It is the objective of this study to identify the biochemical differences in the burn fluid of burns with hypertrophic scarring and those without. The findings of this study are intended to facilitate the development of diagnostic tools, which could be used to evaluate the healing process and develop therapeutic treatments. A porcine burn model has been used to evaluate healing. PIXIES was used to analyze the cytokines and growth factors present in the burn wounds.

关键词：伯恩斯（伤害）；生物化学；细胞因子

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Mesenchymal stem cells (MSCs) differentiated from Induced pluripotent stem cells (iPSCs) have a potential application in clinic to treat osteoporosis and other skeletal diseases. Further engineering MSCs with homing factors like CXCR4 and osteogenic factors like shNoggin or FGF2 may increase the therapeutic effects. Toward these goals, we have generated iPSCs using lentiviral vectors from blood cells and integration-free iPSCs using episomal vectors. The generated iPSCs are pluripotent, as evident by expression of pluripotency markers and formation of teratoma. After differentiation of iPSCs into MSCs, the cells express MSC markers and can form bone nodule in in vitro culture. To improve the safety of this therapy, we developed an alternative strategy for generating MSCs: direct conversion of blood cells into MSCs rather than reprogramming blood cells into iPSCs followed by re-differentiation.

关键词：干细胞；增强；血细胞；骨

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This year, we finally got our p11 knockout mice and were able to conduct the behavioral experiments (Specific Aim 1-3). Here, we will present two sets of new results: first, a control data set that included data from control mice; second, an experimental data set that included data from experimental mice, which received pharmacological treatment (e.g., mice received corticosterone injection) and foot shock exposure. We found the latency to find platform of knockout mice was shorter than that of non-p11 knockout (wild type) mice during the first three training days, although both of their latencies were the same on the final day of training and probe test. This data indicate that p11 knockout in the mice might enhanced learning. We also found that corticosterone resulted in significant decreases in the time in quadrant and number of island crossing in both p11 knockout and wild type control, suggesting that corticosterone induced impairment of memory retrieval, which independent the p11 expression. The ongoing final experiments will allow us to accomplish all of our proposed aims to understand the possible molecular mechanism of p11 in memory retrieval, a molecule associated with PTSD, a devastating disorder, especially in military service members.

关键词：创伤后应激障碍；行为；皮质类固醇制剂

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Despite the rapid progress in the development of new pharmaceutical products, modern medicine has not been able to keep pace with the infectious diseases that have reached high mortality rates in recent years. Since infectious agents such as bacteria, viruses, and parasites have developed resistance to current drugs, successful treatment of these agents remains insufficient. Furthermore, exposed drugs may lose their efficacy while circulating in the human body, depending on how the drugs were administered. In the other words, such drugs generally cannot reach the site of infection, resulting in uncontrolled treatment of the illness or condition. Because of the development of resistance and the ineffectiveness of these drugs, high dosages are commonly administered, which leads to various side effects. Recently, researchers have primarily focused on drug delivery systems in order to enhance the efficacy of these drugs and to prevent their negative side effects. It has been asserted that delivery of drugs with nanoparticles provides an opportunity for transporting a sufficient amount of drug molecules to the site of infection owing to the unique properties of nanoparticles. Nano-sized delivery systems offer several advantages, such as small particle size, narrow size distribution, surface features for target-specific localization, protection of drug molecules to enhance stability, and the opportunity to develop nanocarriers that respond to physiological stimuli. In this review, we aimed to demonstrate the applications of drug delivery through different nanoparticulate systems for bacterial, viral, and parasitic infections such as H.pylori, Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV), Malaria, and Leishmania infections, conditions that threaten millions of people around the world. Analysis of the literature indicated that nanoparticulate drug delivery systems have so far revealed promising results for the treatment of various infectious diseases. Therefore it is expected that nanoparticulate drug delivery systems might be one of the most important methods for the treatment of infectious diseases in conjunction with the increased interest surrounding the subject.

关键词：纳米粒子；传染性疾病；医药

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Effective in vitro models of myelination, dysmyelination, and/or remyelination would substantially speed the development and testing of potential therapies for myelin disorders such as multiple sclerosis. Tissues engineered from human induced pluripotent stem (iPS) may be effective at accurately modeling aspects of human physiology for screening of potential therapies. Substantial progress has been made toward demonstrating the feasibility of developing microengineered human neural tissues that can be assessed non-invasively. A population of neurons has been derived from human iPS cell lines, a micropatterned hydrogel culture system has been identified for the support of human neurons, and an optical method for monitoring physiological responses in microengineered tissue constructs has been demonstrated. This works represents a unique combination of enabling technologies, including human iPS cells, microfabrication, and optical neural recording, with the goal of showing how it may be possible to create a high-throughput assay of human neural activity.

关键词：体外分析；生理效应；响应（生物学）

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Our goal in year 2 was to use the tissue slice (TSC) NMR compatible bioreactor optimized in year 1 to identify hyperpolarized metabolic biomarkers of prostate cancer presence and aggressiveness. To accomplish this goal my group finished the engineering of a 5 mm bioreactor and acquired hyperpolarized (1-13C)pyruvate data indicating that similar signal to noise and quality data can be achieved with 4 to 5 prostate tissue slices in the 5 mm bioreactor as was acquired from 30-40 tissue slices in the prior 10 mm bioreactor. The time course of viability of the tissue slices prior to and after the bioreactor 5 mm bioreactor study was also established using a live-dead tissue assays performed by the co-PI s Peehl and Ronen on this proposal. We subsequently utilized this optimized 5 mm bioreactor in hyperpolarized (1-13C) MR studies to begin correlating hyperpolarized (1-13C) pyruvate metabolism with pathologic grade (aim 2) and observed a grade dependent increase in the flux of hyperpolarized (1-13C)pyruvate to (1-13C)lactate, with higher levels of lactate in higher pathologic grade cancers. More cancer TSCs need to be studied to demonstrate biologic significance.

关键词：前列腺癌；组织（生物学）；生物化学；化学反应器

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Breast cancer is the most common malignant cancer among American women and the second leading cause of cancer death in women. The analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes. However, the significance of most mutations to cancer development remains unknown. The ability to differentiate between driver and bystander mutations will provide valuable insight into how breast cancers develop and how to tailor individualized strategies for the diagnosis and treatment of cancer. We performed a screen to test the roles of seventy breast cancer mutated genes in mouse mammary tumorigenesis using the MMTV-PyVT mouse breast cancer model and piggyBac insertional mutation strains. We found that insertional mutations in 23 genes altered the onset of tumor formation and four genes exacerbated tumor metastasis. Among the 23 genes, Trim33 and Ahrr, have been recently reported as tumor suppressors, demonstrating the effectiveness of our screen. We have further confirmed the oncogenic roles of two metabolism related genes, Grik3 and HadHB with in vitro tumor assays and are currently performing mechanistic studies. The next phase of questions will be focused on how disruption of metabolism contributes to tumor development and progression.

关键词：乳腺癌；死亡；基因；癌筛查

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On April 25, 2013, FDA held a public meeting to hear perspectives from patients with chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) about their disease, its impact on their daily life, and currently available therapies. For this meeting and summary report, the terms CFS, ME, and CFS and ME are used interchangeably in describing the conditions. CFS and ME is a serious disease or set of diseases for which there are currently no FDA-approved therapies.

关键词：处方药；患者；公共卫生；医疗保健

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In the future, we may be faced with the need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare for this eventuality, our objective was to use a metabolic network-based approach to rapidly identify potential drug targets and prospectively screen and validate novel small- molecule antimicrobials. Our target organism was the fully virulent Francisella tularensis subspecies tularensis Schu S4 strain a highly infectious intracellular pathogen that is the causative agent of tularemia and is classified as a category A biological agent by the Centers for Disease Control and Prevention. We proceeded with a staggered computational and experimental workflow that used a strain-specific metabolic network model, homology modeling and X-ray crystallography of protein targets, and ligand- and structure-based drug design. Selected compounds were subsequently filtered based on physiological-based pharmacokinetic modeling, and we selected a final set of 40 compounds for experimental validation of antimicrobial activity. We began screening these compounds in whole bacterial cell-based assays in biosafety level 3 facilities in the 20th week of the study and completed the screens within 12 weeks. Six compounds showed significant growth inhibition of F. tularensis, and we determined their respective minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished bacterial growth at 13 mM, with putative activity against pantetheine-phosphate adenylyltransferase, an enzyme involved in the biosynthesis of coenzyme A, encoded by gene coaD. The novel antimicrobial compounds identified in this study serve as starting points for lead optimization, animal testing, and drug development against tularemia.

关键词：抗菌药物；药物；含量测定

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Diamond Blackfan Anemia (DBA) is a disorder that results in pure red cell aplasia, congenital abnormalities, and predisposition to cancer. The current treatment of steroids and chronic transfusions leads to significant morbidity. Approximately 25% of patients with DBA have mutations in RPS19. We previously generated a zebrafish model with RPS19 insufficiency that the phenotype is similar to that observed in patients with DBA. We also first described that p53 is upregulated in these fish injected with RPS19 morpholinos. To understand the mechanism by which RPS19 insufficiency leads to defects in erythropoiesis, we identified a p53 target, microRNA34a (miR34a), as being upregulated in human CD34+ fetal liver cells transduced with RPS19shRNA lentivirus. This not only led to decreased erythroid colony formation, but also aberrant erythroid differentiation. We hypothesize that RPS19 insufficiency mediates defects in erythropoiesis through upregulation of p53 and miR34a. To more rigorously test this hypothesis and identify new downstream targets and microRNAs, we propose three specific aims. In Aim 1, we will characterize the role of miR34a in RPS19 insufficient primary human hematopoietic stem cells in vitro. In Aim 2, we will study the role of miR34a in RPS19 insufficient primary human hematopoietic stem cells in vivo. In Aim 3, RNA-seq will be performed to identify novel transcripts and microRNAs that are aberrantly regulated downstream of RPS19 insufficiency in primary human hematopoietic stem cells. These studies will provide new insights into the molecular pathways downstream of ribosomal protein insufficiency in hematopoietic stem cells and potentially new targets for therapy.

关键词：异常；贫血；先天性畸形；发病机制

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