome Analysis ◽  
Fiber Type ◽  
Expression Profiles ◽  
Space Station ◽  
Gene Expression Profiles

AbstractSpaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

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